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Background: The standardized scoring system assessing adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations assigns equal weight for each recommendation, thereby giving higher weight to dietary factors collectively (5 points) than adiposity (1 point) and physical activity (1 point). An alternative score assigning equal weights to the adiposity, physical activity, alcohol, and other dietary (composite) recommendations may better predict cancer associations. Methods: We examined associations between standardized and alternative scores with cancer risk in two US prospective cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression. Results: During 28 years of follow-up, 16,342 incident cancer cases in women and 8729 cases in men occurred. Individuals in the highest versus lowest quintile of the standardized score had a reduced overall cancer risk (women: HR = 0.89, 95% CI: 0.85, 0.94; men: HR = 0.87, 95% CI: 0.81, 0.94). Results were slightly stronger for the alternative score (women: HR = 0.83, 95% CI: 0.79, 0.87; men: HR = 0.81, 95% CI: 0.75, 0.86). Similar patterns were observed for obesity-related, alcohol-related, smoking-related, and digestive system cancers. Conclusions: Greater adherence to the WCRF/AICR cancer prevention recommendations was associated with lower cancer risk. A score assigning equal weights to the adiposity, physical activity, alcohol, and all remaining diet components yielded stronger associations than the standardized score. [ABSTRACT FROM AUTHOR]

Population attributable risk (PAR%) reflects the preventable fraction of disease. However, PAR% estimates of cancer have shown large variation across populations, methods, data sources, and timing of measurements. Three statistical methods to estimate PAR% were identified from a systematic literature review: the Levin's formula, the comparative incidence rate method, and the comparative risk assessment method. We compared the variations in PAR% of postmenopausal breast cancer in the Nurses' Health Study to evaluate the influence by method choice, source of prevalence data, use of single vs repeated exposure measurements, and potential joint effects of obesity, alcohol, physical activity, fruit and vegetable intake. Across models of the three methods, the estimated PAR% using repeated measurements were higher than that using baseline measurement; overall PAR% for the baseline, simple update, and cumulative average models were 13.8%, 21.1%, 18.6% by Levin's formula; 13.7%, 28.0%, 31.2% by comparative risk assessment; and 17.4%, 25.2%, 29.3% by comparative incidence rate method. The estimated PAR% of the combination of multiple risk factors was higher than the product of the individual PAR%: 18.9% when assuming independence and 31.2% when considering the risk factors jointly. The three methods provided similar PAR% based on the same data source, timing of measurements, and target populations. However, sizable increases in the PAR% were observed for repeated measures over a single measure and for calculations based on achieving all recommendations jointly rather than individually. [ABSTRACT FROM AUTHOR]

Routine tumor-node-metastasis (TNM) staging of colorectal cancer is imperfect in predicting survival due to tumor pathobiological heterogeneity and imprecise assessment of tumor spread. We leveraged Bayesian additive regression trees (BART), a statistical learning technique, to comprehensively analyze patient-specific tumor characteristics for the improvement of prognostic prediction. Of 75 clinicopathologic, immune, microbial, and genomic variables in 815 stage II–III patients within two U.S.-wide prospective cohort studies, the BART risk model identified seven stable survival predictors. Risk stratifications (low risk, intermediate risk, and high risk) based on model-predicted survival were statistically significant (hazard ratios 0.19–0.45, vs. higher risk; P < 0.0001) and could be externally validated using The Cancer Genome Atlas (TCGA) data (P = 0.0004). BART demonstrated model flexibility, interpretability, and comparable or superior performance to other machine-learning models. Integrated bioinformatic analyses using BART with tumor-specific factors can robustly stratify colorectal cancer patients into prognostic groups and be readily applied to clinical oncology practice. [ABSTRACT FROM AUTHOR]

Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to identify pathogenic variants in a female patient with primary infertility and recurrent failure of in vitro fertilization with zygotic cleavage failure. Methods: The genomic DNA from the affected individual was subjected to whole-exome sequencing and the variant was confirmed by Sanger sequencing. The functional effect of the identified variant was further investigated in 293 T cells. Results: We identified a novel homozygous deletion in BTG4 (c.580_616del) in the affected individual. The deletion results in frameshift and replacement of the last 29 residues (aa195-223) with 66 random amino acids. The mutated amino acid residues are highly conserved among mammalian species. Co-immunoprecipitation in 293 T cells showed that the mutation abolished the interaction between BTG4 and PABPN1L. Conclusion: This study conforms previous studies and expands the mutational spectrum of BTG4. Our findings prove the functional importance of the C-terminal of BTG4. BTG4 is a potential diagnostic and therapeutic target for patients suffering from zygotic cleavage failure. [ABSTRACT FROM AUTHOR]

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42–68) years at blood collection and 63 (49–75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50– < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100– < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95–1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status. [ABSTRACT FROM AUTHOR]

Background: Although adolescent diet has been proposed to contribute to prostate cancer (PCa) development, no studies have investigated the relation between adolescent dietary patterns and PCa risk or mortality.Methods: Using data from 164,079 men in the NIH-AARP Diet and Health Study, we performed factor analysis to identify dietary patterns at ages 12-13 years and then used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of total (n = 17,861), non-advanced (n = 15,499), advanced (n = 2362), and fatal PCa (n = 832).Results: Although not entirely consistent across analyses, a higher adolescent plant-based pattern (characterised by vegetables, fruits, and dark bread) score was associated with slightly reduced risks of total (fully adjusted HRQ5vs.Q1 = 0.93, 95% CI: 0.89-0.98, p trend=0.003) and non-advanced PCa (HR = 0.91, 95% CI: 0.87-0.96, p trend<0.001), whereas no associations were observed for advanced or fatal PCa, or for Western modern (characterised by sweets, processed meat, beef, cheese, and pizza) or Western traditional (characterised gravy, eggs, potatoes and white bread) patterns.Conclusion: We found evidence to support a modest, protective role for a plant-based dietary pattern during adolescence on PCa risk. If confirmed in future studies, our findings may help to inform the development of new, primary prevention strategies for PCa. [ABSTRACT FROM AUTHOR]

Background: Persistent tinnitus is common, disabling, and difficult to treat. High-dose aspirin may precipitate tinnitus, but longitudinal data on typical dose aspirin and other analgesics are scarce.Objective: To investigate independent associations of aspirin, NSAIDs, and acetaminophen and risk of incident persistent tinnitus.Design: Longitudinal cohort study.Setting: Nurses' Health Study II (1995-2017).Participants: A total of 69,455 women, age 31-48 years, without tinnitus at baseline.Main Measures: Information on analgesic use and tinnitus obtained by biennial questionnaires.Key Results: After 1,120,936 person-years of follow-up, 10,452 cases of incident persistent tinnitus were reported. For low-dose aspirin, the risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. For moderate dose aspirin, frequent use was associated with higher risk of tinnitus among women aged < 60 years, but not among older women (p-interactionage = 0.003). Compared with women aged < 60 using moderate-dose aspirin < 1 day/week, the multivariable-adjusted hazard ratio (MVHR, 95% CI) among women using moderate-dose aspirin 6-7 days per week was 1.16 (1.03, 1.32). Among all women, frequent non-aspirin non-steroidal anti-inflammatory drug (NSAID) or acetaminophen use was associated with higher risk. Compared with women using NSAIDs <1 day/week, the MVHR for use 4-5days/week was 1.17 (1.08, 1.28) and for 6-7days/week was 1.07 (1.00, 1.16) (p-trend=0.001). For acetaminophen, compared with use <1 day/week, the MVHR for use 6-7days/week was 1.18 (1.07, 1.29) (p-trend=0.002).Limitations: Information on tinnitus and analgesic use was self-reported. Information on indications for analgesic use was not available. Studies in non-White women and men are needed.Conclusion: The risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. Among younger women, frequent moderate-dose aspirin use was associated with higher risk. Frequent NSAID use and frequent acetaminophen use were associated with higher risk of incident persistent tinnitus among all women, and the magnitude of the risks tended to be greater with increasing frequency of use. Our results suggest analgesic users are at higher risk for developing tinnitus and may provide insight into the precipitants of this challenging disorder, but additional investigation to determine whether there is a causal association is needed. [ABSTRACT FROM AUTHOR]

Background: Adolescent intake of animal products has been proposed to contribute to prostate cancer (PCa) development because of its potentially carcinogenic constituents and influence on hormone levels during adolescence.Methods: We used data from 159,482 participants in the NIH-AARP Diet and Health Study to investigate associations for recalled adolescent intake of red meat (unprocessed beef and processed red meat), poultry, egg, canned tuna, animal fat and animal protein at ages 12-13 years with subsequent PCa risk and mortality over 14 years of follow-up. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total (n = 17,349), advanced (n = 2,297) and fatal (n = 804) PCa.Results: Suggestive inverse trends were observed for adolescent unprocessed beef intake with risks of total, advanced and fatal PCa (multivariable-adjusted P-trends = 0.01, 0.02 and 0.04, respectively). No consistent patterns of association were observed for other animal products by PCa outcome.Conclusion: We found evidence to suggest that adolescent unprocessed beef intake, or possibly a correlate of beef intake, such as early-life socioeconomic status, may be associated with reduced risk and mortality from PCa. Additional studies with further early-life exposure information are warranted to better understand this association. [ABSTRACT FROM AUTHOR]

Background: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear. Methods: Among 1463 stage I–III CRC patients from the Nurses' Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars. Results: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87–1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95–1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06–2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26–0.75 and 0.70, 95% CI: 0.55–0.89, respectively). Conclusions: Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination. [ABSTRACT FROM AUTHOR]

Purpose: The association between alcohol intake and glioma remains unclear. We evaluated the association between alcohol intake and incidence of glioma in three large, prospective cohort studies with repeated alcohol assessments. Methods: We harnessed data from three studies with repeat alcohol assessment to compute hazard ratios (HR) and 95% confidence intervals (CI) for glioma by overall alcohol intake and intake from specific beverages using Cox proportional hazards regression, adjusted for age, cohort, body mass index, smoking status, and caloric intake. Analyses were conducted separately for glioma overall and for glioblastoma (GBM). Results: We confirmed 554 incident glioma cases (362 GBM) among 237,505 participants with 6,216,378 person-years of follow up. Cumulative average alcohol intake was associated with reduced risk of glioma (HR = 0.75, 95%CI:0.56–0.99 comparing > 8–15 to ≤ 0.5 g/d; HR = 0.71, 95%CI:0.53–0.96 comparing > 15 g/d to ≤ 0.5 g/d). When stratified by sex, for the same comparisons, the HRs for men were 0.57 (95%CI:0.36–0.89) and 0.79 (0.53–1.16), and for women 0.90 (95%CI:0.62–1.30) and 0.62, 95%CI:0.39–0.97. Results were consistent when examining cumulative average, baseline, and recent intake, and with a 4 year lag. Conclusion: These results provide evidence against a positive association between alcohol intake and glioma risk. Alcohol intake was associated with reduced risk of glioma in both men and women. [ABSTRACT FROM AUTHOR]

Purpose: Both long and short sleep duration have been linked with risk of some cancers, but evidence for glioma is lacking. Methods: Using prospective data from the UK Biobank (UKB), the Nurses' Health Study (NHS), and the Health Professionals Follow-Up Study (HPFS), we examined the association between self-reported hours of sleep and incident glioma in multivariable-adjusted Cox proportional hazards models. Results: In the UKB, compared to 7 h, sleep durations of < 7 h (HR = 0.90; 95% CI 0.70–1.16) or > 7 h (HR = 1.05; 95% CI 0.85–1.30) were not significantly associated with glioma risk. Likewise, no significant associations were found between sleep duration and glioma risk in the NHS/HPFS for either < 7 h (HR = 0.93; 95% CI 0.69–1.26) or > 7 h (HR = 1.22; 95% CI 0.94–1.57), compared to 7 h. Results were similar for low-grade and high-grade glioma, did not materially change after lagging 2 years, or after accounting for factors known to disrupt sleep. Conclusion: Sleep duration was not associated with incident glioma in either the UKB or the NHS/HPFS cohorts. [ABSTRACT FROM AUTHOR]

Few prospective studies have evaluated the relation between fat-soluble vitamins and glioma risk. Using three cohorts—UK Biobank (UKB), Nurses' Health Study (NHS), and Health Professionals Follow-Up Study (HPFS), we investigated associations of pre-diagnostic concentrations of fat-soluble vitamins D, A, and E with incident glioma. In 346,785 participants (444 cases) in UKB, associations with vitamin D (25-hydroxyvitamin D [25(OH)D]) were evaluated by Cox proportional hazards regression. In NHS (52 cases, 104 controls) and HPFS (32 cases, 64 controls), associations with 25(OH)D, vitamin A (retinol), and vitamin E (α- and γ-tocopherol) were assessed using conditional logistic regression. Our results suggested plasma concentrations of 25(OH)D and retinol were not associated with glioma risk. Comparing the highest to lowest tertile, the multivariable hazard ratio (MVHR) for 25(OH)D was 0.87 (95% confidence interval [CI] 0.68–1.11) in UKB and the multivariable risk ratio (MVRR) was 0.97 (95% CI 0.51–1.85) in NHS and HPFS. In NHS and HPFS, the MVRR for the same comparison for retinol was 1.16 (95% CI 0.56–2.38). Nonsignificant associations were observed for α-tocopherol (MVRRtertile3vs1 = 0.61, 95% CI 0.29–1.32) and γ-tocopherol (MVRR tertile3vs1 = 1.30, 95% CI 0.63–2.69) that became stronger in 4-year lagged analyses. Further investigation is warranted on a potential association between α- and γ-tocopherol and glioma risk. [ABSTRACT FROM AUTHOR]

Purpose: Evidence is mixed on whether cholesterol plays a role in the pathogenesis of glioma. We explored the associations between circulating lipids and glioma risk in three prospective cohorts. Methods: Using prospective data from the UK Biobank, we examined the associations of total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), and triglycerides (TG) with glioma risk in multivariable (MV)-adjusted Cox proportional hazards models. Within the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS), we carried out a matched, nested case–control study to examine these same associations. Results: In the UK Biobank, 490 gliomas accrued over 2,358,964 person-years. TC was not significantly associated with glioma risk (MV HR = 1.20, 95% CI 0.89–1.61 for highest quartile vs. lowest, p-trend = 0.24). In 4-year lagged analyses (n = 229), higher TC was associated with significantly higher risk of glioma in men (MV HR = 2.26, 95% CI 1.32–3.89, p-trend = 0.002) but not women (MV HR = 1.28, 95% CI 0.61–2.68, p-trend = 0.72); similar findings emerged for HDL-C and, to a lesser extent, LDL-C. In the NHS/HPFS, no significant associations were found between cholesterol and glioma risk. No significant associations were identified for TG. Conclusion: In the UK Biobank, higher prediagnostic TC and HDL-C levels were associated with higher risk of glioma in 4-year lagged analyses, but not in non-lagged analyses, in men only. These findings merit further investigation, given that there are few risk factors and no reliable biomarkers of risk identified for glioma. [ABSTRACT FROM AUTHOR]

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose–response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6–7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively—and nonlinearly—associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18–20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18–20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC. [ABSTRACT FROM AUTHOR]

Purpose: Although a growing body of evidence supports an early-life contribution to prostate cancer (PCa) development, few studies have investigated early-life diet, and only three have examined early-life dairy product intake, a promising candidate risk factor because of its known/suspected influence on insulin-like growth factor levels and height. Methods: We used recalled dietary data from 162,816 participants in the NIH-AARP Diet and Health Study to investigate associations for milk, cheese, ice cream, total dairy, and calcium intake at ages 12–13 years with incident total (n = 17,729), advanced (n = 2,348), and fatal PCa (n = 827) over 14 years of follow-up. We calculated relative risks (RRs) and 95% confidence intervals (CIs) by Cox proportional hazards regression. Results: We observed suggestive positive trends for milk, dairy, and calcium intake with total and/or advanced PCa (p-trends = 0.016–0.148). These trends attenuated after adjustment for additional components of adolescent diet, particularly red meat and vegetables/potatoes. In contrast, suggestive inverse trends were observed for cheese and ice cream intake with total and/or advanced PCa (p-trends = 0.043–0.153), and for milk, dairy, and calcium intake with fatal PCa (p-trend = 0.045–0.117). Conclusion: Although these findings provide some support for a role of adolescent diet in increasing PCa risk, particularly for correlates of milk intake or overall dietary patterns, our protective findings for cheese and ice cream intake with PCa risk and mortality, and for all dairy products with PCa mortality, suggest alternative explanations, such as the influence of early-life socioeconomic status, and increased PCa screening, earlier detection, and better PCa care. [ABSTRACT FROM AUTHOR]

Background: A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features.Methods: We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01.Results: Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations.Conclusion: The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 2 diabetes mellitus has been implicated as a risk factor for hearing loss, with possible mechanisms including microvascular disease, acoustic neuropathy or oxidative stress. A few small studies have examined the longitudinal association between type 2 diabetes and hearing loss, but larger studies are needed. Our objective was to examine whether type 2 diabetes (including diabetes duration) is associated with incident hearing loss in two prospective cohorts: Nurses' Health Studies (NHS) I and II.Methods: We conducted a longitudinal study of 139,909 women to examine the relationship between type 2 diabetes and the risk of self-reported incident hearing loss. A physician-diagnosis of diabetes was ascertained from biennial questionnaires. The primary outcome was hearing loss reported as moderate or worse in severity (categorised as a 'moderate or severe' hearing problem, or 'moderate hearing trouble or deaf') on questionnaires administered in 2012 in NHS I and 2009 or 2013 in NHS II. Cox proportional hazards regression was used to adjust for potential confounders.Results: During >2.4 million person-years of follow-up, 664 cases of moderate or worse hearing loss were reported among those with type 2 diabetes and 10,022 cases among those without type 2 diabetes. Compared with women who did not have type 2 diabetes, those with type 2 diabetes were at higher risk for incident moderate or worse hearing loss (pooled multivariable-adjusted HR 1.16 [95% CI 1.07, 1.27]). Participants who had type 2 diabetes for ≥8 years had a higher risk of moderate or worse hearing loss compared with those without type 2 diabetes (pooled multivariable-adjusted HR 1.24 [95% CI 1.10, 1.40]).Conclusions/interpretation: In this large longitudinal study, type 2 diabetes was associated with a modestly higher risk of moderate or worse hearing loss. Furthermore, longer duration diabetes was associated with a higher risk of moderate or worse hearing loss. [ABSTRACT FROM AUTHOR]

In the analysis of time-to-event data with multiple causes using a competing risks Cox model, often the cause of failure is unknown for some of the cases. The probability of a missing cause is typically assumed to be independent of the cause given the time of the event and covariates measured before the event occurred. In practice, however, the underlying missing-at-random assumption does not necessarily hold. Motivated by colorectal cancer molecular pathological epidemiology analysis, we develop a method to conduct valid analysis when additional auxiliary variables are available for cases only. We consider a weaker missing-at-random assumption, with missing pattern depending on the observed quantities, which include the auxiliary covariates. We use an informative likelihood approach that will yield consistent estimates even when the underlying model for missing cause of failure is misspecified. The superiority of our method over naive methods in finite samples is demonstrated by simulation study results. We illustrate the use of our method in an analysis of colorectal cancer data from the Nurses' Health Study cohort, where, apparently, the traditional missing-at-random assumption fails to hold. [ABSTRACT FROM AUTHOR]

As one of causal inference methodologies, the inverse probability weighting (IPW) method has been utilized to address confounding and account for missing data when subjects with missing data cannot be included in a primary analysis. The transdisciplinary field of molecular pathological epidemiology (MPE) integrates molecular pathological and epidemiological methods, and takes advantages of improved understanding of pathogenesis to generate stronger biological evidence of causality and optimize strategies for precision medicine and prevention. Disease subtyping based on biomarker analysis of biospecimens is essential in MPE research. However, there are nearly always cases that lack subtype information due to the unavailability or insufficiency of biospecimens. To address this missing subtype data issue, we incorporated inverse probability weights into Cox proportional cause-specific hazards regression. The weight was inverse of the probability of biomarker data availability estimated based on a model for biomarker data availability status. The strategy was illustrated in two example studies; each assessed alcohol intake or family history of colorectal cancer in relation to the risk of developing colorectal carcinoma subtypes classified by tumor microsatellite instability (MSI) status, using a prospective cohort study, the Nurses’ Health Study. Logistic regression was used to estimate the probability of MSI data availability for each cancer case with covariates of clinical features and family history of colorectal cancer. This application of IPW can reduce selection bias caused by nonrandom variation in biospecimen data availability. The integration of causal inference methods into the MPE approach will likely have substantial potentials to advance the field of epidemiology. [ABSTRACT FROM AUTHOR]

Purpose: Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease. Methods: In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated. Results: The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle ( n = 6). The Phase II study ( n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment. Conclusions: In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients. [ABSTRACT FROM AUTHOR]

A number of epidemiologic studies have described what appear to be paradoxical associations, where an incongruous relationship is observed between a certain well-established risk factor for disease incidence and favorable clinical outcome among patients with that disease. For example, the 'obesity paradox' represents the association between obesity and better survival among patients with a certain disease such as coronary heart disease. Paradoxical observations cause vexing clinical and public health problems as they raise questions on causal relationships and hinder the development of effective interventions. Compelling evidence indicates that pathogenic processes encompass molecular alterations within cells and the microenvironment, influenced by various exogenous and endogenous exposures, and that interpersonal heterogeneity in molecular pathology and pathophysiology exists among patients with any given disease. In this article, we introduce methods of the emerging integrative interdisciplinary field of molecular pathological epidemiology (MPE), which is founded on the unique disease principle and disease continuum theory. We analyze and decipher apparent paradoxical findings, utilizing the MPE approach and available literature data on tumor somatic genetic and epigenetic characteristics. Through our analyses in colorectal cancer, renal cell carcinoma, and glioblastoma (malignant brain tumor), we can readily explain paradoxical associations between disease risk factors and better prognosis among disease patients. The MPE paradigm and approach can be applied to not only neoplasms but also various non-neoplastic diseases where there exists indisputable ubiquitous heterogeneity of pathogenesis and molecular pathology. The MPE paradigm including consideration of disease heterogeneity plays an essential role in advancements of precision medicine and public health. [ABSTRACT FROM AUTHOR]

Purpose: Vitamins A, C, and E and folate have anticarcinogenic properties and thus might protect against cancer. Few known modifiable risk factors for ovarian cancer exist. We examined the associations between dietary and total (food and supplemental) vitamin intake and the risk of invasive epithelial ovarian cancer. Methods: The primary data from 10 prospective cohort studies in North America and Europe were analyzed. Vitamin intakes were estimated from validated food frequency questionnaires in each study. Study-specific relative risks (RRs) were estimated using the Cox proportional hazards model and then combined using a random-effects model. Results: Among 501,857 women, 1,973 cases of ovarian cancer occurred over a median follow-up period of 7-16 years across studies. Dietary and total intakes of each vitamin were not significantly associated with ovarian cancer risk. The pooled multivariate RRs [95 % confidence intervals (CIs)] for incremental increases in total intake of each vitamin were 1.02 (0.97-1.07) for vitamin A (increment: 1,300 mcg/day), 1.01 (0.99-1.04) for vitamin C (400 mg/day), 1.02 (0.97-1.06) for vitamin E (130 mg/day), and 1.01 (0.96-1.07) for folate (250 mcg/day). Multivitamin use (vs. nonuse) was not associated with ovarian cancer risk (pooled multivariate RR = 1.00, 95 % CI 0.89-1.12). Associations did not vary substantially by study, or by subgroups of the population. Greater vitamin intakes were associated with modestly higher risks of endometrioid tumors ( n = 156 cases), but not with other histological types. Conclusion: These results suggest that consumption of vitamins A, C, and E and folate during adulthood does not play a major role in ovarian cancer risk. [ABSTRACT FROM AUTHOR]

Capecitabine produces an objective response rate of up to 25 % in anthracycline-treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib-capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m twice daily plus oral tipifarnib 300 mg twice daily on days 1-14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40 %. Among 63 eligible, partial response occurred in six patients (9.5 %; 90 % CI 4.2-17.9 %), median progression-free survival was 2.6 months (95 % CI 2.1-4.4), and median overall survival was 11.4 months (95 % CI 7.7-14.0). Dose modifications were required for 43 patients (68 %) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44 %; 90 % CI 44.4-67.0 %) and 11 patients (16 %; 90 % CI 10.8-29.0 %), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib-capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine health-related quality of life (HRQL) among women with metastatic breast cancer treated on E2100 with paclitaxel or paclitaxel plus bevacizumab. Trial participants ( N = 670) completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) pre-treatment and following 4 and 8 cycles of treatment to assess HRQL and breast cancer-specific concerns. A significantly higher proportion of missing FACT-B assessments was observed among patients receiving paclitaxel only, due to faster time to death. To account for this non-ignorable pattern of missing data, we conducted a survival-adjusted HRQL analysis by jointly modeling the longitudinal HRQL outcome and time to non-ignorable dropout using a two-stage model. FACT scores assessing HRQL did not differ following 4 and 8 cycles of treatment; however mean scores on the 9-item Breast Cancer Scale were significantly higher after 4 and 8 cycles of treatment among patients receiving paclitaxel plus bevacizumab. No differences were observed between treatment arms on FACT-B total scores. The addition of bevacizumab was not associated with additional side effect burden from the patient perspective and was associated with a greater reduction in breast cancer-specific concerns. No other differences were noted. [ABSTRACT FROM AUTHOR]

PALB2 (Partner And Localizer of BRCA2) binds to and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1-2% of familial breast cancer and 3-4% of familial pancreatic cancer cases. The goal of this study was to evaluate the prevalence of PALB2 mutations in women with breast cancer without BRCA1/2 mutations who also had a personal or family history of pancreatic cancer. PALB2 mutation analysis was performed in 94 non- BRCA1/2 breast cancer patients with a personal or family history of pancreatic cancer. Two truncating PALB2 mutations, c.3549C>CA and c.2962C>CT, were identified resulting in a mutation prevalence of 2.1%. The proband found to carry the c.3549C>CA PALB2 mutation had a mother diagnosed with both breast and pancreatic cancer; this relative was subsequently confirmed to carry the identical mutation. The proband with the c.2962C>CT mutation had a father and paternal aunt diagnosed with pancreatic cancer; neither relative was available for testing. Two novel PALB2 missense variants were also found, one of which was deemed potentially deleterious. The prevalence rate of PALB2 mutations in a non- BRCA1/2 breast cancer population specifically selected for a family history of pancreatic cancer does not appear to be significantly increased compared to that observed in other breast cancer populations studied thus far. Further evaluation is needed to determine the prevalence of PALB2 mutations and the clinical utility of such testing in those individuals affected with both breast and pancreatic cancers. [ABSTRACT FROM AUTHOR]

The purpose of this trial was to determine cardiac toxicity and overall efficacy of the pegylated liposome doxorubicin (PLD)–docetaxel couplet alone if HER2-negative metastatic breast cancer (internal control) or with trastuzumab if HER2-positive disease. Upon central HER2 confirmation, 84 eligible patients received induction with PLD (30 mg/m2) and docetaxel (60 mg/m2) every 3 weeks (maximum eight cycles), alone if HER2-negative (arm A; N = 38) or plus trastuzumab (4 mg/kg once, then 2 mg/kg weekly) if HER2-positive disease (arm B; N = 46) as first-line therapy. Maintenance therapy (without PLD) allowed. Primary objectives were to determine whether congestive heart failure (CHF) rate >3% and the efficacy/toxicity of each arm. CHF rate was <3% in each arm. Response rate, median progression-free-, and overall survival in arms A and B were 47.4 and 45.7%, 11 and 10.6 months, and 24.6 and 31.8 months, respectively. Trastuzumab arm was associated with higher rates of hand foot syndrome (grade 3: 22 vs. 38%; P = 0.16; overall 51 vs. 75%, P = 0.03) and treatment discontinuation due to toxicity/patient withdrawal (13 vs. 28%; P = 0.11). Febrile neutropenia occurred in ~10% of patients. In conclusion, concurrent administration of trastuzumab with PLD–docetaxel was not associated with higher risk of cardiac toxicity compared with PLD–docetaxel alone, but led to excessive hand-foot syndrome. [ABSTRACT FROM AUTHOR]

The epothilone B analogue, ixabepilone, binds to β-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC), and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin (C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m2 IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective response occurred in 26 patients (44%; 95% CI 31–58%), median time to progression was 8.2 months (95% CI 6.3–9.9), and median overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2+ cancers. Grade 3–4 adverse events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%). One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab. [ABSTRACT FROM AUTHOR]

Background: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 “early onset,” 50–54 “intermediate onset,”  ≥ 55 “later onset”).We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039).This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.Methods: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 “early onset,” 50–54 “intermediate onset,”  ≥ 55 “later onset”).We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039).This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.Results: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 “early onset,” 50–54 “intermediate onset,”  ≥ 55 “later onset”).We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039).This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.Conclusions: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 “early onset,” 50–54 “intermediate onset,”  ≥ 55 “later onset”).We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells.Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039).This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis. [ABSTRACT FROM AUTHOR]