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Context: The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer.Objective: To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men.Design, Setting, and Participants: A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011.Interventions: Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years.Main Outcome Measures: Prostate cancer incidence.Results: This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination.Conclusion: Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.Trial Registration: Clinicaltrials.gov Identifier: NCT00006392. [ABSTRACT FROM AUTHOR]

Effects of variations in agent, dose, and route of treatment administration on patient reported quality of life (QOL) were examined for 279 patients enrolled on a seven-arm randomized clinical trial (S8905) of 5-FU and its modulation for advanced colorectal cancer. Patients completed QOL questionnaires at randomization and weeks 6, 11, and 21 post-randomization with five QOL endpoints considered primary: three treatment-specific symptoms (stomatitis, diarrhea, and hand/foot sensitivity); physical functioning; and emotional functioning. Patient compliance with the QOL assessment schedule was good, supporting the feasibility of including QOL measures in cooperative group trials. However, death and deteriorating health produced substantial missing data. Cross-sectional analyses indicated that the seven therapeutic arms did not differ in their impact on QOL. Unfortunately, longitudinal analyses of the QOL data were inappropriate given non-random missing data. Graphical presentation of non-random missing data identified the seriousness of this problem and its effect on potential conclusions about QOL during treatment. This problem appears to be particularly challenging in the context of advanced-stage disease. Failure to recognize the presence of non-random missing data can lead to serious overestimates of patient QOL over time. [ABSTRACT FROM AUTHOR]

Background: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality.Purpose: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention.Methods: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests.Results: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations.Conclusions: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland. [ABSTRACT FROM AUTHOR]

BACKGROUND: Interferon alfa has modest but definite activity in the treatment of metastatic melanoma and is the only agent currently available for adjuvant therapy of high-risk resected disease. A variety of retinoic acid derivatives have been shown to be synergistic with interferon alfa in vitro and in vivo, with nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have clinical relevance for the treatment of advanced as well as localized disease. PURPOSE: To determine the efficacy and toxicity of a combination of interferon alfa-2a and all-trans-retinoic acid in patients with measurable metastatic melanoma, the South-west Oncology Group conducted a phase II clinical trial. PATIENTS AND METHODS: Fifty-seven patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered; five patients were unevaluable. Treatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m2 orally twice daily for 21 days followed by 7 days' rest) plus subcutaneously administered interferon alfa-2a (6 MU/m2 three times a week). RESULTS: Two complete and three partial responses were observed among 52 evaluable patients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or subcutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side effects. There was one case of grade III hyperlipidemia. CONCLUSION: The combination of recombinant human interferon alfa-2a with all-trans-retinoic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma in either the advanced disease or the adjuvant settings. [ABSTRACT FROM AUTHOR]

Neoplasm arising from the keratinocytes or melanocytes in the skin is the most prevalent type of cancer in the United States and worldwide. Since ultraviolet (UV) radiation may be a causing factor for several types of skin cancer, effective strategies to manage skin cancer include preventive measures such as minimizing exposure to UV and applying sunscreens. However, the effect of sunscreen in reducing skin cancer incidence remains uncertain. An alternative approach to prevent skin cancer is chemoprevention, which is defined as using either natural products or synthetic compounds to inhibit, delay, or reverse the development of cancer. Preclinical studies have demonstrated the effectiveness of multiple pharmacological agents and dietary supplements. However, whether preclinical findings can be translated into clinical application is unknown. This review evaluates the state of recent clinical trials investigating chemopreventive agents focusing on skin cancer to compare the target populations, interventions, endpoints, and outcomes of these trials. The ClinicalTrials and PubMed databases were searched for their available literature using the key words "skin cancer" and "chemoprevention". The objective of this review is to provide updated information on the effectiveness and side effects of promising chemopreventive agents in human subjects and to identify research gaps.

The R-carvedilol enantiomer, present in the racemic mixture of the chiral drug carvedilol, does not bind to the β-adrenergic receptors, but exhibits skin cancer preventive activity. For skin delivery, R-carvedilol-loaded transfersomes were prepared using various ratios of drug, lipids, and surfactants, and characterized for particle size, zeta potential, encapsulation efficiency, stability, and morphology. Transfersomes were compared for in vitro drug release and ex vivo skin penetration and retention. Skin irritation was evaluated by viability assay on murine epidermal cells and reconstructed human skin culture. Single-dose and repeated-dose dermal toxicity was determined in SKH-1 hairless mice. Efficacy was evaluated in SKH-1 mice exposed to single or multiple ultraviolet (UV) radiations. Transfersomes released the drug at a slower rate, but significantly increased skin drug permeation and retention compared with the free drug. The transfersome with a drug-lipid-surfactant ratio of 1:3:0.5 (T-RCAR-3) demonstrated the highest skin drug retention and was selected for further studies. T-RCAR-3 at 100 µM did not induce skin irritation in vitro and in vivo. Topical treatment with T-RCAR-3 at 10 µM effectively attenuated acute UV-induced skin inflammation and chronic UV-induced skin carcinogenesis. This study demonstrates feasibility of using R-carvedilol transfersome for preventing UV-induced skin inflammation and cancer.

The β-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but systemic drug administration may cause unwanted cadiovascular effects. To overcome this limitation, a topical delivery system based on transfersome (T-CAR) was characterized ex vivo and in vivo. T-CAR was visualized by Transmission Electron Microscopy as nanoparticles of spherical and unilamellar structure. T-CAR incorporated into carbopol gel and in suspension showed similar drug permeation and deposition profiles in Franz diffusion cells loaded with porcine ear skin. In mice exposed to a single dose UV, topical T-CAR gel (10 µM) significantly reduced UV-induced skin edema and cyclobutane pyrimidine dimer formation. In mice exposed to chronic UV radiation for 25 weeks, topical T-CAR gel (10 µM) significantly delayed the incidence of tumors, reduced tumor number and burden, and attenuated Ki-67 and COX-2 expression. The T-CAR gel was subsequently examined for skin deposition, systemic absorption and cardiovascular effects in mice. In mice treated with repeated doses of T-CAR gel (100 µM), the drug was undetectable in plasma, the heart rate was unaffected, but skin deposition was significantly higher than mice treated with oral carvedilol (32 mg/kg/day). These data indicate that the carbopol-based T-CAR gel holds great promise for skin cancer prevention with negligible systemic effects., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The β-blocker carvedilol has been shown to prevent skin carcinogenesis in vitro and in vivo. Since systemic absorption of the β-blocker may cause cardiovascular disturbance, we developed a carvedilol loaded transfersome for skin-targeted delivery. Transfersomes were prepared using phospholipids and surfactants at various ratios and characterized. One formulation (F18) selected for further analysis was composed of carvedilol, soy phosphatidylcholine, and Tween-80 at a ratio of 1:3:0.5, which had a particle size of 115.6 ± 8.7 nm, a zeta potential of 11.34 ± 0.67 mV, and an encapsulation efficiency of 93.7 ± 5.1%. F18 inhibited EGF-induced neoplastic transformation of mouse epidermal JB6 P+ cells at non-toxic concentrations, while only high concentrations induced cytotoxicity in JB6 P+ and human keratinocytes HaCaT. Compared to the free drug, F18 released through the dialysis membrane and permeated through the porcine ear skin at a slower rate, but similarly depositing the drug in the epidermis and dermis of the skin. Consistently, surface application of F18 on reconstructed full-thickness human skin showed slower drug permeation, while it suppressed ultraviolet-induced DNA damage, inflammatory gene expression, and apoptosis. These data indicate that transfersome is a promising topical delivery system of carvedilol for preventing ultraviolet-induced skin damage and carcinogenesis.

Importance: The combined 28 years of data of medical aid in dying (MAID) between Oregon (OR) and Washington (WA) are the most comprehensive in North America. No reports to date have compared MAID use in different US states., Objective: To evaluate and compare patterns of MAID use between the states with the longest-running US death with dignity programs., Design, Setting, and Participants: A retrospective observational cohort study of OR and WA patients with terminal illness who received prescriptions as part of their states' legislation allowing MAID. All published annual reports, from 1998 to 2017 in OR and from 2009 to 2017 in WA, were reviewed. A total of 3368 prescriptions were included., Main Outcomes and Measures: Number of deaths from self-administration of lethal medication vs number of prescriptions written., Results: A combined 3368 prescriptions were written in OR and WA, with 2558 patient deaths from lethal ingestion (76.0%). Of the 2558 patients, most were male (1311 [51.3%]), older than 65 years (1851 [72.4%]), and non-Hispanic white (2426 [94.8%]). The most common underlying illnesses were cancer (1955 [76.4%]), neurologic illness (261 [10.2%]), lung disease (144 [5.6%]), and heart disease (117 [4.6%]). Loss of autonomy (2235 [87.4%]), impaired quality of life (2203 [86.1%]), and loss of dignity (1755 [68.6%]) were the most common reasons for pursuing MAID. Time between drug intake to coma ranged from 1 to 660 minutes and time from drug intake to death ranged from 1 to 6240 minutes. In the 1557 patients for whom rates of complications were reported, 1494 (96.0%) did not experience a complication (592 of 626 [94.6%] in OR and 902 of 931 [96.8%] in WA). Eight patients (<0.5%) regained consciousness after drug ingestion in OR. Annual rates per year for percentage of patients who received a prescription ingesting the prescribed medication ranged from 48% to 87%, with no significant time trend in OR (adjusted odds ratio per year, 1.01; 95% CI, 0.99-1.02; P = .59) but with an increase over time in WA (adjusted odds ratio per year, 1.13; 95% CI, 1.08-1.19; P < .001). In both OR and WA there were increases in the number of patient deaths due to MAID per 1000 deaths over time., Conclusions and Relevance: In this study, MAID results in Oregon and Washington were similar, although MAID use measured as a percentage of patients prescribed lethal medications and then self-administering them increased only in WA. Most patients who acquired lethal prescriptions had cancer or terminal illnesses that are difficult to palliate and lead to loss of autonomy, dignity, and quality of life.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years., (© 2018 American Cancer Society.)

Background: Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma., Methods: The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential., Results: Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors., Conclusions: The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer.

In previous studies, the β-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P + cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV-induced neoplastic transformation. Both carvedilol and 4-OHC (1 μmol/L) blocked transformation induced by chronic UV (15 mJ/cm 2 ) exposure for 8 weeks. However, EGF-mediated transformation was inhibited by only carvedilol but not by 4-OHC. Carvedilol (1 and 5 μmol/L), but not 4-OHC, attenuated UV-induced AP-1 and NF-κB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single-dose UV (200 mJ/cm 2 )-induced skin inflammation mouse model, carvedilol (10 μmol/L), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL1β, IL6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm 2 ) three times a week for 25 weeks, topical administration of carvedilol (10 μmol/L) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect. These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer. Cancer Prev Res; 10(10); 598-606. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The NOX (nicotinamide adenine dinucleotide phosphate oxidase) family includes seven unique members that are involved in a multitude of physiological functions, including extensive interaction with UVR and the skin. NOX1 is uniquely present and activated by UVB radiation with biphasic expression of the enzyme immediately and then after a several-hour delay. Specific inhibition of both early and late NOX1 activation leads to evidence of decreased photocarcinogenesis in in vitro keratinocytes and in well-characterized mouse models in which antitumor efficacy has been shown; inhibiting only late NOX activation does not exhibit such effects. These results suggest a crucial function of early NOX activation in transducing a signal for cellular protection after UVB carcinogenesis provocation. We term this an intrinsic cellular ROS priming function for quenching DNA damage and promoting survival. Evolutionally, this type of priming function may be essential for addressing various types of stimuli from adverse environments., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Redox homeostasis plays multiple roles in essentially all aspects of cellular function, and hence, reliable methods for measuring cellular or tissue redox status are key elements in understanding the redox related signal pathways. However, in the free radical biology field, there are many controversies on the methods to measure reactive oxygen species. In this chapter we describe our experience in measuring superoxide, hydrogen peroxide, and a general redox status using redox-sensitive green fluorescence proteins (roGFPs) in human melanoma cells.

The UDP-glucuronosyltransferases (UGTs) are integrally involved in the clearance of a wide range of drugs used to combat human diseases. UGT expression levels and activity can be induced by drug addition to cells and has been proposed as a potential intratumoral drug resistance mechanism. Traditional methods of assaying UGT activity are drug-centric and require HPLCs with multiple detectors (dependent on individual drug). Here, we describe a generalized method to detect total UGT activity (intrinsic or induced) via the UGT-Glo assay which utilizes a general UGT substrate with luminescence as the readout eliminating the need for multiple HPLC detectors to detect total UGT activity in a given sample. The method detailed here can be applied for any UGT containing sample, allowing for the efficient detection of total UGT activity to be the functional endpoint using a plate reader. In this manner, global changes in UGT activity can be monitored in response to a wide variety of stimuli.

Purpose: To assist in determining barriers to an oncology career incorporating cancer prevention, the American Society of Clinical Oncology (ASCO) Cancer Prevention Workforce Pipeline Work Group sponsored surveys of training program directors and oncology fellows., Methods: Separate surveys with parallel questions were administered to training program directors at their fall 2013 retreat and to oncology fellows as part of their February 2014 in-training examination survey. Forty-seven (67%) of 70 training directors and 1,306 (80%) of 1,634 oncology fellows taking the in-training examination survey answered questions., Results: Training directors estimated that ≤ 10% of fellows starting an academic career or entering private practice would have a career focus in cancer prevention. Only 15% of fellows indicated they would likely be interested in cancer prevention as a career focus, although only 12% thought prevention was unimportant relative to treatment. Top fellow-listed barriers to an academic career were difficulty in obtaining funding and lower compensation. Additional barriers to an academic career with a prevention focus included unclear career model, lack of clinical mentors, lack of clinical training opportunities, and concerns about reimbursement., Conclusion: Reluctance to incorporate cancer prevention into an oncology career seems to stem from lack of mentors and exposure during training, unclear career path, and uncertainty regarding reimbursement. Suggested approaches to begin to remedy this problem include: 1) more ASCO-led and other prevention educational resources for fellows, training directors, and practicing oncologists; 2) an increase in funded training and clinical research opportunities, including reintroduction of the R25T award; 3) an increase in the prevention content of accrediting examinations for clinical oncologists; and 4) interaction with policymakers to broaden the scope and depth of reimbursement for prevention counseling and intervention services., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Approaches to reduce the global burden of cancer include two major strategies: screening and early detection and active preventive intervention. The latter is the topic of this Commentary and spans a broad range of activities. The genetic heterogeneity and complexity of advanced cancers strongly support the rationale for early interruption of the carcinogenic process and an enhanced focus on prevention as a priority strategy to reduce the burden of cancer; however, the focus of cancer prevention management should be on individuals at high risk and on primary localized disease in which screening and detection should also play a vital role. The timing and dose of (chemo-)preventive intervention also affects response. The intervention may be ineffective if the target population is very high risk or already presenting with preneoplastic lesions with cellular changes that cannot be reversed. The field needs to move beyond general concepts of carcinogenesis to targeted organ site prevention approaches in patients at high risk, as is currently being done for breast and colorectal cancers. Establishing the benefit of new cancer preventive interventions will take years and possibly decades, depending on the outcome being evaluated. We also propose that comparative effectiveness research designs and the value of information obtained from large-scale prevention studies are necessary in order for preventive interventions to become a routine part of cancer management., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Robust methods are needed to efficiently conduct large, multisite, randomized, controlled clinical trials of acupuncture protocols. The Southwest Oncology Group (SWOG) S1200 trial is a randomized, controlled (i.e., sham-controlled and waitlist-controlled) trial of a standardized acupuncture protocol for treating aromatase inhibitor (AI)-associated arthralgias in early-stage breast cancer patients (n = 228). The primary objective of this study was to determine whether true acupuncture administered twice weekly for 6 weeks, as compared to sham acupuncture or a waitlist control, reduced AI-associated joint pain at 6 weeks as assessed by patient reports. The study was conducted at 11 institutions across the United States. The true acupuncture protocol was developed using a consensus-based process. The true acupuncture and the sham acupuncture protocols each consisted of 12 sessions administered for 6 weeks, followed by one weekly session for 6 weeks. The true acupuncture protocol used standardized protocol points, and the standardized acupoints were tailored to a patient's joint symptoms. The similarly standardized sham acupuncture protocol utilized superficial needling of nonacupoints. Standardized methods were developed to train and monitor acupuncturists and included online and in-person training, study manuals, monthly phone calls, and remote quality assurance monitoring throughout the study period. The research staff similarly received online and in-person training and monthly phone calls., (Copyright © 2015. Published by Elsevier B.V.)

Background: Ovarian failure is a common toxic effect of chemotherapy. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists to protect ovarian function have shown mixed results and lack data on pregnancy outcomes., Methods: We randomly assigned 257 premenopausal women with operable hormone-receptor-negative breast cancer to receive standard chemotherapy with the GnRH agonist goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The primary study end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone (FSH) in the postmenopausal range. Rates were compared with the use of conditional logistic regression. Secondary end points included pregnancy outcomes and disease-free and overall survival., Results: At baseline, 218 patients were eligible and could be evaluated. Among 135 with complete primary end-point data, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group (odds ratio, 0.30; 95% confidence interval [CI], 0.09 to 0.97; two-sided P=0.04). Owing to missing primary end-point data, sensitivity analyses were performed, and the results were consistent with the main findings. Missing data did not differ according to treatment group or according to the stratification factors of age and planned chemotherapy regimen. Among the 218 patients who could be evaluated, pregnancy occurred in more women in the goserelin group than in the chemotherapy-alone group (21% vs. 11%, P=0.03); women in the goserelin group also had improved disease-free survival (P=0.04) and overall survival (P=0.05)., Conclusions: Although missing data weaken interpretation of the findings, administration of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk of early menopause and improving prospects for fertility. (Funded by the National Cancer Institute and others; POEMS/S0230 ClinicalTrials.gov number, NCT00068601.).

Melanoma has traditionally been viewed as an ultraviolet (UV) radiation-induced malignancy. While UV is a common inducing factor, other endogenous stresses such as metal ion accumulation or the melanin pigment itself may provide alternative pathways to melanoma progression. Eumelanosomes within melanoma often exhibit disrupted membranes and fragmented pigment which may be due to alterations in their amyloid-based striated matrix. The melanosomal amyloid can itself be toxic, especially in combination with reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by endogenous NADPH oxidase (NOX) and nitric oxide synthase (NOS) enzymes, a toxic mix that may initiate melanomagenesis. Further understanding of the loss of the melanosomal organization, the behaviour of the exposed melanin and the induction of ROS/RNS in melanomas may provide critical insights into this deadly disease., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Reactive oxygen species (ROS) play crucial roles in all aspects of melanoma development, however, the source of ROS is not well defined. In this review we summarize recent advancement in this rapidly developing field. The cellular ROS pool in melanocytes can be derived from mitochondria, melanosomes, NADPH oxidase (NOX) family enzymes, and uncoupling of nitric oxide synthase (NOS). Current evidence suggests that Nox1, Nox4 and Nox5 are expressed in melanocytic lineage. While there is no difference in Nox1 expression levels in primary and metastatic melanoma tissues, Nox4 expression is significantly higher in a subset of metastatic melanoma tumors as compared to the primary tumors; suggesting distinct and specific signals and effects for NOX family enzymes in melanoma. Targeting these NOX enzymes using specific NOX inhibitors may be effective for a subset of certain tumors. ROS also play important roles in BRAF inhibitor induced drug resistance; hence identification and blockade of the source of this ROS may be an effective way to enhance efficacy and overcome resistance. Furthermore, ROS from different sources may interact with each other and interact with reactive nitrogen species (RNS) and drive the melanomagenesis process at all stages of disease. Further understanding ROS and RNS in melanoma etiology and progression is necessary for developing new prevention and therapeutic approaches.

The incidence of melanoma is one of the fastest growing of all tumor types in the United States and the number of cases worldwide has doubled in the past 30 years. Melanoma, which arises from melanocytes, is an extremely aggressive tumor that invades the vascular and lymphatic systems to establish tumors elsewhere in the body. Melanoma is a particularly resilient cancer and systemic therapy approaches have achieved minimal success against metastatic melanoma resulting in only a few FDA-approved treatments with limited benefit. Leading treatments offer minimal efficacy with response rates generally under 15% in the long term with no clear effect on melanoma-related mortality. Even the recent success of the specific BRAF mutant inhibitor vemurafenib has been tempered somewhat since acquired resistance is rapidly observed. Thus, understanding the mechanism(s) of melanoma carcinogenesis is paramount to combating this deadly disease. Not only for the treatment of melanoma but, ultimately, for prevention. In this report, we will summarize our work to date regarding the characterization of ultraviolet radiation (UVR)-mediated melanomagenesis and highlight several promising avenues of ongoing research., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed higher prostate cancer incidence in men supplemented with high-dose α-tocopherol. We, therefore, examined whether presupplementation plasma α-tocopherol or γ-tocopherol was associated with overall or high-grade prostate cancer. A stratified case-cohort sample that included 1,746 incident prostate cancer cases diagnosed through June 2009 and a subcohort of 3,211 men was derived from the SELECT trial of 35,533 men. Plasma was collected at entry from 2001 to 2004, and median follow-up was 5.5 years (range, 0-7.9 years). Incidence of prostate cancer as a function of plasma α-tocopherol, γ-tocopherol, and supplementation with α-tocopherol or selenomethionine was estimated by the hazard ratio (HR). Plasma γ-tocopherol was not associated with prostate cancer. Men with higher α-tocopherol concentrations seemed to have risk similar to that of men with lower concentrations [overall HR for fifth (Q5) vs. first quintile (Q1), 1.21; 95 % confidence interval (CI), 0.88-1.66; P-trend = 0.24; in the trial placebo arm, Q5 HR, 0.85; 95% CI, 0.44-1.62; P-trend = 0.66]. We found a strong positive plasma α-tocopherol association among men receiving the trial selenomethionine supplement [Q5 HR, 2.04; 95% CI, 1.29-3.22; P-trend = 0.005]. A positive plasma α-tocopherol-prostate cancer association also seemed limited to high-grade disease (Gleason grade, 7-10; overall Q5 HR, 1.59; 95% CI, 1.13-2.24; P-trend = 0.001; among men receiving selenomethionine, Q5 HR, 2.12; 95% CI, 1.32-3.40; P-trend = 0.0002). Our findings indicate that higher plasma α-tocopherol concentrations may interact with selenomethionine supplements to increase high-grade prostate cancer risk, suggesting a biologic interaction between α-tocopherol and selenium itself or selenomethionine., (©2014 American Association for Cancer Research.)

Background: In vitro, animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent., Methods: Data for this case (n = 1,731) and cohort (n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2-6, 7-10, and 8-10 prostate cancer., Results: There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66-1.03; P = 0.092], 0.74 (95% CI, 0.59-0.92; P = 0.008), 0.86 (95% CI, 0.69-1.07; P = 0.181), and 0.98 (95% CI, 0.78-1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7-10 cancer, corresponding HRs were 0.63 (95% CI, 0.45-0.90; P = 0.010), 0.66 (95% CI, 0.47-0.92; P = 0.016), 0.79 (95% CI, 0.56-1.10; P = 0.165), and 0.88 (95% CI, 0.63-1.22; P = 0.436). Among African American men (n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7-10 cancer only: in the a posteriori contrast of quintiles 1-2 versus 3-5, the HR was 0.55 (95% CI, 0.31-0.97; P = 0.037), with no evidence of dose-response or a U-shaped association., Conclusions: Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease., Impact: The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. Cancer Epidemiol Biomarkers Prev; 23(8); 1494-504. ©2014 AACR., (©2014 American Association for Cancer Research.)

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed.

Background: The Selenium and Vitamin E Cancer Prevention Trial found no effect of selenium supplementation on prostate cancer (PCa) risk but a 17% increased risk from vitamin E supplementation. This case-cohort study investigates effects of selenium and vitamin E supplementation conditional upon baseline selenium status., Methods: There were 1739 total and 489 high-grade (Gleason 7-10) PCa cases and 3117 men in the randomly selected cohort. Proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effects of supplementation within quintiles of baseline toenail selenium. Cox proportional hazards models were used to estimate hazard ratios, and all statistical tests are two-sided., Results: Toenail selenium, in the absence of supplementation, was not associated with PCa risk. Selenium supplementation (combined selenium only and selenium + vitamin E arms) had no effect among men with low selenium status (<60th percentile of toenail selenium) but increased the risk of high-grade PCa among men with higher selenium status by 91% (P = .007). Vitamin E supplementation (alone) had no effect among men with high selenium status (≥40th percentile of toenail selenium) but increased the risks of total, low-grade, and high-grade PCa among men with lower selenium status (63%, P = .02; 46%, P = .09; 111%, P = .008, respectively)., Conclusions: Selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status. Vitamin E increased the risk of PCa among men with low selenium status. Men should avoid selenium or vitamin E supplementation at doses that exceed recommended dietary intakes.

Resveratrol, a natural polyphenol found in grapes, berries and other plants, has been proposed as an ideal chemopreventative agent due to its plethora of health promoting activities. However, despite its lofty promise as a cancer prevention agent its success in human clinical trials has been limited due to its poor bioavailability. Thus, interest in other natural polyphenols is intensifying including the naturally occurring dimethylated analog of resveratrol, pterostilbene. The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the metabolism of both resveratrol and pterostilbene. The current study sought to elucidate the UGT family members responsible for the metabolism of pterostilbene and to examine gender differences in the glucuronidation of resveratrol and pterostilbene. We demonstrate that UGT1A1 and UGT1A3 are mainly responsible for pterostilbene glucuronidation although UGT1A8, UGT1A9 and UGT1A10 also had detectable activity. Intriguingly, UGT1A1 exhibits the highest activity against both resveratrol and pterostilbene despite altered hydroxyl group specificity. Using pooled human liver microsomes, enzyme kinetics were determined for pterostilbene and resveratrol glucuronides. In all cases females were more efficient than males, indicating potential gender differences in stilbene metabolism. Importantly, the glucuronidation of pterostilbene is much less efficient than that of resveratrol, indicating that pterostilbene will have dramatically decreased metabolism in humans.

In vitro and in vivo preclinical results suggest that inhibition of polyamine synthesis inhibits the progression of prostate cancer. These findings has led to two clinical trials in patients at risk for invasive prostate cancer with difluoromethylornithine which specifically and irreversibly inhibits ornithine decarboxylase which catalyses the conversion of ornithine to putrescine the rate limiting step in polyamines synthesis. We have conducted a phase IIa one month and placebo randomized phase IIb 12 months trials in patients at increased risk for invasive prostate cancer. Favorable reduction in prostate polyamine levels and prostate volume was documented with no difference in clinical hearing changes. Patients with Gleason's VI lesions in a surveillance cohort would be appropriate candidates for a definitive risk reduction trial although the unavailability of validated biomarkers for invasive progression would require a large and lengthy study.

Background: Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood concentrations of long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA] 20:5ω3; 22:5ω3; 22:6ω3]. This case-cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial., Methods: Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided., Results: Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response., Conclusions: This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.

Oral premalignancy serves as an ideal model for study of chemopreventive agents. Although 13-cis-retinoic acid showed reversal of oral premalignancy, toxicity, and reversal of clinical response after cessation of therapy obviated its widespread use. A search for nontoxic agents with cancer preventive activity led us to evaluate Bowman Birk Inhibitor (BBI) formulated as BBI Concentrate (BBIC). We previously reported encouraging results in a phase IIa trial of BBIC in patients with oral leukoplakia with measurable clinical responses and favorable biomarker changes. On the basis of these results, we undertook a randomized, placebo controlled phase IIb trial with patients receiving BBIC or placebo for 6 months, with assessment of clinical response and change in lesion area as primary end point and an intent-to-treat analysis. One hundred and thirty two subjects were randomized; and 89 subjects completed six months on study drug or placebo. Both placebo and BBIC showed a statistically significant decrease in mean lesion area of 17.1% and 20.6%, respectively, and partial or greater clinical responses of 30% and 28% respectively. No significant difference between placebo and study drug arms was observed. Histologic review, review of photographs of lesions, and comparison of serum neu protein and oral mucosal cell protease activity also did not show significant differences between study arms. Probable reasons for these negative results were considered, are discussed, and include a placebo with non-BBIC clinical activity and reduced pharmacokinetic availability of the second batch of BBIC. This experience should be a strong cautionary note to those considering "Green" chemoprevention.

Treatment of metastatic melanoma has long been a challenge because of its resistance to traditional chemotherapeutics, leading to the search for alternative strategies. Aurora kinases are key mitotic regulators that are frequently overexpressed in various cancers including melanoma, making them ideal targets for drug development. Several Aurora kinase inhibitors have been developed and tested preclinically and clinically. PHA-739358 is currently one of the most advanced clinical compounds being tested in phase II clinical trials; however, its antitumor effect has not been tested in melanoma. In this study, the antiproliferative and anti-invasive effects of PHA-739358 were investigated in melanoma cell lines. The results demonstrated that PHA-739358 produces a time-dependent and dose-dependent inhibition of cell proliferation, induction of apoptosis, and inhibition of cell migration. Downregulation of matrix metalloproteinase-2 by the inhibition of NFκB-signaling pathway may contribute to PHA-739358-induced inhibition of migration. Furthermore, PHA-739358 enhanced temozolomide and Plx4032-induced apoptosis. This study suggests that Aurora kinase inhibitors may provide a new strategy for the treatment of advanced melanoma., (© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.)

Using US SEER17 Registry data, age-specific melanoma incidence rates were calculated and comparisons were made between males and females. Relative Risk (RR) for males and females in each age group was computed and compared with that from Nordic Cancer Registry data set and to that for non-melanoma skin cancer (NMSC). For age groups 44 and younger, females showed higher incidence rates, with a peak difference at age 20-24 (RR = 2.01, 95% CI = 1.21-3.33). Males exhibited higher incidence rates after age 44. The same bimodal gender difference was confirmed by the Nordic Cancer Registry data set, but it was not observed for NMSC, which is known to be strongly associated with cumulative exposure to solar UV radiation. We conclude that exposure to solar ultraviolet (UV) radiation is the major causative factor for melanoma at older age (>44 yr), but that other factors may play a role in early onset melanomas, particularly in females., (© 2012 John Wiley & Sons A/S.)

NADPH oxidase 1 (Nox1) is a member of the NADPH oxidase family that has not been well characterized in the melanocytic cell lineage. Here we demonstrated that Nox1 and Nox4 were detected in melanocytic lineage, with only Nox1 detected in normal human melanocytes and Nox4 in a subset of metastatic melanoma cell lines. The protein level and enzymatic activity of Nox1 was elevated in all melanoma cells as compared with normal melanocytes. Overexpression of GFP-Nox1 protein in Wm3211 primary melanoma cells increased invasion rate by 4- to 6-fold as measured by Matrigel invasion assay, whereas knocking down or inhibiting Nox1 decreased invasion by approximately 40-60% in Wm3211 and SK-Mel-28 cells. Matrix metalloproteinase-2 (MMP-2) was increased by Nox1 overexpression at the mRNA, protein, and activity levels, and decreased by Nox1 knockdown. MMP-2 promoter activity was also regulated by Nox1 knockdown. In addition, stable clones overexpressing Nox1 exhibited an epithelial-mesenchymal transition (EMT) as examined by cell morphology and EMT markers; knockdown or inhibiting Nox1 led to a reversal of EMT. Supplementing MMP-2 to culture media did not induce EMT, suggesting that EMT induction by Nox1 was not through MMP-2 upregulation. In summary, Nox1 was overexpressed in all melanoma cell lines examined, and enhanced cell invasion by MMP-2 upregulation and EMT induction.

The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the detoxification of carcinogens as well as clearance of anti-cancer drugs. In humans, 19 UGT family members have been identified and are expressed in a tissue specific manner throughout the body. However, the UGTs have not been previously characterized in melanocytes or melanoma. In the present study, UGT2B7, UGT2B10, and UGT2B15 were identified as being normally expressed in human melanocytes. The same three UGT family members were also expressed in the primary melanoma cell line WM115. No UGT expression was detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line examined. These results suggest that UGT expression is lost during melanoma progression. Treatment of WM3211 or metastatic melanoma cell lines with anti-cancer agents (including vemurafenib) induced expression of UGT2B7, UGT2B10 and UGT2B15 demonstrating that melanoma cells retain the ability to re-express these same three UGTs. The corresponding increase in glucuronidation activity in melanoma cells following anti-cancer treatment was also observed. Furthermore, knockdown of UGT2B7 in WM115 cells sensitized these cells to treatment by adriamycin and epirubicin indicating that UGT2B7 is involved in resistance to these drugs. However, knockdown of UGT2B7 had no effect on temozolomide toxicity. Taken together, these results clearly demonstrate a role for UGTs in melanoma etiology. Since the UGTs are drug metabolism enzymes, we propose that re-expression of the UGTs constitutes a previously unsuspected mechanism for intratumoral drug resistance in melanoma.