New Malignancies after Squamous Cell Carcinoma and Melanomas: A Population-Based Study from Norway

Skin cancer survivors experience an increased risk for subsequent malignancies but the associated risk factors are poorly understood. This study examined the risk of a new primary cancer following an initial skin cancer and assessed risk factors associated with second primary cancers

Trends in Initial Management of Prostate Cancer in New Hampshire

Purpose Prostate cancer management strategies are evolving with increased understanding of the disease. Specifically, there is emerging evidence that ‘‘low-risk’’ cancer is best treated with observation, while localized ‘‘high-risk’’ cancer requires aggressive curative therapy. In this study, we evaluated trends in management of prostate cancer in New Hampshire to determine adherence to evidence- based practice. Methods From the New Hampshire State Cancer Registry, cases of clinically localized prostate cancer diagnosed in 2004–2011 were identified and classified according to D’Amico criteria. Initial treatment modality was recorded as surgery, radiation therapy, expectant management, or hormone therapy. Temporal trends were assessed by Chi-square for trend. Results Of 6,203 clinically localized prostate cancers meeting inclusion criteria, 34, 30, and 28 % were low-, intermediate-, and high-risk disease, respectively. For lowrisk disease, use of expectant management (17–42 %, p\0.001) and surgery (29–39 %, p\0.001) increased, while use of radiation therapy decreased (49–19 %, p\0.001). For intermediate-risk disease, use of surgery increased (24–50 %, p\0.001), while radiation decreased (58–34 %, p\0.001). Hormonal therapy alone was rarely used for low- and intermediate-risk disease. For high-risk patients, surgery increased (38–47 %, p = 0.003) and radiation decreased (41–38 %, p = 0.026), while hormonal therapy and expectant management remained stable. Discussion There are encouraging trends in the management of clinically localized prostate cancer in New Hampshire, including less aggressive treatment of low-risk cancer and increasing surgical treatment of high-risk disease

Lifestyle and Other Factors Explain One-Half of the Variability in the Serum 25-Hydroxyvitamin D Response to Cholecalciferol Supplementation in Healthy Adults

Background: Many factors have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in observational studies, with variable consistency. However, less information is available on factors affecting the magnitude of changes in serum 25(OH)D resulting from vitamin D supplementation. Objective: This study aimed to identify factors associated with the serum 25(OH)D response to supplementation with 1000 IU cholecalciferol/d during the first year of a large, multicenter, randomized, placebo-controlled colorectal adenoma chemoprevention trial. Methods: Eligible older adults who were not vitamin D–deficient [serum 25(OH)D12 ng/mL] were randomly assigned in a modified 2 3 2 factorial design to 1 of 4 groups: daily 1000 IU cholecalciferol, 1200 mg Ca as carbonate, both, or placebo. Women could elect 2-group (calcium 6 cholecalciferol) random assignment. In secondary analyses, we used multivariable models to assess factors associated with serum 25(OH)D concentrations in all enrollees (n = 2753) and with relative changes in serum 25(OH)D after 1 y cholecalciferol supplementation among those randomly assigned (n = 2187). Results: In multivariable models, 8 factors accounted for 50% of the variability of proportional change in serum 25(OH)D after cholecalciferol supplementation. Larger increases were associated with being female (34.5% compared with 20.5%; P \u3c 0.001) and with lower baseline serum 25(OH)D (P \u3c 0.0001), optimal adherence to study pill intake (P = 0.0002), wearing long pants and sleeves during sun exposure (P = 0.0002), moderate activity level (P = 0.01), use of extra vitamin D–containing supplements during the trial (P = 0.03), and seasons of blood draw (P # 0.002). Several genetic polymorphisms were associated with baseline serum 25(OH)D and/or serum response, but these did not substantially increase the models of R2 values. Other factors, including body mass index, were associated with serum 25(OH)D at baseline but not with its response to supplemental cholecalciferol. Conclusions: The factors that most affected changes in serum 25(OH)D concentrations in response to cholecalciferol supplementation included sex, baseline serum 25(OH)D, supplement intake adherence, skin-covering clothes, physical activity, and season. Genetic factors did not play a major role. This trial was registered at www.clinicaltrials.gov as NCT00153816

The Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas

BACKGROUND Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2Å~2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist’s recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.

Risk of Death from Cardiovascular Disease Associated with Low-level Arsenic Exposure Among Long-term Smokers in a US Population-based Study

High levels of arsenic exposure have been associated with increases in cardiovascular disease risk. However, studies of arsenic’s effects at lower exposure levels are limited and few prospective studies exist in the United States using long-term arsenic exposure biomarkers. We conducted a prospective analysis of the association between toenail arsenic and cardiovascular disease mortality using longitudinal data collected on 3939 participants in the New Hampshire Skin Cancer Study. Using Cox proportional hazard models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals associated with the risk of death from any cardiovascular disease, ischemic heart disease, and stroke, in relation to natural-log transformed toenail arsenic concentrations. In this US population, although we observed no overall association, arsenic exposure measured from toenail clipping samples was related to an increased risk of ischemic heart disease mortality among long-term smokers (as reported at baseline), with increased hazard ratios among individuals with ≥ 31 total smoking years (HR: 1.52, 95% CI: 1.02, 2.27), ≥ 30 pack-years (HR: 1.66, 95% CI: 1.12, 2.45), and among current smokers (HR: 1.69, 95% CI: 1.04, 2.75). These results are consistent with evidence from more highly exposed populations suggesting a synergistic relationship between arsenic exposure and smoking on health outcomes and support a role for lower-level arsenic exposure in ischemic heart disease mortality

Non Melanoma Skin Cancer and Subsequent Cancer Risk

Introduction: Several studies have shown an increased risk of cancer after non melanoma skin cancers (NMSC) but the individual risk factors underlying this risk have not been elucidated, especially in relation to sun exposure and skin sensitivity to sunlight. Purpose: The aim of this study was to examine the individual risk factors associated with the development of subsequent cancers after non melanoma skin cancer. Methods: Participants in the population-based New Hampshire Skin Cancer Study provided detailed risk factor data, and subsequent cancers were identified via linkage with the state cancer registry. Deaths were identified via state and national death records. A Cox proportional hazard model was used to estimate risk of subsequent malignancies in NMSC patients versus controls and to assess the potential confounding effects of multiple risk factors on this risk. Results: Among 3584 participants, risk of a subsequent cancer (other than NMSC) was higher after basal cell carcinoma (BCC) (adjusted HR 1.40 [95% CI 1.15, 1.71]) than squamous cell carcinoma (SCC) (adjusted HR 1.18 [95% CI 0.95, 1.46]) compared to controls (adjusted for age, sex and current cigarette smoking). After SCC, risk was higher among those diagnosed before age 60 (HR 1.96 [95% CI 1.24, 3.12]). An over 3-fold risk of melanoma after SCC (HR 3.62; 95% CI 1.85, 7.11) and BCC (HR 3.28; 95% CI 1.66, 6.51) was observed, even after further adjustment for sun exposure-related factors and family history of skin cancer. In men, prostate cancer incidence was higher after BCC compared to controls (HR 1.64; 95% CI 1.10, 2.46). Conclusions: Our population-based study indicates an increased cancer risk after NMSC that cannot be fully explained by known cancer risk factors

Does Travel Time to a Radiation Facility Impact Patient Decision-making Regarding Treatment for Prostrate Cancer? A Study of the New Hampshire State Cancer Registry

Purpose: We sought to determine whether further distance from a radiation center is associated with lower utilization of external beam radiation therapy (XRT). Methods: We retrospectively identified patients with a new diagnosis of localized prostate cancer (CaP) within the New Hampshire State Cancer Registry from 2004 to 2011. Patients were categorized by age, D’Amico risk category, year of treatment, marital status, season of diagnosis, urban/rural residence, and driving time to the nearest radiation facility. Treatment decisions were stratified into those requiring multiple trips (XRT) or a single trip (surgery or brachytherapy). Multivariable regression analysis was performed. Results: A total of 4,731 patients underwent treatment for newly diagnosed CaP during the study period, including 1,575 multitrip (XRT) and 3,156 singletrip treatments. Of these, 87.6% lived within a 30-minute drive to a radiation facility. In multivariable analysis, time to the nearest radiation facility was not associated with treatment decisions (P = .26). However, higher risk category, older age, married status, and winter diagnosis were associated with XRT (P \u3c .05). More recent year of diagnosis and urban residence were associated with single-trip therapy (primarily surgery) (P \u3c .05). There was a significant interaction between travel time and season of diagnosis (P = .03), as well as a marginally significant interaction with urban/rural status (P = .07). Conclusion: Overall, further travel time to a radiation facility was not associated with lower utilization of XRT. These data are encouraging regarding access to care for CaP in New Hampshire

Changes in Beliefs Identify Unblinding in Randomized Controlled Trials: A Method to Meet CONSORT Guidelines

Double-blinded trials are often considered the gold standard for research, but significant bias may result from unblinding of participants and investigators. Although the CONSORT guidelines discuss the importance of reporting evidence that blinding was successful , it is unclear what constitutes appropriate evidence. Among studies reporting methods to evaluate blinding effectiveness, many have compared groups with respect to the proportions correctly identifying their intervention at the end of the trial. Instead, we reasoned that participants\u27 beliefs, and not their correctness, are more directly associated with potential bias, especially in relation to self-reported health outcomes. During the Water Evaluation Trial performed in northern California in 1999, we investigated blinding effectiveness by sequential interrogation of participants about their blinded intervention assignment (active or placebo). Irrespective of group, participants showed a strong tendency to believe they had been assigned to the active intervention; this translated into a statistically significant intergroup difference in the correctness of participants\u27 beliefs, even at the start of the trial before unblinding had a chance to occur. In addition, many participants (31%) changed their belief during the trial, suggesting that assessment of belief at a single time does not capture unblinding. Sequential measures based on either two or all eight questionnaires identified significant group-related differences in belief patterns that were not identified by the single, cross-sectional measure. In view of the relative insensitivity of cross-sectional measures, the minimal additional information in more than two assessments of beliefs and the risk of modifying participants\u27 beliefs by repeated questioning, we conclude that the optimal means of assessing unblinding is an intergroup comparison of the change in beliefs (and not their correctness) between the start and end of a randomized controlled trial

Cofactor Molecules Maintain Infectious Conformation and Restrict Strain Properties in Purified Prions

Prions containing misfolded prion protein (PrP(Sc)) can be formed with cofactor molecules using the technique of serial protein misfolding cyclic amplification. However, it remains unknown whether cofactors materially participate in maintaining prion conformation and infectious properties. Here we show that withdrawal of cofactor molecules during serial propagation of purified recombinant prions caused adaptation of PrP(Sc) structure accompanied by a reduction in specific infectivity of >10(5)-fold, to undetectable levels, despite the ability of adapted “protein-only” PrP(Sc) molecules to self-propagate in vitro. We also report that changing only the cofactor component of a minimal reaction substrate mixture during serial propagation induced major changes in the strain properties of an infectious recombinant prion. Moreover, propagation with only one functional cofactor (phosphatidylethanolamine) induced the conversion of three distinct strains into a single strain with unique infectious properties and PrP(Sc) structure. Taken together, these results indicate that cofactor molecules can regulate the defining features of mammalian prions: PrP(Sc) conformation, infectivity, and strain properties. These findings suggest that cofactor molecules likely are integral components of infectious prions

A protocol for prospective studies 5-hydroxyvitamin D, leptin and b ass index in relation to cutaneou elanoma incidence and survival

Introduction The incidence and mortality rates of cutaneous melanoma (CM) are increasing among fai skinned populations worldwide. Ultraviolet radiation s the principal risk factor for CM, but is also the mai source of 25-hydroxyvitamin D (25(OH)D), which has associated with reduced risk and better prognosis of cancer types. However, both low and high 25(OH)D l have been associated with increased risk of CM. Obe as measured by body mass index (BMI) is associated risk of several cancers and has also been suggested risk factor for CM, and may also be related to insuffi 25(OH)D and/or high leptin levels. Moreover, contract CM diagnosis has been associated with increased ri developing second cancer. We aim to study whether prediagnostic serum levels of 25(OH)D, high prediag evels of BMI and high serum leptin levels influence ncidence, Breslow thickness and CM mortality, and second cancer and survival after a CM diagnosis. Methods and analysis Cohort and nested case–co studies will be carried out using the population-base Janus Serum Bank Cohort (archival prediagnostic se BMI, smoking and physical activity), with follow-up fr 1972 to 2014. Additional data will be received from t Cancer Registry of Norway, the national Cause of De Registry, Statistics Norway (education and occupatio and exposure matrices of UVR. Time-to-event regres models will be used to analyse the cohort data, whil he nested case–control studies will be analysed by conditional logistic regression. A multilevel approach be applied when incorporating group-level data. Ethics and dissemination The project is approved he Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Res will be published in peer-reviewed journals, at scient conferences and in the news media