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ImportanceSuccessful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.ObjectiveTo compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor–positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of −6%.Design, Setting, and ParticipantsThis multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor–positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021.InterventionsExemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.Main Outcomes and MeasuresSerum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography–tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry.ResultsA total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was −89%, −85%, and −60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was −3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, −5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of −7.5%, −5.0%, and −4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and −17.0%, −9.0%, and −7.0% for progesterone receptor, respectively. Sex hormone–binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms.Conclusions and RelevanceIn this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.Trial RegistrationClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16

553 Background: Low-grade noninvasive (LGTa) bladder cancer is a relatively quiescent but heterogenous malignancy, characterized by downstream recurrences requiring repeated transurethral resections and frequent surveillance. Investigations to elucidate drivers of recurrence have been sparse, but will help risk-stratify patients with LGTa and allow augmentation of follow up protocols. Methods: Patients with LGTa index tumors were stratified by those with no downstream recurrences (nonrecurrent) vs. those with later recurrences (recurrent). RNA sequencing identified differentially expressed genes (DEGs), deconvoluted for cell-type using xCell. Pathologic analysis was performed by a genitourinary pathologist, then a deep-learning artificial intelligence (AI) platform was leveraged to correlate recurrence risk and recurrence-free survival (RFS) based on deep-learning algorithm of segmented nuclei. Results: Thirty index bladder tumors/patients were identified, 18 (60%) of which had later recurrence (Table). There were 238 DEGs recognized, with recurrent tumors expressing signatures for epithelial mesenchymal transition, myogenesis, TNFα signaling via NFκB, and angiogenesis. Recurrent tumors also demonstrated a higher tissue micoenvironment, stroma, and cancer-associated fibroblast score. Pathologic TME analysis validated these findings, with recurrent tumors demonstrating a higher frequency of inverted growth pattern and a higher median stroma percentage. Finally, the AI-derived signature was predictive of recurrence and risk-stratified the cohort (HR= 5.43 [95% CI 1.1-26.76]) for predicting high vs. low risk of recurrence. Patients in the high risk group had a 87.5% recurrence rate while those in the low risk group had a 28.5% recurrence rate (p

Clinical trials play a critical role in evidence-based medicine, when rigorous scientific methodology is utilized to discover and test the effectiveness and safety of new drugs to prevent or cure diseases, including cancer. Participation in clinical trials thus becomes key to successful completion of these trials. Although it is estimated that >70% of Americans are inclined to participate in clinical trials, less than 5% of adult cancer patients participate in clinical trials. There is thus a large gap between those inclined to participate in clinical trials and actual participation in clinical trials. As with trials targeting men with prostate cancer (PCa) on active surveillance (AS), where the target population is mostly over 50 years of age, others have observed several challenges with recruitment and accrual in clinical trials. The participation rate is currently unavailable for men on primary and secondary chemoprevention trials. Additionally, with unanticipated environmental factors such as a pandemic or other natural emergencies that may severely impact the economy, personal property, travel and person-to person contact for study-related procedures, there is a need to continuously identify these challenges and determine solutions to recruitment barriers in chemoprevention trials to ensure timely completion of early phase trials. Recent studies regarding the impact of the pandemic on clinical trial recruitment have shown that cancer prevention trials were relatively more negatively impacted compared to cancer treatment trials. The goal of this manuscript is to review our experience in continuously evaluating the protocol and patient level challenges to recruiting subjects on AS for PCa in this cancer chemoprevention trial conducted at the Comprehensive Cancer Center (CCC) and report the contemporary strategies that we are utilizing to continue to recruit subjects in this trial. We provide data from our current trial as an example while discussing future strategies to improve overall clinical trial recruitment. These strategies can inform future design of contemporary cancer chemoprevention trials and, additionally, better select, focus and invest in strategies that are the most productive and efficient for recruiting target populations.

Background: Tamoxifen uptake for risk reduction has remained low due to concerns about toxicity despite the efficacy and effectiveness data available. Studies of tamoxifen in the adjuvant and preventive setting have demonstrated that a decline in mammographic density (MD) of approximately 10% is consistently associated with better outcomes. Additionally, MD is one of the strongest independent predictors of breast cancer risk, apart from older age and BRCA1/2 mutation, among women. 4-hydroxytamoxifen topical gel (4-OHT) is a transdermal agent, shown in preliminary studies to be well-tolerated with similar decreases in Ki-67 to oral tamoxifen in presurgical DCIS studies and significant drug concentration in breast parenchyma but very low levels in the systemic circulation. This study examines changes in MD, a potential surrogate biomarker of prevention activity, as the primary endpoint for this one-year early-phase prevention trial using 4-OHT gel in high risk women. Trial design: Multicenter, randomized, placebo-controlled study of 4-OHT gel (2mg per breast) versus placebo in 152 women with heterogeneously or extremely dense breast tissue for 12 months using standard of care imaging, stratified by enrollment site and baseline breast density category. The primary objective of this study is to evaluate the change in percent MD (using Cumulus software) from baseline to the week 52 in women applying 4 mg (2mg per breast) 4-OHT gel versus placebo. The secondary objectives are to compare the Cumulus vs Volpara breast density measurement methods; evaluate the percentage of women with lowering of BIRADS density; estimate percentage of women with ≥ 10% absolute decrease in quantitative MD percentage; explore patient reported experience assessed by BESS questionnaire; laboratory toxicity assessment (F VIII, vWB factor, SHBG, lipid profile); compare the 2D vs. 3D breast density measurement methods to estimate percent change in mammographic breast density; evaluate serum measurements of parent drug and related metabolite levels and factors related to 4-OHT exposures, such as IGF pathway members, CRP, estradiol, and 4-OHT; collect tissue for biomarkers (among women undergoing optional pre- and post-treatment biopsies); examine the persistence in change of mammographic density one year after 4-OHT vs. placebo gel application has stopped. Eligibility criteria: Inclusion: Women age 40-69 years, or less than 40 years if 5-year breast cancer Gail risk is greater than/equal to 1.66%; heterogeneously or extremely dense breast tissue based on mammography. Exclusion: abnormal uterine bleeding, or prior diagnosis of endometrial hyperplasia, endometrial polyps, or endometrial cancer; prior use of SERMS and AIs, except for a maximum of 3 months and at least 12 months prior. Statistical methods: Considering an attrition rate of 15%, 128 evaluable women are expected to have both baseline and 52-week measurements of percent MD. With 64 women in each group, there is 80% power to detect a decrease of 6% in the 4-OHT group versus 2% in the placebo group with a common standard deviation of 8% using a two-sided t-test with a significance level of 0.05. Study accrual: Activated January 2018, as of July 1, 2019, 92 patients have been recruited and 79 were randomized. Citation Format: Banu K. Arun, Gretchen Gierach, Marion E Scoggins, Seema Khan, Sandra S Rao, Judy Garber, Sughra Raza, Nagi B. Kumar, Heather H Han, John Heine, Bethany Niell, Pavani Chalasani, Kimberly Fitzpatrick, Lee G Wilke, Amy Fowler, Heather C Beckwith, Carrie Mays, Saba Abutaseh, Lana Vornik, Oukseub Lee, Eileen Dimond, Marjorie Perloff, Diane Liu, J. Jack Lee, Powell Brown, Brandy Heckman-Stoddard. A randomized, double-blind, placebo-controlled study of 4-hydroxytamoxifen topical gel in women with mammographically dense breasts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-15-02.

Background: The aromatase inhibitor exemestane (EXE) has shown to lower cancer incidence in high-risk postmenopausal women. However, undesirable symptoms and side effects (i.e., bone density loss, musculoskeletal ache, climacteric syndrome) may compromise patient motivation and adherence to a long-term preventive treatment. A less frequent drug schedule, compared to the standard regimen, may be more acceptable to healthy at-risk women. We hypothesized that comparison of two alternative less frequent dose regimens with the standard daily dose regimen will show that it is possible to decrease undesirable symptoms of EXE while still effectively reducing serum estradiol. Trial Design: We are conducting a multi-center, pre-surgical, double-blind, non-inferiority phase IIb study in which 180 postmenopausal women will be randomized to receive either EXE 25 mg/day or 25 mg/three times a week or 25 mg/week for 4 to 6 weeks prior to surgery. Surgery will occur on day 29, 36 or 43 after treatment initiation. Eligible subjects are postmenopausal women with histologically-confirmed ER-positive (ER >10%) primary breast cancer candidates for surgery. Participants with T0-2, N0-1, Mx or with larger tumors who refuse neo-adjuvant therapy before surgery are eligible. Subjects are stratified according to participating site and body mass index (25 kg/m2). The primary objective is to assess if the reduction in estradiol with EXE 25 mg/three times a week and EXE 25 mg/week is comparable with the standard dose of 25 mg/day of EXE. Methods: Blood will be collected at baseline and at the end of treatment. Tissue samples will be collected from the diagnostic biopsy and at the time of surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery in the three arms in a CLIA certified laboratory. Given the expected reduction of at least 80% change with EXE at 25 mg daily considered as reference group (control arm) against 25 mg/three times a week or 25 mg weekly, for the power calculation we assume a non-inferiority difference of 6% in percentage changes of circulating estradiol after treatment from baseline, using a one-sided, two-sample t-test. Secondary outcome measures are the incidence of toxicity and menopausal symptoms according to the CTCAE (v4) and by the self-administered MENQoL; the effect of the three regimens on sex hormones (estrone, estrone sulphate, SHBG, testosterone, DHEAS and FSH) and the effect on circulating estradiol levels using an ultrasensitive method given that the serum levels in postmenopausal women under EXE may be very low. Drug and metabolites levels will be measured in blood, cancer tissue and non-cancer tissue. Evaluation of serum insulin, glucose (homeostatic model assessment index), and lipid profile (total cholesterol, high-density lipoprotein cholesterol and triglycerides), leptin and adiponectin will be performed before and after treatment. Additionally, we will measure breast estradiol concentration in cancer and non-cancer tissue and compare changes in ER, PgR, and proliferation in cancer and non-cancer tissue samples obtained at time of biopsy and definitive surgery. Finally, we will also analyze the role of the polymorphic UGT2B17 gene (involved in EXE and 17-dihydroexemestane metabolism) as well as tissue proteomics. Preliminary results: Enrollment started in February 2017 and as of July 3, 2019, a total of 170/180 participants have been randomized (94% of the expected sample size). Preliminary data will be presented at the conference. IND Sponsor: NCI/DCP NCI contract: HHSN26120120034I Citation Format: Aliana Guerrieri-Gonzaga, Parjhitham Thomas, Andrea DeCensi, Katherine D Crew, Nagi Kumar, Sara Gandini, Lana Vornik, Brandy Heckman-Stoddard, Eva Szabo, Eileen Dimond, Jack Lee, Diane Liu, Matteo Lazzeroni, Sara Cagnacci, Davide Serrano, Mauro D'Amico, Flavio Guasone, Tania Buttiron Webber, Powel Brown, Bernardo Bonanni. Alternative dosing of exemestane before surgery in postmenopausal patients with stage 0-II estrogen receptor positive breast cancer: Design and methodology [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-03.

Accumulating evidence supports green tea catechins (GTCs) in chemoprevention for prostate cancer (PCa), a leading cause of cancer morbidity and mortality among men. GTCs include (−)-epigallocatechin-3-gallate, which may modulate the molecular pathways implicated in prostate carcinogenesis. Prior studies of GTCs suggested that they are bioavailable, safe, and effective for modulating clinical and biological markers implicated in prostate carcinogenesis. GTCs may be of particular benefit to those with low-grade PCas typically managed with careful monitoring via active surveillance (AS). Though AS is recommended, it has limitations including potential under-grading, variations in eligibility, and anxiety reported by men while on AS. Secondary chemoprevention of low-grade PCas using GTCs may help address these limitations. When administrated orally, the gut microbiome enzymatically transforms GTC structure, altering its bioavailability, bioactivity, and toxicity. In addition to xenobiotic metabolism, the gut microbiome has multiple other physiological effects potentially involved in PCa progression, including regulating inflammation, hormones, and other known/unknown pathways. Therefore, it is important to consider not only the independent roles of GTCs and the gut microbiome in the context of PCa chemoprevention, but how gut microbes may relate to individual responses to GTCs, which, in turn, can enhance clinical decision-making.

One of the most burdensome symptoms reported by breast cancer patients is chemotherapy-related neurocognitive impairment. It is estimated that of the 11 million cancer survivors in the USA, 22% of them are breast cancer patients. The National Cancer Institute classified chemotherapy-related cognitive impairment (CRCI) as one of the most debilitating sequelae of cancer therapy, limiting this patient population from recommencing their lives prior to the diagnosis of breast cancer. Currently, there are no strategies that are established to prevent, mitigate, or treat CRCI. In addition to surviving cancer, quality of life is critical to cancer survivors. Based on the multiple and complex biological and psychosocial etiology, the varying manifestation and extent of cognitive decline documented in breast cancer survivors, possibly attributed to varying combinations of chemotherapy and dose and duration of therapy, multimodal interventions combining promising nutrient-derived bioactive compounds with antioxidant and anti-inflammatory properties, in addition to structured cognitive training and exercise regimens, can work synergistically to reduce inflammation and oxidative stress with significant improvement in cognitive function resulting in improvements in quality of life of breast cancer survivors.

519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

Background: Well-annotated, high-quality biorepositories provide a valuable platform to support translational research. However, most biorepositories have poor representation of minority groups, limiting the ability to address health disparities. Methods: We describe the establishment of the Florida Pancreas Collaborative (FPC), the first state-wide prospective cohort study and biorepository designed to address the higher burden of pancreatic cancer (PaCa) in African Americans (AA) compared to Non-Hispanic Whites (NHW) and Hispanic/Latinx (H/L). We provide an overview of stakeholders, study eligibility and design, recruitment strategies, standard operating procedures to collect, process, store, and transfer biospecimens, medical images, and data, our cloud-based data management platform, and progress regarding recruitment and biobanking. Results: The FPC consists of multidisciplinary teams from fifteen Florida medical institutions. From March 2019 through August 2020, 350 patients were assessed for eligibility, 323 met inclusion/exclusion criteria, and 305 (94%) enrolled, including 228 NHW, 30 AA, and 47 H/L, with 94%, 100%, and 94% participation rates, respectively. A high percentage of participants have donated blood (87%), pancreatic tumor tissue (41%), computed tomography scans (76%), and questionnaires (62%). Conclusions: This biorepository addresses a critical gap in PaCa research and has potential to advance translational studies intended to minimize disparities and reduce PaCa-related morbidity and mortality.

BackgroundWell-annotated, high-quality biorepositories provide a valuable platform to support translational research and discovery. However, most biorepositories have poor representation of minority groups, limiting the ability to address cancer health disparities and improve disease outcomes. This report describes the establishment of the Florida Pancreas Collaborative (FPC), the first state-wide prospective longitudinal cohort study and biorepository specifically designed to address the higher burden of pancreatic cancer (PaCa) in African Americans (AA) compared to Non-Hispanic Whites (NHW) and Hispanic/Latinx (H/L).MethodsWe describe rationale for establishing the FPC and provide an overview of key stakeholders; study eligibility and design; ascertainment and recruitment strategies; and standard operating procedures (SOPs) developed to collect, process, store, and transfer biospecimens, medical images, and data. We also describe the customized cloud-based, secure data management platform built to facilitate recruitment, track study-related workflow, house data, and perform queries. We also present progress to date regarding recruitment and biobanking.ResultsThe FPC consists of multidisciplinary teams from fifteen Florida medical institutions. From March 2019 through August 2020, 350 patients were assessed for study eligibility, 323 met inclusion/exclusion criteria, and 305 (94%) enrolled, including 228 NHW, 30 AA, and 47 H/L, with 94%, 100%, and 94% participation rates, respectively. A high percentage of participants have donated blood (87%), pancreatic tumor tissue (41%), computed tomography scans (76%), and baseline questionnaire data (62%).ConclusionsThis biorepository addresses a critical gap in PaCa research with the potential to advance basic, clinical, population-based, and translational studies intended to minimize disparities, increase quality of life, and reduce PaCa-related morbidity and mortality.ImpactThis multi-institutional infrastructure can serve as a prototype for development of similar resources across the country and disease sites.

// Nagi B. Kumar 1 , Angelina Fink 1 , Silvina Levis 3 , Ping Xu 2 , Roy Tamura 2 and Jeffrey Krischer 2 1 H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA 2 Geriatric Research, Education and Clinical Center, Miami Veterans Affairs Medical Center, Miami, FL 33125, USA 3 Pediatrics Epidemiology Center at University of South Florida, Health Informatics Institute, Tampa, FL 33612, USA Correspondence to: Nagi B. Kumar, email: nagi.kumar@moffitt.org Keywords: thyroid function; fatigue; hypothyroidism; subclinical hypothyroidism; breast cancer Received: March 15, 2018 Accepted: April 27, 2018 Published: May 22, 2018 ABSTRACT Background: Cancer related fatigue (CRF), reported in about 90% of breast cancer patients receiving chemotherapy, and has a profound impact on physical function, psychological distress and quality of life. Although several etiological factors such as anemia, depression, chronic inflammation, neurological pathology and alterations in metabolism have been proposed, the mechanisms of CRF are largely unknown. Methods: We conducted a pilot, prospective, case-control study to estimate the magnitude of change in thyroid function in breast cancer patients from baseline to 24 months, compared to cancer-free, age-matched controls. Secondary objectives were to correlate changes in thyroid function and obesity over time with fatigue symptoms scores in this patient population. Results: The proportion of women with breast cancer who developed subclinical or overt hypothyroidism (TSH >4.0 mIU/L) from baseline to year 1 was significantly greater compared to controls (9.6% vs. 5%; p=0.02). Subjects with breast cancer reported significantly worse fatigue symptoms than age-matched controls, as indicated by higher disruption indices (p 30. Conclusion: Screening breast cancer patients for thyroid function status at baseline and serially post-treatment to evaluate the need for thyroid hormone replacement may provide for a novel strategy for treating chemotherapy-induced fatigue.

On November 3, 2014, in Bethesda, MD, the Office of Cancer Complementary and Alternative Medicine of the National Cancer Institute held a meeting to examine the potential utility and feasibility of establishing an international consortium for Chinese medicine and cancer. There is significant interest in the West in using components of Chinese medicine (CM) —such as botanicals and herbal medicines, acupuncture and acupressure, and qigong—in the field of oncology, as potential anticancer agents, for symptom management, and to improve quality of life. The proposal for a consortium on CM came from the Chinese Academy of Chinese Medical Sciences, with the aims of improving scientific communications and collaborations and modernizing the studies of CM for cancer. The US National Cancer Institute’s Office of Cancer Complementary and Alternative Medicine agreed to work with Chinese Academy of Chinese Medical Sciences to explore the feasibility of establishing an international consortium for Chinese medicine and cancer. At the meeting, participants from the United States, China, Canada, Australia, and Korea discussed issues in CM and cancer research, treatment, and management, including potential mechanisms of action, proof of efficacy, adverse effects, regulatory issues, and the need for improving the quality of randomized clinical trials of CM treatments and supportive care interventions. Presented in these proceedings are some of the main issues and opportunities discussed by workshop participants.

Author(s): Guerrieri-Gonzaga, Aliana; Serrano, Davide; Thomas, Parjhitham; Crew, Katherine D; Kumar, Nagi B; Gandini, Sara; Vornik, Lana A; Lee, Jack; Cagnacci, Sara; Vicini, Elisa; Accornero, Chiara A; D'Amico, Mauro; Guasone, Flavio; Spinaci, Stefano; Webber, Tania B; Brown, Powel H; Szabo, Eva; Heckman-Stoddard, Brandy; Bonanni, Bernardo | Abstract: IntroductionAromatase inhibitors are effective in lowering breast cancer incidence among postmenopausal women, but adverse events represent a barrier to their acceptability and adherence as a preventive treatment. This study aims to assess whether lowering exemestane schedule may retain biological activity while improving tolerability in breast cancer patients.Methods/designWe are conducting a, pre-surgical, non-inferiority phase IIb study in postmenopausal women with newly diagnosed estrogen receptor-positive breast cancer. Participants are randomized to receive either exemestane 25nmg/day or 25nmg/three times-week or once a week for 4 to 6nweeks prior to surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery comparing the three arms. Sample size of 180 women was calculated assuming a 6% non-inferiority of the percent change of estradiol in the lower dose arms compared with the 80% decrease predicted in the full dose arm, with 80% power and using a one-sided 5% significance level and a two-sample t-test. Main secondary outcomes are: safety; change in Ki-67 in cancer and adjacent pre-cancer tissue, circulating sex hormones, adipokines, lipid profile, insulin and glucose changes, in correlation with drug and metabolites concentrations.Results and discussionThe present paper is focused on methodology and operational aspects of the study. A total of 180 participants have ben enrolled. The trial is still blinded, and the analyses are ongoing. Despite the short term duration, results may have relevant implications for clinical management of women at increased risk of developing a ER positive breast cancer.

Previous research has shown that nutrition can influence cognitive abilities in older adults. We examined whether nutritional factors or inflammatory biomarkers moderate the age-cognition association.Analyses included 1,308 participants (age ≥60) from the National Health and Nutrition Examination Survey III. Macronutrients (% of calories from fat, protein, and carbohydrates), micronutrients/amino acids (blood serum values: Vitamins B12, C, D, E, folate, iron, homocysteine, and β-carotene), and inflammatory biomarkers (serum C-reactive protein, plasma fibrinogen, and serum ferritin) were examined as moderators with cognition. Cognition was measured by six tasks: immediate and delayed story recall, immediate and delayed word memory, digit subtraction, and questions about place/orientation.Higher values of serum folate were significantly associated with better cognitive scores. Specifically, the interaction between age-cognition and folate indicated the associations of higher age and lower global cognition and lower immediate story recall were weaker in those with higher folate values (p's.05). A significant interaction between age and plasma fibrinogen indicated that the association between age and worse digit subtraction was stronger with values3.1 g/L.Folate and fibrinogen were significant moderators between age and cognition. Further research into the relationship between nutrition, inflammation, and cognitive aging is needed.

// Andrew Leone 1 , Gregory Diorio 1 , Wade Sexton 1 , Michael Schell 2 , Mark Alexandrow 3 , Jed W. Fahey 4 and Nagi B. Kumar 5 1 Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Inc., Tampa, FL, USA 2 Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Inc., Tampa, FL, USA 3 Cancer Biology and Evolution, H. Lee Moffitt Cancer Center & Research Institute, Inc., Tampa, FL, USA 4 Clinical Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, USA 5 Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Inc., Tampa, FL, USA Correspondence to: Nagi B. Kumar, email: // Keywords : sulforaphane, bladder cancer, chemoprevention, safety, toxicity Received : October 21, 2016 Accepted : February 22, 2017 Published : March 08, 2017 Abstract The clinical course for both early and late stage Bladder Cancer (BC) continues to be characterized by significant patient burden due to numerous occurrences and recurrences requiring frequent surveillance strategies, intravesical drug therapies, and even more aggressive treatments in patients with locally advanced or metastatic disease. For these reasons, BC is also the most expensive cancer to treat. Fortunately, BC offers an excellent platform for chemoprevention interventions with potential to optimize the systemic and local exposure of promising agents to the bladder mucosa. However, other than smoking cessation, there is a paucity of research that systematically examines agents for chemoprevention of bladder cancers. Adopting a systematic, molecular-mechanism based approach, the goal of this review is to summarize epidemiological, in vitro , and preclinical studies, including data regarding the safety, bioavailability, and efficacy of agents evaluated for bladder cancer chemoprevention. Based on the available studies, phytochemicals, specifically isothiocyanates such as sulforaphane, present in Brassicaceae or “cruciferous” vegetables in the precursor form of glucoraphanin are: (a) available in standardized formulations; (b) bioavailable- both systemically and in the bladder; (c) observed to be potent inhibitors of BC carcinogenesis through multiple mechanisms; and (d) without toxicities at these doses. Based on available evidence from epidemiological, in vitro , preclinical, and early phase trials, phytochemicals, specifically isothiocyanates (ITCs) such as sulforaphane (SFN) represent a promising potential chemopreventitive agent in bladder cancer.

Prostate cancer (PCa) is the most common cancer in American men. Additionally, African American Men (AAM) are 60% more likely to be diagnosed with PCa and 2.4 times more likely to die from this disease compared to Caucasian men (CM). To date, there are few strategies effective for chemoprevention for men with localized PCa. There is thus a need to continue to evaluate agents and strategies for chemoprevention of prostate cancer. Epidemiological, laboratory and early phase clinical trials have shown that the isoflavones modulates several biomarkers implicated in prostate carcinogenesis. The goal of this phase II randomized clinical trial was to explore the comparative effectiveness and safety of 40 mgs of aglycone isoflavones in AAM and CM with localized PCa in the pre-surgical period prior to radical prostatectomy. Thirty six participants (25 CM, 6AAM) were randomized to the isoflavone arm and 34 (25 CM, 7AAM) to the placebo arm, with 62 completing the intervention. Results indicated that isoflavones at a dose of 20 mgs BID for 3-6 weeks was well tolerated but did not reduce tissue markers of proliferation. A significant reduction in serum PSA was observed with isoflavone supplementation in CM compared to the placebo arm, but not observed in AAM. We observed no changes in serum steroid hormones with isoflavone supplementation. In AAM, a reduction in serum IGF-1 concentrations and IGF1: IGFBP-3 ratios were observed with isoflavone supplementation. Well-powered studies for longer duration of intervention may inform future trials with isoflavones, for chemoprevention of PCa.

There has been an increasing interest in using complementary and alternative medicine (CAM) approaches to treat cancer. It is therefore relevant and timely to determine if CAM biomarkers can be identified and developed to guide cancer diagnosis and treatment. Herein, we review the status of cancer biomarkers in CAM research and treatment to stimulate further research in this area. Studies on promising anti-cancer natural products, such as PHY906, honokiol, bryostatin-1, and sulforaphane have demonstrated the existence of potential cancer biomarker(s). Additional studies are required to further develop and ultimately validate these biomarkers that can predict clinical activity of the anti-cancer natural products used alone or in combination with chemotherapeutic agents. A systematic approach is needed to identify and develop CAM treatment associated biomarkers and to define their role in facilitating clinical decision-making. The expectation is to use these biomarkers in determining potential options for CAM treatment, examining treatment effects and toxicity and/or clinical efficacy in patients with cancer.

Background Recommendations for cancer screening are uncertain for the early detection or prevention of prostate cancer in African American men. Thus, chemoprevention strategies are needed to specifically target African American men. Methods The evidence was examined on the biological etiology of disparities in African Americans related to prostate cancer. Possible chemopreventive agents and biomarkers critical to prostate cancer in African American men were also studied. Results High-grade prostatic intraepithelial neoplasia may be more prevalent in African American men, even after controlling for age, prostate-specific antigen (PSA) level, abnormal results on digital rectal examination, and prostate volume. Prostate cancer in African American men can lead to the overexpression of signaling receptors that may mediate increased proliferation, angiogenesis, and decreased apoptosis. Use of chemopreventive agents may be useful for select populations of men. Conclusions Green tea catechins are able to target multiple pathways to address the underlying biology of prostate carcinogenesis in African American men, so they may be ideal as a chemoprevention agent in these men diagnosed with high-grade prostatic intraepithelial neoplasia.

// Nagi B. Kumar 1, 2 , Julio Pow-Sang 2 , Philippe E. Spiess 2 , Jong Park 1 , Raoul Salup 3 , Christopher R. Williams 4 , Howard Parnes 5 , Michael J. Schell 6 1 H. Lee Moffitt Cancer Center & Research Institute, Inc., Cancer Epidemiology, Tampa, FL 33612-9497, USA 2 H. Lee Moffitt Cancer Center & Research Institute, Inc., Genitourinary Oncology, Tampa, FL 33612-9497, USA 3 University of South Florida College of Medicine, Urology, Tampa, FL 33612, USA 4 University of Florida – Jacksonville, UF Health Jacksonville, Urologic Oncology, Jacksonville, FL 32209, USA 5 National Cancer Institute, Division of Cancer Prevention, Bethesda, MD 20892, USA 6 Moffitt Cancer Center & Research Institute, Inc., Biostatistics and Bioinformatics, Tampa, FL 33612-9497, USA Correspondence to: Nagi B. Kumar, email: Nagi.Kumar@Moffitt.org Keywords: green tea, catechins, safety, prostate cancer Received: April 27, 2016 Accepted: September 13, 2016 Published: September 23, 2016 ABSTRACT Purpose: Although preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk, several preclinical studies and case reports have reported liver toxicities and acute gastrointestinal bleeding. Based on these observations, regulatory bodies have required stringent inclusion criteria with frequent, excessive toxicity monitoring and early stopping rules in clinical trials. These requirements have impeded recruitment and retention of subjects in chemoprevention trials and subsequent progress in agent development efforts. Experimental Design: We conducted a placebo-controlled, randomized clinical trial of Polyphenon E® (PolyE®), a proprietary mixture of decaffeinated GTCs, containing 400 mg (−)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). PolyE® containing 200 mg EGCG was administered with food, BID. A secondary study endpoint in this trial was a comparison of the overall one-year treatment related adverse events and grade 3 or higher adverse event on the two study arms. Monthly assessments of toxicity (CTCAE 4.0), concomitant medications and organ function, including hepatic panel, PT/PTT and LDH, were performed. Results: Daily intake of a standardized, decaffeinated, catechin mixture containing 200 mg EGCG BID taken with food for 1 year accumulated in plasma and was well tolerated and did not produce treatment related adverse effects in men with baseline HGPIN or ASAP. Conclusion: The current data provides evidence of safety of decaffeinated, catechin mixture containing 200 mg EGCG BID to be further tested for prostate cancer prevention or other indications.

// Nagi B. Kumar 1 , Shohreh I. Dickinson 2 , Michael J. Schell 3 , Brandon J. Manley 4 , Michael A. Poch 4 and Julio Pow-Sang 4 1 H. Lee Moffitt Cancer Center & Research Institute, Inc., Cancer Epidemiology, MRC/CANCONT, Tampa, FL 33612-9497, USA 2 H. Lee Moffitt Cancer Center & Research Institute, Inc., Pathology Anatomic MMG, WCB-GU PROG, Tampa, FL 33612-9497, USA 3 H. Lee Moffitt Cancer Center & Research Institute, Inc., Biostatics and Bioinformatics, MRC-BIOSTAT, Tampa, FL 33612-9497, USA 4 H. Lee Moffitt Cancer Center & Research Institute, GU Oncology MMG, Tampa, FL 33612-9497, USA Correspondence to: Nagi B. Kumar, email: nagi.kumar@moffitt.org Keywords: chemoprevention; prostate cancer; active surveillance; green tea catechins; prostate cancer progression Received: October 03, 2018 Accepted: December 10, 2018 Published: December 28, 2018 ABSTRACT Background: Active surveillance (AS) has evolved as a management strategy for men with low grade prostate cancer (PCa). However, these patients report anxiety, doubts about the possible progression of the disease as well as higher decisional conflict regarding selection of active surveillance, and have been reported to ultimately opt for treatment without any major change in tumor characteristics. Currently, there is a paucity of research that systematically examines alternate strategies for this target population. Methods: We conducted a review the evidence from epidemiological, in vitro , preclinical and early phase trials that have evaluated green tea catechins (GTC) for secondary chemoprevention of prostate cancer, focused on men opting for active surveillanceof low grade PCa. Results: Results of our review of the in vitro , preclinical and phase I-II trials, demonstrates that green tea catechins (GTC) can modulate several relevant intermediate biological intermediate endpoint biomarkers implicated in prostate carcinogenesis as well as clinical progression of PCa, without major side effects. Discussion: Although clinical trials using GTC have been evaluated in early phase trials in men diagnosed with High-Grade Prostatic Intraepithelial Neoplasia, Atypical Small Acinar Proliferation and in men with localized disease before prostatectomy, the effect of GTC on biological and clinical biomarkers implicated in prostate cancer progression have not been evaluated in this patient population. Conclusion: Results of these studies promise to provide a strategy for secondary chemoprevention, reduce morbidities due to overtreatment and improve quality of life in men diagnosed with low-grade PCa.

Therapies originating from traditional medical systems are widely used by patients in both India and the United States. The first India-US Workshop on Traditional Medicine was held in New Delhi, India, on March 3 and 4, 2016, as a collaboration between the Ministry of Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homoeopathy (AYUSH) of the Government of India, the US National Cancer Institute (NCI), National Institutes of Health, and the Office of Global Affairs, US Department of Health and Human Services. It was attended by Indian and US policymakers, scientists, academics, and medical practitioners from various disciplines. The workshop provided an opportunity to open a dialogue between AYUSH and NCI to identify promising research results and potential topics for Indo-US collaboration. Recommendations that emerged from the workshop underlined the importance of applying rational and scientific approaches for drug development; standardizing traditional medicine products and procedures to ensure reliability and reproducibility; promotion of collaboration between Indian traditional medicine practitioners and researchers and US researchers; greater integration of evidence-based traditional medicine practices with mainstream medical practices in India; and development of training programs between AYUSH and NCI to facilitate crosstraining. Several positive developments took place after the thought-provoking deliberations.

Gliomas are a highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. Although the current WHO grading system (2016) demonstrates promise towards identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. With several molecular and metabolic pathways implicated in the carcinogenesis of CNS tumors, including glioma, we postulate that a systemic, broad spectrum approach to produce robust targeting of relevant and multiple molecular and metabolic regulation of growth and survival pathways, critical to the modulation of hallmarks of carcinogenesis, without clinically limiting toxicity, may provide a more sustained impact on clinical outcomes compared to the modalities of treatment evaluated to date. The objective of this review is to examine the emerging hallmark of reprogramming energy metabolism of the tumor cells and the tumor microenvironment during carcinogenesis, and to provide a rationale for exploiting this hallmark and its biological capabilities as a target for secondary chemoprevention and treatment of glioma. This review will primarily focus on interventions to induce ketosis to target the glycolytic phenotype of many cancers, with specific application to secondary chemoprevention of low grade glioma- to halt the progression of lower grade tumors to more aggressive subtypes, as evidenced by reduction in validated intermediate endpoints of disease progression including clinical symptoms.

Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate cancer. The discussion highlights key findings from previous studies, which reported the role of miRNAs in risk and progression of prostate cancer, providing an understanding of the influence of miRNA on prostate cancer. Our review indicates that somewhat consistent results exist between these studies and reports on several prostate cancer related miRNAs. Present promising candidates are miR-1, -21, 106b, 141, -145, -205, -221, and -375, which are the most frequently studied and seem to be the most promising for diagnosis and prognosis for prostate cancer. Nevertheless, the findings from previous studies suggest miRNAs may play an important role in the risk and progression of prostate cancer as promising biomarkers.

Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer. Cancer Prev Res; 7(4); 435–44. ©2014 AACR.

// Nagi B. Kumar 1 , Roshni Patel 1 , Julio Pow-Sang 2 , Philippe E. Spiess 2 , Raoul Salup 3 , Christopher R. Williams 4 and Michael J. Schell 5 1 H. Lee Moffitt Cancer Center and Research Institute, Inc., MRC/CANCONT, Tampa, FL 33612, USA 2 H. Lee Moffitt Cancer Center and Research Institute, Inc., WCB-GU PROG, Tampa, FL 33612, USA 3 James A Haley Veterans Hospital, Tampa, FL 33612, USA 4 Urologic Oncology, Research, and Robotic Surgery, University of Florida and Shands Medical Center, Jacksonville, FL 32209, USA 5 H. Lee Moffitt Cancer Center and Research Institute, Inc., MRC/BIOSTAT, Tampa, FL 33612, USA Correspondence to: Nagi B. Kumar, email: nagi.kumar@moffitt.org Keywords: green tea catechins, prostate cancer risk, obesity, body mass index and abdominal obesity Received: November 16, 2016 Accepted: June 03, 2017 Published: June 29, 2017 ABSTRACT Background: Evidence continues to demonstrate the role of obesity in prostate carcinogenesis and prognosis, underscoring the need to identify and continue to evaluate the effective interventions to reduce obesity in populations at high risk. The aim of the study was to determine the effect of daily consumption of decaffeinated green tea catechins (GTC) formulation (Polyphenon E ® (PolyE)) for 1 year on biomarkers of obesity in men who are at high risk for prostate cancer. Materials and Methods: A randomized, double-blinded trial was conducted targeting 97 men diagnosed with HGPIN or ASAP. Subjects were randomized to receive GTC (PolyE) ( n = 49) or placebo ( n = 48) for 1 year. Anthropometric data were collected at baseline, 6 and 12 months and data analyzed to observe change in weight, body mass index (indicator of obesity) and waist: hip ratio (indicator of abdominal obesity). Results: Decaffeinated GTC containing 400 mgs of the bioactive catechin, EGCG administered for 1 year to men diagnosed with ASAP and HGPIN appears to be bioavailable, well tolerated but not effective in reducing biomarkers of obesity including body weight, body mass index and waist: hip ratio. Conclusions: The results of our trial demonstrates that men who are obese and at high risk for prostate cancer should resort to effective weight management strategies to reduce obesity and not resort to ineffective measures such as taking supplements of green tea to reduce biomarkers of obesity. Changes in body mass index and abdominal obesity seen in other studies were potentially due to caffeine and not GTC.

Prostate cancer is the most frequently diagnosed malignancy in men. However, African American / Black men are 60% more likely to be diagnosed with and 2.4 times more likely to die from prostate cancer, compared to Non-Hispanic White men. Despite the increased burden of this particular malignancy, no evidence-based recommendation regarding prostate cancer screening exists for the high risk population. Moreover, in addition to screening and detection, high-risk African American men may constitute a prime population for chemoprevention. Early detection and chemoprevention may thus represent an integral part of prostate cancer control in this population. Importantly, recent research have elucidated biological differences in the prostate tumors of African American compared to European American men,. The latter may enable a more favorable response in African American men to specific chemopreventive agents that target relevant signal transduction pathways. Based on this evolving evidence, the aims of this review are three-fold. First, we aim to summarize the biological differences that were reported in the prostate tumors of African American and European American men. Second, we will review the single and multi target chemopreventive agents placing specific emphasis on targeting the pathways implicated in prostate carcinogenesis. And lastly, we will discuss the most promising multi-target nutraceutical chemopreventive compounds. Our review underscores the promise of chemoprevention in prostate cancer control, as well as provides justification for further growth and investment in this filed to ultimately reduce prostate cancer morbidity and mortality in this high risk population of African American men.

With the evolving evidence of the promise of botanicals/biologics for cancer chemoprevention and treatment, an Indo-U.S. collaborative Workshop focusing on “Accelerating Botanicals Agent Development Research for Cancer Chemoprevention and Treatment” was conducted at the Moffitt Cancer Center, 29–31 May 2012. Funded by the Indo-U.S. Science and Technology Forum, a joint initiative of Governments of India and the United States of America and the Moffitt Cancer Center, the overall goals of this workshop were to enhance the knowledge (agents, molecular targets, biomarkers, approaches, target populations, regulatory standards, priorities, resources) of a multinational, multidisciplinary team of researcher's to systematically accelerate the design, to conduct a successful clinical trials to evaluate botanicals/biologics for cancer chemoprevention and treatment, and to achieve efficient translation of these discoveries into the standards for clinical practice that will ultimately impact cancer morbidity and mortality. Expert panelists were drawn from a diverse group of stakeholders, representing the leadership from the National Cancer Institute's Office of Cancer Complementary and Alternative Medicine (OCCAM), NCI Experimental Therapeutics (NExT), Food and Drug Administration, national scientific leadership from India, and a distinguished group of population, basic and clinical scientists from the two countries, including leaders in bioinformatics, social sciences, and biostatisticians. At the end of the workshop, we established four Indo-U.S. working research collaborative teams focused on identifying and prioritizing agents targeting four cancers that are of priority to both countries. Presented are some of the key proceedings and future goals discussed in the proceedings of this workshop.

Multiple studies from independent groups find evidence for signal transducer and activator of transcription 3 (Stat3) activation in nearly 50% of lung cancers, suggesting a functional role for this target in subsets of lung cancer. On the basis of the existing evidence, we hypothesized that bioavailable curcuminoid complex may modulate lung carcinogenesis, primarily by inhibiting Stat3 activation. With the safety of this being botanically well established, the objective of these studies was to test our hypothesis in vitro and in vivo in an effort to inform the design of a phase II chemoprevention trial in former smokers. We treated non-tumor-derived, normal (but immortalized) human bronchial epithelial cells (AALE) (Lundberg et al., 2002; Pillai et al., 2011) and lung adenocarcinoma-derived cells (H441) with bioactive curcumin C3 complex. Asynchronous cells in each case were treated with curcumin for 24 h, followed by immunoblotting for Stat3 and activated Stat3-P, prior signal of which was used for normalization. We also completed a preclinical trial in which 12 mice were randomly divided into three groups and subjected to 3 days or 9 days of curcumin intraperitoneal injections, followed by analysis of lung tissues for Stat3-P changes and growth suppressive effects of the curcumin. The growth suppressive effects were measured using Cyclin D1 and the replicative helicase subunit, Mcm2, as surrogates for the proliferative capacity of the tissues. In-vitro studies with curcuminoid complex demonstrated that the activity of Stat3 in both normal bronchoepithelial cells and lung cancer-derived cells is sensitive to curcumin exposure. In a dose-dependent manner, curcumin treatment resulted in significant suppression of Stat3 phosphorylation and reduction in the proliferative capacity of both cell types. In the preclinical trial with rodent models, curcumin reduced Stat3-P and the proliferative markers CycD1 and Mcm2 in mice lung tissues in vivo. These culture and preclinical studies indicate that the activity of the Stat3 pathway can be suppressed by curcumin treatment, concomitant with a reduction in cell proliferation, supporting our hypothesis that inhibition of the Stat3 pathway represents at least one important mechanism by which curcumin elicits its effects on the bronchoepithelium. These data provide a rationale for the use of curcumin as a promising chemopreventive agent in high-risk populations such as former smokers.

The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer.We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure -related barriers impacting accrual and revisions to protocol implemented.Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety-four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies.A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials.

Under a Creative Commons license.-- Review.-- et al., Targeted therapies and the consequent adoption of >personalized> oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity >broad-spectrum> therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered., Amr Amin was funded by Terry Fox Foundation Grant # TF-13-20 and UAEU Program for Advanced Research (UPAR) #31S118; Jack Arbiser was funded by NIHAR47901; Alexandra Arreola was funded by NIH NRSA Grant F31CA154080; Alla Arzumanyan was funded by NIH (NIAID) R01: Combination therapies for chronic HBV, liver disease, and cancer (AI076535); Work in the lab of Asfar S. Azmi is supported by NIH R21CA188818 as well as from Sky Foundation Inc. Michigan; Fabian Benencia was supported by NIH Grant R15 CA137499-01; Alan Bilsland was supported by the University of Glasgow, Beatson Oncology Centre Fund, CRUK (www.cancerresearchuk.org) Grant C301/A14762; Amancio Carnero was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-6844 and CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012). His work on this project has also been made possible thanks to the Grant PIE13/0004 co-funded by the ISCIII and FEDER funds; Stephanie C. Casey was supported by NIH Grant F32CA177139; Mrinmay Chakrabarti was supported by the United Soybean Board; Rupesh Chaturvedi was supported by an NIH NCCAM Grant (K01AT007324); Georgia Zhuo Chen was supported by an NIH NCI Grant (R33 CA161873-02); Helen Chen acknowledges financial support from the Michael Cuccione Childhood Cancer Foundation Graduate Studentship; Sophie Chen acknowledges financial support from the Ovarian and Prostate Cancer Research Trust, UK; Yi Charlie Chen acknowledges financial support from the West Virginia Higher Education Policy Commission/Division of Science Research, his research was also supported by NIH grants (P20RR016477 and P20GM103434) from the National Institutes of Health awarded to the West Virginia IDeA Network of Biomedical Research Excellence; Maria Rosa Ciriolo was partially supported by the Italian Association for Cancer Research (AIRC) Grants #IG10636 and #15403; Helen M. Coley acknowledges financial support from the GRACE Charity, UK and the Breast Cancer Campaign, UK; Marisa Connell was supported by a Michael Cuccione Childhood Cancer Foundation Postdoctoral Fellowship; Sarah Crawford was supported by a research grant from Connecticut State University; Charlotta Dabrosin acknowledges financial support from the Swedish Research Council and the Swedish Research Society; Giovanna Damia gratefully acknowledges the generous contributions of The Italian Association for Cancer Research (IG14536 to G.D.), Santanu Dasgupta gratefully acknowledges the support of the University of Texas Health Science Centre at Tyler, Elsa U. Pardee Foundation; William K. Decker was supported in part by CPRIT, the Cancer Prevention and Research Institute of Texas; Anna Mae E. Diehl was supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA), Gilead and Shire Pharmaceuticals; Q. Ping Dou was partially supported by NIH/NCI (1R01CA20009, 5R01CA127258-05 and R21CA184788), and NIH P30 CA22453 (to Karmanos Cancer Institute); Janice E. Drew was supported by the Scottish Government's Rural and Environment Science and Analytical Services Division; Eyad Elkord thanks the National Research Foundation, United Arab Emirates University and the Terry Fox Foundation for supporting research projects in his lab; Bassel El-Rayes was supported by Novartis Pharmaceutical, Aveo Pharmaceutical, Roche, Bristol Myers Squibb, Bayer Pharmaceutical, Pfizer, and Kyowa Kirin; Mark A. Feitelson was supported by NIH/NIAID Grant AI076535, Dean W. Felsher was supported by NIH grants (R01CA170378, U54CA149145, and U54CA143907); Lynnette R Ferguson was financially supported by the Auckland Cancer Society and the Cancer Society of New Zealand; Gary L. Firestone was supported by NIH Public Service Grant CA164095 awarded from the National Cancer Institute; Christian Frezza “would like to acknowledge funding from a Medical Research Council CCU-Program Grant on cancer metabolism, and a unique applicant AICR project grant”; Mark M. Fuster was supported by NIH Grant R01-HL107652; Alexandros G. Georgakilas was supported by an EU Marie Curie Reintegration Grant MC-CIG-303514, Greek National funds through the Operational Program ‘Educational and Lifelong Learning of the National Strategic Reference Framework (NSRF)-Research Funding Program THALES (Grant number MIS 379346) and COST Action CM1201 ‘Biomimetic Radical Chemistry’; Michelle F. Green was supported by a Duke University Molecular Cancer Biology T32 Training Grant; Brendan Grue was supported by a National Sciences Engineering and Research Council Undergraduate Student Research Award in Canada; Dorota Halicka was supported by by NIH NCI grant NCI RO1 28704; Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, by the Czech Science Foundation projects 15-03834Y and P301/12/1686, by the Czech Health Research Council AZV project 15-32432A, and by the Internal Grant Agency of the Ministry of Health of the Czech Republic project NT13663-3/2012; Matthew D. Hirschey wishes to acknowledge Duke University Institutional Support, the Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research supported by the National Institute of Aging (P30AG028716-01) and NIH/NCI training grants to Duke University (T32-CA059365-19 and 5T32-CA059365), Lorne J. Hofseth was supported by NIH grants (1R01CA151304, 1R03CA1711326, and 1P01AT003961); Kanya Honoki was supported in part by the grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 24590493); Hsue-Yin Hsu was supported in part by grants from the Ministry of Health and Welfare (CCMP101-RD-031 and CCMP102-RD-112) and Tzu-Chi University (61040055-10) of Taiwan; Lasse D. Jensen was supported by Svenska Sallskapet for Medicinsk Forskning, Gosta Fraenkels Stiftelse, Ak.e Wibergs Stiftelse, Ollie och Elof Ericssons Stiftelse, Linkopings Universitet and the Karolinska Institute, Sweden; Wen G. Jiang wishes to acknowledge the support by Cancer Research Wales, the Albert Hung Foundation, the Fong Family Foundation, and Welsh Government A4B scheme; Lee W. Jones was supported in part by grants from the NIH NCI; W Nicol Keith was supported by the University of Glasgow, Beatson Oncology Centre Fund, CRUK (www.cancerresearchuk.org) Grant C301/A14762; Sid P. Kerkar was supported by the NIH Intramural Research Program; Rob J. Kulathinal was supported by the National Science Foundation, and the American Cancer Society; Byoung S. Kwon was supported in part by National Cancer Center (NCC-1310430-2) and National Research Foundation (NRF-2005-0093837); Anne Le was supported by Sol Goldman Pancreatic Cancer Research Fund Grant 80028595, a Lustgarten Fund Grant 90049125 and Grant NIHR21CA169757 (to Anne Le); Michael A. Lea was funded by the The Alma Toorock Memorial for Cancer Research; Ho-Young Lee., This work was supported by grants from the National Research Foundation of Korea (NRF), the Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea (Nos. 2011-0017639 and 2011-0030001) and by a NIH Grant R01 CA100816; Liang-Tzung Lin was supported in part by a grant from the Ministry of Education of Taiwan (TMUTOP103005-4); Jason W. Locasale acknowledges support from NIH awards (CA168997 and AI110613) and the International Life Sciences Institute; Bal L. Lokeshwar was supported in part by United States’ Public Health Services Grants: NIH R01CA156776 and VA-BLR&D Merit Review Grant No. 5I01-BX001517-02; Valter D. Longo acknowledges support from NIH awards (P01AG034906 and R01AG020642) and from the V Foundation; Costas A. Lyssiotis was funded in part by the Pancreatic Cancer Action Network as a Pathway to Leadership Fellow and through a Dale F. Frey Breakthrough award from the Damon Runyon Cancer Research Foundation; Karen L. MacKenzie wishes to acknowledge the support from the Children's Cancer Institute Australia (affiliated with the University of New South Wales, Australia and the Sydney Children's Hospital Network); Maria Marino was supported by grant from University Roma Tre to M.M. (CLA 2013) and by the Italian Association for Cancer Research (AIRC-Grant #IG15221), Ander Matheu is funded by Carlos III Health Institute (AM: CP10/00539), Basque Foundation for Science (IKERBASQUE) and Marie Curie CIG Grant (AM: 2012/712404); Christopher Maxwell was supported by funding from the Canadian Institutes of Health Research, in partnership with the Avon Foundation for Women (OBC-134038) and the Canadian Institutes of Health Research New Investigator Salary Award (MSH-136647); Eoin McDonnell received Duke University Institutional Support; Kapil Mehta was supported by Bayer Healthcare System G4T (Grants4Targets); Gregory A. Michelotti received support from NIH NIDDK, NIH NIAAA, and Shire Pharmaceuticals; Vinayak Muralidhar was supported by the Harvard-MIT Health Sciences and Technology Research Assistantship Award; Elena Niccolai was supported by the Italian Ministry of University and the University of Italy; Virginia R. Parslow gratefully acknowledges the financial support of the Auckland Cancer Society Research Centre (ACSRC); Graham Pawelec was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) Grant number 16SV5536K, and by the European Commission (FP7 259679 “IDEAL”); Peter L. Pedersen was supported by NIH Grant CA-10951; Brad Poore was supported by Sol Goldman Pancreatic Cancer Research Fund Grant 80028595, the Lustgarten Fund Grant 90049125, and Grant NIHR21CA169757 (to Anne Le); Satya Prakash was supported by a Canadian Institutes of Health Research Grant (MOP 64308); Lizzia Raffaghello was supported by an NIH Grant (P01AG034906-01A1) and Cinque per Mille dell’IRPEF–Finanziamento della Ricerca Sanitaria; Jeffrey C. Rathmell was supported by an NIH Grant (R01HL108006); Swapan K. Ray was supported by the United Soybean Board; Domenico Ribatti received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under Grant agreement n°278570; Luigi Ricciardiello was supported by the AIRC Investigator Grants 10216 and 13837, and the European Community's Seventh Framework Program FP7/2007–2013 under Grant agreement 311876; Francis Rodier acknowledges the support of the Canadian Institute for Health Research (FR: MOP114962, MOP125857), Fonds de Recherche Québec Santé (FR: 22624), and the Terry Fox Research Institute (FR: 1030), Gian Luigi Russo contributed to this effort while participating in the Fulbright Research Scholar Program 2013–14; Isidro Sanchez-Garcia is partially supported by FEDER and by MICINN (SAF2012-32810), by NIH Grant (R01 CA109335-04A1), by Junta de Castilla y León (BIO/SA06/13) and by the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program). Isidro Sanchez-Garcia's lab is also a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program; Andrew J. Sanders wishes to acknowledge the support by Cancer Research Wales, the Albert Hung Foundation, the Fong Family Foundation, and Welsh Government A4B scheme; Neeraj K. Saxena was supported by grant funding from NIH NIDDK (K01DK077137, R03DK089130); Dipali Sharma was partially funded by NIH NCI grants (R01CA131294, R21 CA155686), the Avon Foundation and a Breast Cancer Research Foundation Grant (90047965); Markus David Siegelin received funding from National Institute of Health, NINDS Grant K08NS083732, and the 2013 AACR-National Brain Tumor Society Career Development Award for Translational Brain Tumor Research, Grant Number 13-20-23-SIEG; Neetu Singh was supported by funds from the Department of Science and Technology (SR/FT/LS-063/2008), New Delhi, India; Carl Smythe was supported by Yorkshire Cancer Research and The Wellcome Trust, UK; Carmela Spagnuolo was supported by funding from Project C.I.S.I.A., act n. 191/2009 from the Italian Ministry of Economy and Finance Project CAMPUS-QUARC, within program FESR Campania Region 2007/2013, objectives 2.1, 2.2; Diana M. Stafforini was supported by grants from the National Cancer Institute (5P01CA073992), IDEA Award W81XWH-12-1-0515 from the Department of Defense, and by the Huntsman Cancer Foundation; John Stagg was supported by the Canadian Institutes of Health Research; Pochi R. Subbarayan was supported by the University of Miami Clinical and Translational Science Institute (CTSI) Pilot Research Grant (CTSI-2013-P03) and SEEDS You Choose Awards; Phuoc T. Tran was funded by the DoD (W81XWH-11-1-0272 and W81XWH-13-1-0182), a Kimmel Translational Science Award (SKF-13-021), an ACS Scholar award (122688-RSG-12-196-01-TBG) and the NIH (R01CA166348); Kathryn E. Wellen receives funding from the National Cancer Institute, Pancreatic Cancer Action Network, Pew Charitable Trusts, American Diabetes Association, and Elsa U. Pardee Foundation; Huanjie Yang was partially supported by the Scientific Research Foundation for the Returned Oversea Scholars, State Education Ministry and Scientific and Technological Innovation Project, Harbin (2012RFLXS011), Paul Yaswen was supported by funding from the United States National Institutes of Health (ES019458) and the California Breast Cancer Research Program (17UB-8708); Clement Yedjou was supported by a grant from the National Institutes of Health (Grant # G1200MD007581), through the RCMI-Center for Environmental Health; Xin Yin was supported by NIH/National Heart, Lung, and Blood Institute Training Grant T32HL098062.; Jiyue Zhu was supported by NIH Grant R01GM071725; Massimo Zollo was supported by the European FP7-TuMIC HEALTH-F2-2008-201662, the Italian Association for Cancer research (AIRC) Grant IG # 11963 and the Regione Campania L.R:N.5, the European National Funds PON01-02388/1 2007-2013.

Although the benefits of current treatment strategies are well established, many cancer survivors are at risk for developing physiologic and psychological late effects of cancer treatment that might lead to premature mortality and morbidity and compromise their quality of life. Psychological symptoms include anxiety, depression, fatigue, difficulty sleeping, and loss of self-esteem. Physiologic symptoms include pain, numbness, cognitive impairment, weight gain, loss of sexual interest, spontaneous menopause, and peripheral neuropathy. Both length and quality of survival are important end points. The goal of this review is to summarize the psychological and physiologic symptoms related to breast cancer treatment; the prevalence, contributing therapies, and inter-relatedness of these symptoms; current interventions to prevent, ameliorate, or treat these symptoms; and effectiveness and safety of these interventions. The results of this review will identify the gaps in knowledge and assist in the design of assessments and approaches to improve mortality and quality of life and provide the foundation for the development of evidence-based guidelines to standardize palliative care in cancer survivors.

BACKGROUND Prostate cancer (PCa) remains the most common malignancy and the second leading cause of cancer death among men in the United States. PCa exhibits the most striking racial disparity, as African American men are at 1.4 times higher risk of being diagnosed, and 2–3 times higher risk of dying of PCa, compared to Caucasian men. The etiology of the disparity has not been clearly elucidated. The objective of this article is to critically review the literature and summarize the most prominent PCa racial disparities accompanied by proposed explanations. METHODS The present literature on disparities at presentation, diagnosis, treatment, and survival of African American men affected by PCa was systematically reviewed. Original research as well as relevant review articles were included. RESULTS African American men persistently present with more advanced disease than Caucasian men, are administered different treatment regimens than Caucasian men, and have shorter progression-free survival following treatment. In addition, African American men report more treatment-related side-effects that translates to the diminished quality of life (QOL). CONCLUSIONS PCa racial disparity exists at stages of presentation, diagnosis, treatment regimens, and subsequent survival, and the QOL. The disparities are complex involving biological, socio-economic, and socio-cultural determinants. These mounting results highlight an urgent need for future clinical, scientific, and socio-cultural research involving transdisciplinary teams to elucidate the causes for PCa racial disparities. Prostate 71: 985–997, 2011. © 2010 Wiley-Liss, Inc.

Opinion statement The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status.

Background Although African men may share a common genetic predisposition contributing to the higher incidence of prostate cancer (CaP), the etiology of the variability in risk observed even among African men living in varying environments and cultures, highlights the strong and evolving research regarding the contribution of behavioral factors that may modify these biological risk factors. Objective Our aim was to recruit Nigerian men from West Africa who had migrated and currently living in the US and indigenous men living in Nigeria to evaluate and compare differences in behavioral variables that are implicated to in contribute to CaP mortality and morbidity. Methods Using a cross-sectional study design, we recruited participants between age 35 and 70 during a CaP screening event in Abeokuta (Nigeria) and Houston (US). Data were collected using standard questionnaires and subject interviews on factors such as smoking, dietary intake, intake of traditional and non-traditional supplements, physical activity and alcohol consumption. Descriptive analyses were used to characterize the demographic characteristics of the study participants. Sample t-test analyses were then used to compare the behavioral variables of the migrant and indigenous men from Nigeria. Results Immigrant men from Nigeria had significantly higher fruit and whole grain intake, higher number of hours of purposeful physical activity and significantly lower tobacco use and intake of trans fats in their diet compared to their indigenous counterparts which may potentially contribute to decreased CaP risk in this cohort. However, greater intake of meats, oils, alcohol and reduction in fish intake may contribute to greater risk, although the proportion of risk reduction or risk increase is difficult to estimate in this sample size. Factors associated to acculturation, the relative accessibility and the affordability may contribute to the choices made by immigrant Nigerian men compared to their indigenous counterparts. Conclusion Although these results are provocative and significant, future well powered studies controlling for variability in population sampling should validate these observations.

Objective: The purpose of our study was to examine the association of regular tea consumption with the risk of breast cancer in a large population-based case-control study from the United States. Methods: Five thousand and eighty-two women with incident breast cancer between the ages of 20 and 74 years old from population-based cancer registries in Wisconsin, Massachusetts, and New Hampshire and 4,501 age-matched controls from lists of licensed drivers and Medicare beneficiaries completed a structured telephone interview that included information on usual tea consumption 5 years prior to the interview and other breast cancer risk factors. Logistic regression was used to obtain covariate-adjusted odds ratios and 95% confidence intervals associated with quantities of tea consumed. Results: Tea consumption was not related to breast cancer risk overall (P for trend = 0.18). However, when stratified by age, an inverse association was observed among women less than 50 years: those consuming three or more cups per day had a 37% reduced breast cancer risk when compared with women reporting no tea consumption (age and study site–adjusted odds ratios, 0.63; 95% confidence intervals, 0.44-0.89; P = 0.01) with a significant test for trend (P = 0.01). The inverse association noted among younger women was consistent for in situ and invasive breast cancer, and for ductal and lobular breast cancer. All results were unchanged after adjustment for established risk factors. Conclusion: We observed evidence to support a potential beneficial influence for breast cancer associated with moderate levels of tea consumption (three or more cups per day) among younger women. Further research is needed to confirm this association. (Cancer Epidemiol Biomarkers Prev 2009;18(1):341–5)

Concerns have been raised regarding the possible adverse health effects of consumption of unpasteurized milk and risk of cancer. We examined the association of self-reported intake of unpasteurized milk with subsequent risk of cancer in a large population-based cohort study. The Iowa Women's Health Study is a prospective cohort study of 55-69 year old women at baseline in 1986. Of the 41,836 women in the cohort at baseline, 22,808 cancer-free women completed the fourth follow-up questionnaire in 1997. Risk ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression analysis. Reported intake of unpasteurized milk was high: 59.2% consumed only as a child, 2.5% consumed only as an adult, and 16.5% consumed as a child and an adult. A total of 2,379 cancers were identified in the cohort at risk. Overall, the age-adjusted risk of cancer was lower among women who reported consumption of unpasteurized milk only as a child (RR = 0.90, 95% CI: 0.82-0.99) or as a child and an adult (RR = 0.85; 95% CI: 0.75-0.97). Adjustment for confounding factors attenuated these associations (RR = 0.92, 95% CI: 0.83-1.02 for consumption only as a child, and RR = 0.91; 95% CI: 0.79-1.04 for consumption as a child and an adult). These data suggest that consumption of unpasteurized milk does not increase risk of cancer.

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

In this paper we report on findings from the first known study using qualitative methods to explore factors influencing physicians' participation in an ongoing federally-funded prostate cancer chemoprevention clinical trial. We sought to identify ways to improve collaboration between researchers and physicians and enhance the success of future projects and employed purposive sampling to recruit physician/investigators who were involved or invited to participate in the trial. Using the data from open-ended semi-structured interviews, we examined patterns in their languaging and created themes. We found that individual and structural factors served as barriers and facilitators to participation. Willingness and desire to participate in the trial (individual factors) were not always enough to result in actual participation due to practice environment (structural) constraints. Our research provides a better understanding of the complex intersection of factors in this setting and through our findings we extend the theory of competing demands into the arena of prostate cancer prevention clinical trials, moving the science towards solutions to current challenges in recruitment to this type of trial. Keywords: Competing Demands, Barriers and Facilitators, Cancer, Screening and Prevention, Access to Participants, Open-Ended Semi-Structured InterviewsI, Dr. Crocker, conducted this research in partial fulfillment of the requirements for my doctorate in Applied Anthropology. During my doctoral program, I was uniquely situated, also working as a project director for a federally funded, multi-site, prostate cancer prevention intervention clinical trial (PCPICT). This resulted in the creation of a liminal space, often requiring navigation between the "rules" and languages of two very disparate worlds, biomedicine and anthropology, that seemed would never intersect. As the project director, I became increasingly aware of the challenges inherent in the design, implementation, and daily work of conducting a prostate cancer prevention trial. Simultaneously, through the requirements of the doctoral program, I experienced an increased skill set in which I acquired new perspectives and an expanded toolkit with which to examine the world. The overarching aim of my dissertation research was to show how the two worlds could merge, with each informing the other.As project director, I had observed recruitment below goal at most sites participating in the PCPICT. Upon review of detailed screening logs, our team was able to delineate patient, protocol and infrastructure related barriers that were contributing (Kumar et ah, 2012). Similar challenges to recruitment in chemoprevention clinical trials had been welldocumented by others (Chlebowski, Menon, Chaisanguanthum, & Jackson, 2010; Ruffin & Baron, 2000). What we also recognized as an important influence in recruitment was the support of committed physicians (Kumar et ah, 2012). Referring physicians had been recognized in other arenas for the major role they play in getting patients involved in clinical trials (Ford et ak, 2003; Miller, Crabtree, McDaniel, & Stange, 1998). In fact, physician involvement is considered essential for the provision of much of today's healthcare, and physicians serve as a critical link in the chain of events leading to the delivery of preventative services including cancer screening (Jaen et al., 2001; Nutting et al., 2001). What had not been explored using qualitative methods, and was the driving force behind this project was the role of physicians as the "link" to participation in prostate cancer prevention intervention trials (as PCPICT gatekeepers).Stange and Nutting (1994) used the theory of competing demands to describe the multiple factors competing for the provision and delivery of preventative services by primary care physicians. The main components (physician, patient, and practice environment) are thought to be influenced by factors such as attitudes, knowledge, expectations, practice organization, and alternative demands. …

Basic research has identified some nutrients as agents that inhibit mutagenesis and hyperproliferation, as well as some that induce apoptosis or differentiation, which are critical characteristics for chemoprevention regardless of the nutrient’s specific molecular targets. Some of the most promising nutrients identified as chemopreventive agents in prostate cancer are green tea polyphenols. The components of green tea are epigallocatechin-3-gallate [(−)-EGCG], epigallocatechin [(−)-EGC], epicatechin-3-gallate [(−)-ECG], epicatechin [(−)-EC] and their epimers (−)-GCG, (−)-CG, (−)-GC and (−)-C. Of these components, (−)-EGCG has been the most extensively investigated because of its relative abundance and strong cancer-preventive properties. Recently, several epidemiological, animal and laboratory studies have demonstrated the cancer-preventive properties of green tea polyphenols, specifically in prostate cancer. This article reviews the evidence to date in the role of green tea polyphenols in prostate cancer, and the future directions of this field of research.

Patients’ use of herbal and other dietary supplements and poor reporting of this to medical practitioners is widely documented in the literature. Many herbal supplements have potent pharmacological activity that can lead to potential adverse effects and drug interactions. The perioperative setting is a critical point in patient care for preventing these potential complications. A literature review was conducted regarding commonly used herbal and natural supplements and their potential for adverse effects in the surgical setting. Several herbal supplements or botanicals used by patients may, because of their chemical structure and pharmacokinetics, have adverse effects if used during the perioperative period. With the increasing use of herbal supplements by patients, it is critical for healthcare workers to screen patients pre-surgically for use of herbal and other natural supplements and to be knowledgeable about their potential adverse effects.