Chemoprevention Programs Research Articles

Adherence to referral advice and its associated factors among community drug distributors and caregiver during SMC implementation in nine states

BackgroundMalaria is a global public health problem that disproportionately affects under-five children in poor resource countries. Nigeria accounted for the highest burden of malaria in Western Africa. Thus, seasonal malaria chemoprevention (SMC) programmes have been recommended and have been implemented across 9 states (Bauchi, Borno, FCT, Kebbi, Kogi, Nasarawa, Plateau, Oyo and Sokoto) in Nigeria. The study aims to measure the adherence to referral protocol and its associated factors among community drug distributors (CDs) and caregivers during SMC implementation in nine states.MethodsThe data of caregiver-child pairs that were identified with fever during the cycle one SMC implementation was extracted from the End-of-cycle (EoC) surveys carried out following cycles one SMC implementation in the study states. The surveys were completed within two weeks of the completion of SMC cycle one. Mixed-effects multivariable logistic regression models were fitted to explore the factors associated with adherence to referrals among caregivers-child pairs.ResultsThe socio-demographic characteristics of caregiver considered in the model were not found to be significantly associated with children down with fever taking to hospital for treatment, however the caregiver whose child was referred by CDs had significantly higher odds of seeking healthcare compared to those that were not referred (OR: 1.892, 95% CI 1.081–3.310, p = 0.025). There are higher odds of children seeking treatment among those that were referred by CDs.ConclusionThe study's findings shed light on the adherence to referral advice and the factors influencing caregiver behaviour during SMC implementation. Referral of sick child during SMC campaign appears to ensure health-seeking for malaria case management among caregivers-child peer in target communities.

Comparing approaches for chemoprevention for school-based malaria control in Malawi: an open label, randomized, controlled clinical trial

School-age children in sub-Saharan Africa suffer an underappreciated burden of malaria which threatens their health and education. To address this problem, we compared the efficacy of two school-based chemoprevention approaches: giving all students intermittent preventive treatment (IPT) or screening and treating only students with detected infections (IST). In a three-arm, open-label, randomized, controlled trial (NCT05244954) in Malawi, 746 primary school students, aged 5-19 years, were individually randomized within each grade-level to IPT (n=249), IST with a high-sensitivity rapid diagnostic test (hs-RDT, n=248), or control (n=249). At six-week intervals three times within the peak malaria transmission season (February-June 2022) treatment with dihydroartemisinin-piperaquine (DP) was administered to girls <10 years and all boys, and chloroquine to older girls. The primary outcome was Plasmodium falciparum (Pf) infection detected by PCR 6-8 weeks after the final intervention. Secondary outcomes included anaemia, clinical malaria, and scores on tests of attention, literacy, and math. Analysis was by modified intention-to-treat. Outcomes analyses included 727 (97%) participants. At the end of the study, prevalence of Pf infection was 17% (41/243) in the IPT arm, 24% (58/244) in the IST arm, and 53% (127/240) in the control arm. Compared to controls, IPT and IST reduced the odds of Pf infection (IPT adjusted odds ratio [aOR]: 0.18 (95% CI: 0.11, 0.27); p<0.0001; IST aOR: 0.27 (95% CI: 0.18, 0.40); p<0.0001). However, only participants receiving IPT had a lower incidence of clinical malaria (0.19 cases per person per six months (95% CI: 0.14, 0.27) vs 0.56 (95% CI: 0.46, 0.68); incidence rate ratio: 0.38 (95% CI: 0.26, 0.55); p<0.0001)) and prevalence of anaemia (8% [20/243] vs 15% [36/240]; aOR: 0.49 (95% CI: 0.27, 0.91); p=0.023) compared to controls. Literacy scores were higher in both intervention arms. No between group differences in tests of attention or math or number of serious adverse events were found. Results support implementation of IST with hs-RDTs or IPT for reduction in the prevalence of infection. Based on reductions in clinical malaria, IPT may provide additional benefits warranting further consideration by school-based malaria chemoprevention programs. Doris Duke Charitable Foundation Clinical Scientist Development Award 2021191, U.S. NIH K24AI114996 & K23AI135076.

From efficacy to effectiveness: a comprehensive framework for monitoring, evaluating and optimizing seasonal malaria chemoprevention programmes

BackgroundSeasonal Malaria Chemoprevention (SMC) is a highly effective intervention for preventing malaria, particularly in areas with highly seasonal transmission. Monitoring and evaluating (M&E) SMC programmes are complex due to the scale, time-sensitive delivery of the programme, and influence of external factors. This paper describes the process followed to develop a comprehensive M&E framework tailored specifically for the SMC context.MethodsThe Framework was developed through a literature and programme review, and stakeholder dialogues across three implementing countries—Burkina Faso, Chad, and Nigeria. Expert consultation further refined the Framework through an iterative approach drawing upon data collected through the three sources. The Framework was designed using the Logical Framework Approach incorporating external factors and intentionally aligned with global malaria M&E standards.ResultsAn overall aim and seven programme objectives were developed measured by 70 indicators. The indicators also capture the causal links between the implementation and results of the programme. The Framework leverages the use of current data sources and existing mechanisms, ensuring efficient data use without requiring a significant increase in resources for overall programme optimization. It also promotes the use of data triangulation, and stratification for a more nuanced understanding of factors affecting programme performance and timely data informed decision-making.ConclusionsThe SMC M&E Framework presented here provides a standardized approach for programme implementers to enhance decision-making for optimal programme performance. This is an essential tool as the scope of SMC programmes expands to new geographies and target age groups.

Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1–11-month-old infants in Mali

BackgroundThe Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP).Methods/designLAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering.ConclusionThe SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results.Trial registrationClinicalTrials.gov ID NCT04424511. Registered on 11 June 2020.

Evolution of Spatial Risk of Malaria Infection After a Pragmatic Chemoprevention Program in Response to Severe Flooding in Rural Western Uganda.

Malaria epidemics result from extreme precipitation and flooding, which are increasing with global climate change. Local adaptation and mitigation strategies will be essential to prevent excess morbidity and mortality. We investigated the spatial risk of malaria infection at multiple timepoints after severe flooding in rural western Uganda employing longitudinal household surveys measuring parasite prevalence and leveraging remotely sensed information to inform spatial models of malaria risk in the 3 months after flooding. We identified clusters of malaria risk emerging in areas (1) that showed the greatest changes in Normalized Difference Vegetation Index from pre- to postflood and (2) where residents were displaced for longer periods of time and had lower access to long-lasting insecticidal nets, both of which were associated with a positive malaria rapid diagnostic test result. The disproportionate risk persisted despite a concurrent chemoprevention program that achieved high coverage. The findings enhance our understanding not only of the spatial evolution of malaria risk after flooding, but also in the context of an effective intervention. The results provide a "proof of concept" for programs aiming to prevent malaria outbreaks after flooding using a combination of interventions. Further study of mitigation strategies-and particularly studies of implementation-is urgently needed.

Allelic frequencies of mutants of the Plasmodium falciparum, quinoline and folate metabolizing genes in the west region of Cameroon

The emergence and spread of Plasmodium falciparum (P.f) drug resistance is still a major concern in Sub-Saharan Africa and warrants that its evolution be monitored continuously. The present study aimed at determining the distribution of key P.f drug resistance-mediating alleles in circulating malaria parasites in the West region of Cameroon. A cross sectional hospital-based study was conducted in Dschang and Ngounso in the West region of Cameroon. The Pfcrt, Pfmdr1, and the Pfdhps genes were amplified through nested PCR in 208 malaria-infected samples of the 301 febrile outpatients enrolled. The presence or absence of mutations in the K76T, N86Y, A437G and A581G codons of these P.f. genes respectively were determined through restriction digestion analysis. The proportion of different alleles were estimated as percentages and compared between two study sites using the Chi square test. A p value <0.05 was considered significant. A high prevalence (75.6%) of the 437G allele was observed. It was significantly different between Dschang and Ngounso (62% vs. 89.2%, X2 = 19.6, P = 0.00005). Equally observed was a 19.2% (95%CI: 13.3–25.6) of the dhps-581G mutant allele. Furthermore, we observed the Pfcrt-76T, Pfmdr1-N86 mutations in 73.0% (67.5–79.7) and 87.2% (83.2–91.9), and 3.0% (0.0–9.6) and 12.8% was observed for the Pfcrt-K76T and Pfmdr1-N86Y respectively. When biallelic haplotypes were constructed from alleles of the three genes, same pattern was seen. Overall, 73% and 87% of circulating P. falciparum isolates carried wild type alleles at Pfmdr1-N86Y and Pfcrt-K76T. On the other hand, we found more parasites with mutant alleles at dhps (437G and 581G) loci which may reflect possible drug-related selection of this mutant in the parasite population. Continuous monitoring of these mutations is recommended to pre-empt a loss in sulphadoxine-pyrimethamine efficacy in malaria chemoprevention programs.

Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia.

Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

Malaria hospitalisation in East Africa: age, phenotype and transmission intensity

BackgroundUnderstanding the age patterns of disease is necessary to target interventions to maximise cost-effective impact. New malaria chemoprevention and vaccine initiatives target young children attending routine immunisation services. Here we explore the relationships between age and severity of malaria hospitalisation versus malaria transmission intensity.MethodsClinical data from 21 surveillance hospitals in East Africa were reviewed. Malaria admissions aged 1 month to 14 years from discrete administrative areas since 2006 were identified. Each site-time period was matched to a model estimated community-based age-corrected parasite prevalence to provide predictions of prevalence in childhood (PfPR2–10). Admission with all-cause malaria, severe malaria anaemia (SMA), respiratory distress (RD) and cerebral malaria (CM) were analysed as means and predicted probabilities from Bayesian generalised mixed models.Results52,684 malaria admissions aged 1 month to 14 years were described at 21 hospitals from 49 site-time locations where PfPR2–10 varied from < 1 to 48.7%. Twelve site-time periods were described as low transmission (PfPR2–10 < 5%), five low-moderate transmission (PfPR2–10 5–9%), 20 moderate transmission (PfPR2–10 10–29%) and 12 high transmission (PfPR2–10 ≥ 30%). The majority of malaria admissions were below 5 years of age (69–85%) and rare among children aged 10–14 years (0.7–5.4%) across all transmission settings. The mean age of all-cause malaria hospitalisation was 49.5 months (95% CI 45.1, 55.4) under low transmission compared with 34.1 months (95% CI 30.4, 38.3) at high transmission, with similar trends for each severe malaria phenotype. CM presented among older children at a mean of 48.7 months compared with 39.0 months and 33.7 months for SMA and RD, respectively. In moderate and high transmission settings, 34% and 42% of the children were aged between 2 and 23 months and so within the age range targeted by chemoprevention or vaccines.ConclusionsTargeting chemoprevention or vaccination programmes to areas where community-based parasite prevalence is ≥10% is likely to match the age ranges covered by interventions (e.g. intermittent presumptive treatment in infancy to children aged 2–23 months and current vaccine age eligibility and duration of efficacy) and the age ranges of highest disease burden.

Dihydroartemisinin-Piperaquine Chemoprevention and Malaria Incidence After Severe Flooding: Evaluation of a Pragmatic Intervention in Rural Uganda

Malaria epidemics are a well-described phenomenon after extreme precipitation and flooding. Yet, few studies have examined mitigation measures to prevent post-flood malaria epidemics. We evaluated a malaria chemoprevention program implemented in response to severe flooding in western Uganda. Children aged ≤12 years from 1 village were eligible to receive 3 monthly rounds of dihydroartemisinin-piperaquine (DP). Two neighboring villages served as controls. Malaria cases were defined as individuals with a positive rapid diagnostic test result as recorded in health center registers. We performed a difference-in-differences analysis to estimate changes in the incidence and test positivity of malaria between intervention and control villages. A total of 554 children received at least 1 round of chemoprevention, with 75% participating in at least 2 rounds. Compared with control villages, we estimated a 53.4% reduction (adjusted rate ratio [aRR], 0.47; 95% confidence interval [CI]: .34-.62; P < .01) in malaria incidence and a 30% decrease in the test positivity rate (aRR, 0.70; 95% CI: .50-.97; P = .03) in the intervention village in the 6 months post-intervention. The impact was greatest among children who received the intervention, but decreased incidence was also observed in older children and adults (aRR, 0.57; 95% CI: .38-.84; P < .01). Three rounds of chemoprevention with DP delivered under pragmatic conditions reduced the incidence of malaria after severe flooding in western Uganda. These findings provide a proof-of-concept for the use of malaria chemoprevention to reduce excess disease burden associated with severe flooding.

Near-term climate change impacts on sub-national malaria transmission

The role of climate change on global malaria is often highlighted in World Health Organisation reports. We modelled a Zambian socio-environmental dataset from 2000 to 2016, against malaria trends and investigated the relationship of near-term environmental change with malaria incidence using Bayesian spatio-temporal, and negative binomial mixed regression models. We introduced the diurnal temperature range (DTR) as an alternative environmental measure to the widely used mean temperature. We found substantial sub-national near-term variations and significant associations with malaria incidence-trends. Significant spatio-temporal shifts in DTR/environmental predictors influenced malaria incidence-rates, even in areas with declining trends. We highlight the impact of seasonally sensitive DTR, especially in the first two quarters of the year and demonstrate how substantial investment in intervention programmes is negatively impacted by near-term climate change, most notably since 2010. We argue for targeted seasonally-sensitive malaria chemoprevention programmes.

Inherited Rare, Deleterious Variants in ATM Increase Lung Adenocarcinoma Risk.

Lung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals. To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing data of 1083 patients with LUAD and 7650 controls, split into discovery and validation cohorts. Of these, we performed whole-exome sequencing on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using the guidelines of the American College of Medical Genetics and Genomics and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided. We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in patients with LUAD versus controls (combined cohort OR= 4.6; p= 1.7e-04; 95% confidence interval= 2.2-9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1594 patients from the MSK-IMPACT study (0.63%). In addition, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (combined AJ cohort OR= 2.7, p= 6.9e-03, 95% confidence interval= 1.3-5.3). Our results indicate that ATM is a moderate-penetrance LUAD risk gene and that LUAD may be a part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at an elevated LUAD risk and can benefit from increased surveillance (particularly computed tomography scanning), early detection, and chemoprevention programs, improving prognosis.

The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data

BackgroundThe majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas.MethodsWe analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment.ResultsWe estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7–15.7) for AL and 15.2 days (95% CI 12.8–18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7–18.6 days for AL and 10.2–18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission.ConclusionChoosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.

Seasonality and heterogeneity of malaria transmission determine success of interventions in high-endemic settings: a modeling study

BackgroundMalaria transmission is both seasonal and heterogeneous, and mathematical models that seek to predict the effects of possible intervention strategies should accurately capture realistic seasonality of vector abundance, seasonal dynamics of within-host effects, and heterogeneity of exposure, which may also vary seasonally.MethodsPrevalence, incidence, asexual parasite and gametocyte densities, and infectiousness measurements from eight study sites in sub-Saharan Africa were used to calibrate an individual-based model with innate and adaptive immunity. Data from the Garki Project was used to fit exposure rates and parasite densities with month-resolution. A model capturing Garki seasonality and seasonal heterogeneity of exposure was used as a framework for characterizing the infectious reservoir of malaria, testing optimal timing of indoor residual spraying, and comparing four possible mass drug campaign implementations for malaria control.ResultsSeasonality as observed in Garki sites is neither sinusoidal nor box-like, and substantial heterogeneity in exposure arises from dry-season biting. Individuals with dry-season exposure likely account for the bulk of the infectious reservoir during the dry season even when they are a minority in the overall population. Spray campaigns offer the most benefit in prevalence reduction when implemented just prior to peak vector abundance, which may occur as late as a couple months into the wet season, and targeting spraying to homes of individuals with dry-season exposure can be particularly effective. Expanding seasonal malaria chemoprevention programs to cover older children is predicted to increase the number of cases averted per treatment and is therefore recommended for settings of seasonal and intense transmission.ConclusionsAccounting for heterogeneity and seasonality in malaria transmission is critical for understanding transmission dynamics and predicting optimal timing and targeting of control and elimination interventions.

Abstract A21: A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index

Abstract Background: Despite advances in colorectal cancer (CRC) screening, early detection, and treatment, CRC remains the 2nd most common cancer cause of death in the U.S.. Obesity is increasing in incidence in the U.S., and has been implicated in colorectal adenoma (CRA) risk, risk of CRA recurrence, and risk of CRC. Obese patients with history of CRA are a high-risk group that may benefit from novel CRC prevention strategies. There is early evidence for reduced cancer mortality among metformin users. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in ApcMin/+ mice, as evidenced by metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPk, decreased ratio of pmTOR/mTOR, and decreased ratio of pS6Ser235/S6Ser235 in polyp specimens. We hypothesized that metformin would affect colorectal tissue S6Ser235 similarly in humans, targeting obese patients with recent history of CRAs as a high-risk group. Methods: A phase IIa clinical biomarker trial was conducted across 3 clinical sites via the NCI-funded Southern California Chemoprevention Program. Eligible participants included non-diabetic, obese patients (BMI &amp;gt;30) with history of colorectal adenoma within the past 3 years, age ≥ 35 years and ≤ 80 years. All patients received an upward titration of metformin over 3 weeks to 1000mg po bid, which was continued until the end-of-study (EOS) at 12 weeks. Rectal mucosa biopsies were obtained at baseline (BL) and at time of EOS endoscopy. Tissue S6Ser235 immunostaining was analyzed in a blinded fashion by the study pathologist using Histo Score (HScore) analysis. A paired t-test was used to examine the effect of metformin on activated S6serine235 (i.e., the ratio of pS6serine235/ S6serine235). Results: 45 patients were consented to achieve 32 eligible subjects. 4 subjects were removed from study due to Adverse Events (1 SAE, unrelated). In order of frequency, the most common AEs were diarrhea, cramping, flatulence, nausea, stomach pain; 80% of participants had Grade 1 AE, 27% had grade 2 AE. Mean (SD) weight and body mass index at BL were 105.2 (17.42) kg and 34.9 (5.57) respectively. Weight did not significantly differ over the course of the study. Glucose levels at EOS did not significantly differ from BL. Vitamin B12 levels were significantly reduced at EOS vs. BL (-46.7 pg/mL, 95% CI -73.2 to -20.2). Comparing EOS to BL tissue S6Ser235 by IHC HScore analysis, no significant differences were observed. Mean (SD) Hscore at BL was 1.1 (0.57) and 1.1 (0.51) at EOS. Median HScore change was 0.032 (p=0.77). Conclusions: Among obese CRA patients, 12 weeks of oral metformin 1000mg twice daily does not reduce pS6 levels in the rectal mucosa. Other potential mechanisms of action have not yet been analyzed. Data from this clinical trial indicate that metformin can be used safely in a non-diabetic population. Further research is needed to determine what effects, if any, metformin has on the target tissue of origin (colorectum) relevant to colorectal carcinogenesis if metformin is to be pursued as a CRC chemopreventive agent. Citation Format: Jason A. Zell, Christine E. McLaren, Timothy R. Morgan, Michael J. Lawson, Sherif Rezk, Gregory C. Albers, Wen-Pin Chen, Joseph C. Carmichael, Luz Rodriguez, Eva Szabo, Leslie Ford, Michael Pollak, Frank L. Meyskens. A Phase IIa trial of metformin for colorectal cancer risk reduction among patients with a history of colorectal adenomas and elevated body mass index. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A21.

Effects of Acute UVB on Retinoid Metabolism

Exposure to UVB light is the largest risk factor for the development of cutaneous squamous cell carcinoma, one of the most common cancers in the United States. UVB light causes changes to occur in the skin such as epidermal thickening, hyperproliferation, and alterations to epidermal differentiation. Retinoids regulate the differentiation and proliferation of the epidermis. The purpose of this study is to examine the effect of acute UVB on the expression of retinoid metabolism proteins. There is limited knowledge of how UVB may affect this pathway, and our results will allow us to gain a more complete understanding of changes in the entire retinoid metabolism pathway. We examined the expression of key retinoic acid metabolism proteins in the epidermis and hair follicle remnants 48 hours after UVB exposure in SKH‐1 mice using immunohistochemistry. UVB exposure increased the expression of retinoid synthesis, degradation, and binding proteins, and decreased the expression of the retinol storage enzyme, lectin:retinol acyltransferase (LRAT). These changes in expression suggest that acute UVB increases in the synthesis of retinoic acid in the epidermis. Many of these proteins changed their localization in the epidermis, concentrating in the more differentiated cells of the stratum granulosum and stratum corneum. This change in retinoic acid synthesis could affect the repair and normalization of UVB‐damaged epidermis. This work was supported by the Department of Human Sciences (Human Nutrition), The Molecular Carcinogenesis and Chemoprevention Program of The Ohio State University Comprehensive Cancer Center (grant P30 CA16058, National Cancer Institute) and the Center for Advanced Functional Foods Research and Entrepreneurship (CAFREE).

Abstract CN14-04: Identifying the premalignant lesion at high risk for progression to cancer

Abstract Oral tumorigenesis is a multistep process requiring the accumulation of multiple molecular alterations such as mutations, genomic deletions and amplifications, as well as epigenetic modifications in oral epithelial cells. These alterations allow the affected cells gaining growth advantages over other cells and other malignant phenotypes. In the past two decades, extensive studies have been conducted to understand molecular abnormalities in oral cancers and oral premalignant lesions (OPLs). Although promising, none of these has translated into a clinical test which can improve patient classification or cancer risk assessment. OPLs can exhibit a variety of histological features from hyperkeratosis, hyperplasia, and mild dysplasia to severe dysplasia. Together with other clinical features, our current practice has limited capability to accurately stratify cancer risk of patients with OPL. Such stratification is critical in our effort to develop surveillance measures for early cancer diagnosis and interventions to prevent or delay cancer development. In this presentation, I will focus on a series of biomarker discovery studies based on patients with OPL and enrolled in a prospective chemoprevention trial to illustrate some of the current efforts in oral cancer risk assessment based underlying molecular abnormalities in OPLs. The chemoprevention trial randomized 167 patients with biopsies obtained at the time of enrollment and certain time points during follow-up. One hundred and sixty-two patients had oral cancer-free survival data with the median time of follow-up about 7.5 years. During the follow-up period, 38 patients developed oral cancer but no statistically significant difference was observed in any of the treatment arms. We examined podoplanin expression, deltaNp63 expression, EGFR expression, EFGR copy numbers, global gene expression, and histopathologic features in OPLs from the patients obtained at either baseline or at 3 months follow-up. Potential roles of these factors in progression of OPLs and oral cancer risk were evaluated. Results suggest that these alterations may outperform previously reported biomarkers and clinicopathologic parameters in stratifying oral cancer risk of patients with OPLs. Development of oral cancer risk assessment strategies faces a number of challenges. Etiologies of OPLs and oral cancer may change over time, such as the emerging evidence of HPV infection in orapharyngeal cancers. Populations tested in many of our studies may be biased and not representative of the general population. Therefore, results may be difficult to validate in independent populations. We lack of systematic research networks at the national level to facilitate oral cancer risk assessment, early detection, and prevention. Efforts are lacking to integrate oral cancer risk assessment and chemoprevention programs. Some progresses and thoughts towards these limitations will be discussed. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN14-04.

Does chemotherapy prevent HCV-related hepatocellular carcinoma? Cons

The accuracy and the reliability of well-recognized clinical, virologic, histologic, and molecular risk factors for hepatocellular carcinoma (HCC) are still insufficient. Thus, accurate risk prediction of cancer development in individual patients with the aim of selecting high risk cohorts of patients for HCC chemoprevention programs remains an elusive goal. Future directions in chemoprevention of HCC will be in the development of molecular risk models and of new chemopreventive agents. Studies examining multiple genes and proteins (genomics and proteomics) in the same HCCs will be required to evaluate this possibility thoroughly. A strategy aiming at preventing chronic liver disease of any etiology (HCV and HBV infection, alcohol, obesity, others) may be required to prevent HCC in low and intermediate incidence areas, and hence, worldwide. In the setting of secondary chemoprevention, literature data pooling suggests a slight preventive effect of interferon (IFN) on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low, and the observed benefit might be due to spurious associations. The preventive effect is limited to sustained virological responders to IFN. So, there is no sound evidence to support a recommendation for widespread use of IFN to prevent HCC in HCV-related cirrhosis. In the setting of tertiary chemoprevention, the risk of recurrence of HCC may be reduced by IFN treatment in selected patient populations. Further large-scale multicenter randomized controlled trials may prove useful to evaluate the benefit on overall survival.

Inhibition of Colon Carcinogenesis by 2-Methoxy-5-Amino-N-Hydroxybenzamide, a Novel Derivative of Mesalamine

Mesalamine has been reported to protect against inflammatory bowel disease-related colorectal cancer (CRC), but several drug-related issues have limited its use in chemopreventive programs. We evaluated the antineoplastic properties of mesalamine derivatives using in vitro and in vivo models of CRC. CRC cell proliferation and cell-cycle progression were evaluated by flow cytometry after exposure to mesalamine or mesalamine derivatives. Cyclins, cyclin-dependent kinases, and endoplasmic reticulum stress-related molecules were examined by immunoblotting. The in vivo antineoplastic effect of 2-methoxy-5-amino-N-hydroxybenzamide (2-14) was evaluated in a syngenic, CT26-derived xenograft mouse model of CRC and in the azoxymethane/dextran sulfate sodium-induced mouse model of colitis-associated CRC. The mesalamine derivative 2-14 was 10-fold more potent than mesalamine in inhibiting CRC cell proliferation. After exposure to 2-14, cyclin D1 expression was reduced and G0/G1 phase cells accumulated. These events were preceded by activation of eukaryotic translation initiation factor 2-alpha kinase 3 (pancreatic endoplasmic reticulum eIF2alpha kinase), phosphorylation of eukaryotic translation initiation factor 2alpha, induction of activating transcription factor 4, and splicing of X-box binding protein 1 messenger RNA, events that define endoplasmic reticulum stress. Silencing of PERK restored cyclin D1 levels, allowing cells to overcome the cell-cycle block induced by 2-14. Mice injected with 2-14 developed fewer CRC xenograft-derived tumors. Moreover, 2-14 injection reduced the development of neoplastic lesions induced by azoxymethane and dextran sulfate sodium in mice. The mesalamine derivative 2-14 inhibited CRC cell proliferation in vitro and prevented CRC progression in mouse models.

Diagnosis and prevention of breast cancer in women at high risk.

Abstract Abstract #MS1-3 The definition of women at highest risk is those possessing a genetic mutation establishing a defined high risk. These and women at high risk by family history but lacking geneticly defined risk should undergo surveillance by MRI as well as mammography. This should begin ten years prior to their youngest first degree relative with breast cancer. Because early stage ovarian carcinoma is so difficult to detect, women with BRCA1 or 2 mutations should be encouraged to have salpingo-oophorectomy as soon as childbearing is finished. Premenopausal oophorectomy will cut the annual risk of breast cancer in half. This means that the risk of breast cancer in the next year is not astronomical, affording the opportunity to make very deliberate decisions about possible prophylactic surgery. With the added safety of MRI surveillance, many women will delay prophylactic surgery for a time, some will never elect it. The additional benefit of tamoxifen in this setting is controversial.&amp;#x2028; Women with known mutations who develop breast cancer will generally elect mastectomy and have the considerations of contralateral prophylactic mastectomy previously reviewed. Breast conserving surgery is an option that is valid, however, and several studies have shown good results at 5 and 10 years. For those electing mastectomy for breast cancer, the options and standards are those for any woman with the same stage of disease.&amp;#x2028; Women without a genetically defined high risk can be followed with MRI/mammographic surveillance, participate in chemo-prevention programs, and be spared prophylactic surgery.&amp;#x2028; Prophylactic mastectomy should be preceded by MRI and mammograms to minimize risk of an unexpected finding of breast cancer. Even when these studies are clear, a good case can be made for performing sentinel lymph node biopsy at the time of the mastectomy so that the discovery of an occult breast cancer need not raise the issue of later axillary dissection for staging. With those caveats, prophylactic mastectomy is a total mastectomy and can be either skin sparing or nipple sparing. The former provides the lowest risk of breast cancer arising in residual breast and seems preferable. Nipple sparing prophylactic mastectomy has minimal data on long term effectiveness in this population. Much of the reason for sparing the nipple skin is cosmetic and experts in breast reconstruction are not uniform in believing that there is any improvement in aesthetics with a spared-nipple over a neo-nipple if the breast tissue beneath the spared-nipple was adequately removed [it is basically a full thickness skin graft over the reconstruction tissue]. With skin sparing mastectomy the flaps must be sufficiently thin to virtually [completely is impossible] eliminate all breast tissue. The pectoralis fascia is taken for the same reason. Depending upon breast volume, sub-muscular expanders, latissimus myo-cutaneous flaps, or TRAM flaps may be used to provide the feeling of normal breast tissue and a new blood supply for the spared skin. The cosmetic result should be excellent. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS1-3.

Aspirin Should Not Be Promoted for Colon Cancer Prevention: Counterpoint

There is little question that aspirin can decrease the risk of large bowel cancer. A large number of observational studies in humans, both case-control and cohort, consistently show a strong protective effect of aspirin ([1][1]). Importantly, three randomized controlled trials show that aspirin