Dietary Iron and Colorectal Cancer Risk: A Review of Human Population Studies.

Iron is an essential micronutrient that is involved in many redox processes and serves as an integral component in various physiological functions. However, excess iron can cause tissue damage through its pro-oxidative effects, potentiating the development of many diseases such as cancer through the generation of reactive oxidative species. The two major forms of iron in the diet are heme and nonheme iron, both of which are found in several different foods. In addition to natural food sources, intake of nonheme iron may also come from fortified foods or in supplement form. This review summarizes the results of human population studies that have examined the role of dietary iron (heme and nonheme), heme iron alone, and iron from supplements in colorectal carcinogenesis.

The effect of UGT1A and UGT2B polymorphisms on colorectal cancer risk: haplotype associations and gene­environment interactions.

UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased cancer risk for the colon [proximal (OR = 0.28, 95% CI = 0.11­0.69) and for the distal colon (OR = 0.32, 95% CI = 0.12­0.91)], and that the C-T-G haplotype in the 3' region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR = 2.56, 95% CI = 1.10­5.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR = 2.57, 95% CI = 1.21­5.04) and in females (OR = 3.08, 95% CI = 1.08­8.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk.

Association of dietary and supplemental folate intake and polymorphisms in three FOCM pathway genes with colorectal cancer in a population-based case-control study.

Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00-2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14-3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC.

The effect of copy number variation in the phase II detoxification genes UGT2B17 and UGT2B28 on colorectal cancer risk.

BACKGROUND: Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. METHODS: To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. RESULTS: A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P = .044). Stratification by sex yielded a decreased risk (P = .020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P = .724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P = .0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. CONCLUSIONS: The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.

Meat-related compounds and colorectal cancer risk by anatomical subsite.

Since meat may be involved in the etiology of colorectal cancer, associations between meat-related compounds were examined to elucidate underlying mechanisms in a population-based case-control study. Participants (989 cases/1,033 healthy controls) completed a food frequency questionnaire with a meat-specific module. Multivariable logistic regression was used to examine associations between meat variables and colorectal cancer; polytomous logistic regression was used for subsite-specific analyses. The following significant positive associations were observed for meat-related compounds: 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and colorectal, distal colon, and rectal tumors; 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and colorectal and colon cancer tumors; nitrites/nitrates and proximal colon cancer; 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and rectal cancer; and benzo[a]pyrene and rectal cancer (P-trends < 0.05). For analyses by meat type, cooking method, and doneness preference, positive associations between red processed meat and proximal colon cancer and pan-fried red meat and colorectal cancer were found (P-trends < 0.05). Inverse associations were observed between unprocessed poultry and colorectal, colon, proximal colon, and rectal tumors; grilled/barbequed poultry and proximal colon cancer; and well-done/charred poultry and colorectal, colon, and proximal colon tumors (P-trends < 0.05). HCAs, PAHs, nitrites, and nitrates may be involved in colorectal cancer etiology. Further examination into the unexpected inverse associations between poultry and colorectal cancer is warranted.

Diet index-based and empirically derived dietary patterns are associated with colorectal cancer risk.

Previous studies have derived patterns by measuring compliance with preestablished dietary guidance or empirical methods, such as principal components analysis (PCA). Our objective was to examine colorectal cancer risk associated with patterns identified by both methods. The study included 431 incident colorectal cancer cases (225 men, 206 women) and 726 healthy controls (330 men, 396 women) participating in a population-based, case-control study. PCA identified sex-specific dietary patterns and the Healthy Eating Index-2005 (HEI-05) assessed adherence to the 2005 Dietary Guidelines for Americans. A fruits and vegetables pattern and a meat, potatoes, and refined grains pattern were identified among men and women; a third pattern (alcohol and sweetened beverages) was identified in men. The fruits and vegetables pattern was inversely associated with risk among men [odds ratio (OR) = 0.38, 95% CI = 0.21-0.69 for the highest compared with the lowest quartile] and women (OR = 0.35, 95% CI = 0.19-0.65). The meat, potatoes, and refined grains pattern was positively associated with risk in women (OR = 2.20, 95% CI = 1.08-4.50) and there was a suggestion of a positive association among men (OR = 1.56, 95% CI = 0.84-2.90; P-trend = 0.070). Men and women with greater HEI-05 scores had a significantly reduced risk of colorectal cancer (OR = 0.56, 95% CI = 0.31-0.99; OR = 0.44, 95% CI = 0.24-0.77, respectively). Following the Dietary Guidelines or a dietary pattern lower in meat, potatoes, high fat, and refined foods and higher in fruits and vegetables may reduce colorectal cancer risk.

Dietary patterns and colorectal adenoma and cancer risk: a review of the epidemiological evidence.

A number of studies exploring associations between individual dietary components and colorectal adenoma or cancer risk have yielded conflicting results. The study of food-based dietary patterns in relation to chronic disease risk represents an alternative approach to the evaluation of single dietary exposures in epidemiological investigations. Results from prospective cohort and population-based case-control studies examining associations between dietary patterns and colorectal cancer or adenoma risk were evaluated and described in this review. Despite notable differences in population characteristics, study design, and methods used for characterizing dietary patterns across the different studies, two general dietary patterns were found to modestly predict colorectal adenoma and cancer risk. A healthier pattern consisting of greater intakes of fruits and vegetables, and lower intakes of red and processed meat, appeared protective against colorectal adenoma and cancer incidence. Findings also suggest that a less healthy pattern characterized by higher intakes of red and processed meat, as well as potatoes and refined carbohydrates, may increase risk. Continued research efforts are needed to evaluate the cumulative and interactive effects of numerous dietary exposures on colorectal cancer risk.

A Group Randomized Trial to Reduce Obesity among Appalachian Church Members: The Walk by Faith Study.

Background: Appalachia is a rural, socioeconomically disadvantaged region with high rates of cancer and obesity. Using community-based participatory research principles, the Appalachia Community Cancer Network tested an initiative to reduce weight among overweight and obese participants by partnering with churches, an important community-based institution in Appalachia.Methods: A group randomized trial was conducted with counties or groups of counties in five Appalachian states. These groups were randomly assigned to receive either monthly diet and exercise education sessions ("Walk by Faith"; WbF) or an educational program focused on cancer screening and education ("Ribbons of Faith"; RoF) to examine effects on weight change. Participants completed questionnaires and biometric measurements at baseline and 12 months. The primary outcome of the study was weight change from baseline to 12 months.Results: The relative difference in weight loss from baseline to 12 months for WbF compared with RoF was 1.4% but was not statistically significant (P = 0.13). However, results varied by sex and marital status. WbF men experienced a significant 2.8% decrease in body weight, married WbF women a 1.5% decrease, and unmarried WbF women a 1.5% increase compared with their respective RoF subgroups (interaction P = 0.016). Among WbF participants, greater participation in monthly educational sessions was associated with greater weight loss (P = 0.002).Conclusions: WbF facilitated weight loss mainly in male participants. Level of participation in WbF activities correlated with weight loss.Impact: Findings suggest that additional research is needed to better understand factors associated with participation in health promotion programs for underserved rural communities. Cancer Epidemiol Biomarkers Prev; 27(11); 1289-97. ©2018 AACR.

Diarrhea in American infants and young children in the community setting: incidence, clinical presentation and microbiology.

OBJECTIVE: The characteristics and microbiology of the full spectrum of pediatric diarrhea occurring in the U.S. community setting are not well-understood. METHODS: Six-month prospective cohort study of 604 healthy 6- to 36-month-old children recruited by the Slone Center Office-based Research Network. RESULTS: The incidence of parent-defined diarrhea was 2.2 episodes per person-year. The median duration of diarrhea was 2 days with a median of 6 stools per episode. Outpatient visits and hospitalization were prompted by 9.7 and 0.3% of episodes, respectively. The most common microorganisms identified in healthy baseline stools were atypical enteropathogenic Escherichia coli (12.2%), enteroaggregative Escherichia coli (3.7%), Clostridium difficile (3.5%) and Clostridium perfringens (2.9%), and each of these was no more common in diarrhea stools. In contrast, all of the viruses analyzed were more prevalent in diarrhea specimens than in baseline specimens: enteric adenovirus (5.7% diarrhea versus 1.4% baseline), rotavirus (5.2% versus 1.4%), astrovirus (3.5% versus 1.4%), Sapporo-like virus (3.0% versus 0.8%) and norovirus (1.9% versus 0.8%). A likely pathogen was detected in 20.6% of diarrhea specimens. Vomiting and > or =16 stools in an episode were predictive of isolating a pathogen from the stool, each with a relative risk of approximately 2. CONCLUSIONS: Healthy young children in this study experienced more than 2 cases of diarrhea per person-year, but most were brief and do not require medical attention. Although most diarrhea-associated pathogens were viruses, no likely pathogen was found in almost 80% of cases; possible etiologies for these cases include currently unknown gastrointestinal infections, nongastrointestinal illnesses and dietary/environmental factors.

Evaluating the impacts of screening and smoking cessation programmes on lung cancer in a high-burden region of the USA: a simulation modelling study.

OBJECTIVE: While the US Preventive Services Task Force has issued recommendations for lung cancer screening, its effectiveness at reducing lung cancer burden may vary at local levels due to regional variations in smoking behaviour. Our objective was to use an existing model to determine the impacts of lung cancer screening alone or in addition to increased smoking cessation in a US region with a relatively high smoking prevalence and lung cancer incidence. SETTING: Computer-based simulation model. PARTICIPANTS: Simulated population of individuals 55 and older based on smoking prevalence and census data from Northeast Pennsylvania. INTERVENTIONS: Hypothetical lung cancer control from 2014 to 2050 through (1) screening with CT, (2) intensified smoking cessation or (3) a combination strategy. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were lung cancer mortality rates. Secondary outcomes included number of people eligible for screening and number of radiation-induced lung cancers. RESULTS: Combining lung cancer screening with increased smoking cessation would yield an estimated 8.1% reduction in cumulative lung cancer mortality by 2050. Our model estimated that the number of screening-eligible individuals would progressively decrease over time, indicating declining benefit of a screening-only programme. Lung cancer screening achieved a greater mortality reduction in earlier years, but was later surpassed by smoking cessation. CONCLUSIONS: Combining smoking cessation programmes with lung cancer screening would provide the most benefit to a population, especially considering the growing proportion of patients ineligible for screening based on current recommendations.

No Association Between Vitamin D Intake, VDR Polymorphisms, and Colorectal Cancer in a Population-Based Case-Control Study.

BACKGROUND: Epidemiologic evidence indicates that greater intakes of vitamin D may decrease the risk of colorectal cancer. Variants in the vitamin D receptor (VDR) gene have the potential to modify associations between vitamin D intake and colorectal cancer. METHODS: Associations between intakes of vitamin D and colorectal cancer were studied in a large case-control study conducted in central and northeastern Pennsylvania including 1,012 cases with histologically confirmed colorectal cancer and 1,080 population-based controls. Associations between 35 tagSNPs encompassing the VDR gene and risk for colorectal cancer as well as gene-diet associations were also assessed among a subset of the population (770 controls, 710 cases). RESULTS: No significant trends were observed between vitamin D intake and colorectal cancer risk. After adjustment for multiple comparisons, none of the SNPs or haplotypes within the VDR gene were associated with colorectal cancer. There were also no interactions between dietary factors and variants in the entire VDR gene. CONCLUSIONS: Overall, results from this study suggest that vitamin D intake and variants in the VDR gene have little effect on risk for colorectal cancer. IMPACT: Increasing vitamin D intake from the diet may not result in decreasing the incidence of colorectal cancer.

Study design, intervention, and baseline characteristics of a group randomized trial involving a faith-based healthy eating and physical activity intervention (Walk by Faith) to reduce weight and cancer risk among overweight and obese Appalachian adults.

BACKGROUND: Increased prevalence of overweight and obesity among Appalachian residents may contribute to increased cancer rates in this region. This manuscript describes the design, components, and participant baseline characteristics of a faith-based study to decrease overweight and obesity among Appalachian residents. METHODS: A group randomized study design was used to assign 13 churches to an intervention to reduce overweight and obesity (Walk by Faith) and 15 churches to a cancer screening intervention (Ribbons of Faith). Church members with a body mass index (BMI) ?25 were recruited from these churches in Appalachian counties in five states to participate in the study. A standard protocol was used to measure participant characteristics at baseline. The same protocol will be followed to obtain measurements after completion of the active intervention phase (12months) and the sustainability phase (24months). Primary outcome is change in BMI from baseline to 12months. Secondary outcomes include changes in blood pressure, waist-to-hip ratio, and fruit and vegetable consumption, as well as intervention sustainability. RESULTS: Church members (n=664) from 28 churches enrolled in the study. At baseline 64.3% of the participants were obese (BMI?30), less than half (41.6%) reported regular exercise, and 85.5% reported consuming less than 5 servings of fruits and vegetables per day. CONCLUSIONS: Church members recruited to participate in a faith-based study across the Appalachian region reported high rates of unhealthy behaviors. We have demonstrated the feasibility of developing and recruiting participants to a faith-based intervention aimed at improving diet and increasing exercise among underserved populations.

Infant sleep position and associated health outcomes.

BACKGROUND: The incidence of sudden infant death syndrome has decreased in the United States as the percentage of infants sleeping prone has decreased, but persisting concerns about the safety of supine sleeping likely contribute to prone sleeping prevalence rates that remain higher than 10%. OBJECTIVE: To document health outcomes in infants aged 1 to 6 months in relation to sleep position. DESIGN: Prospective cohort study. SETTING: Massachusetts and Ohio, from February 21, 1995, to December 31, 1998. STUDY PARTICIPANTS: A total of 3733 infants with consistent sleep positions at ages 1, 3, and 6 months. MAIN OUTCOME MEASURES: Descriptive statistics and multiple logistic regression analysis relating sleep position at each follow-up age to symptoms in the prior week (fever, cough, wheezing, stuffy nose, trouble breathing or sleeping, diarrhea, vomiting, or spitting up) and outpatient visits in the prior month (ear infection, breathing problem, vomiting, spitting up, colic, seizure, accident, or injury). RESULTS: No symptoms or outpatient visits were significantly more common among infants sleeping on the side or supine than in infants sleeping prone, and 3 symptoms were less common: (1) fever at 1 month in infants sleeping in the supine (adjusted odds ratio [OR], 0.56; 95% confidence interval [CI], 0.34-0.93) and side positions (OR, 0.48; 95% CI, 0.28-0.82); (2) stuffy nose at 6 months in the supine (OR, 0.74; 95% CI, 0.61-0.89) and side positions (OR, 0.82; 95% CI, 0.68-0.99); and (3) trouble sleeping at 6 months in the supine (OR, 0.57; 95% CI, 0.44-0.73) and side positions (OR, 0.69; 95% CI, 0.53-0.89). Also, outpatient visits for ear infections were less common at 3 and 6 months in infants sleeping in the supine position (OR, 0.64; 95% CI, 0.46-0.88; and OR, 0.73; 95% CI, 0.58-0.92, respectively) and at 3 months in the side position (OR, 0.68; 95% CI, 0.49-0.96). CONCLUSIONS: No identified symptom or illness was significantly increased among nonprone sleepers during the first 6 months of life. These reassuring results may contribute to increased use of the supine position for infant sleeping.

Frequency of bed sharing and its relationship to breastfeeding.

Bed sharing has been promoted as facilitating breastfeeding but also may increase risks for sudden, unexpected infant deaths. This prospective cohort study was performed to determine the prevalence of adult and infant bed sharing and its association with maternal and infant characteristics. Demographic data were collected from 10,355 infant-mother pairs at birth hospitals in Eastern Massachusetts and Northwest Ohio, and follow-up data were collected at 1, 3, and 6 months by questionnaire. Associations with bed sharing were estimated using odds ratios and 95% confidence intervals from multiple logistic regression models while adjusting for confounding variables. At 1, 3, and 6 months, 22%, 14%, and 13% of infant-mother pairs shared a bed, respectively. On multivariate analysis, race/ethnicity and breastfeeding seemed to have the strongest association with bed sharing. These factors need to be considered in any comprehensive risk to benefit analysis of bed sharing.

Racial/ethnic disparities in the diagnosis of otitis media in infancy.

OBJECTIVE: Otitis media (OM) is an extremely common pediatric diagnosis. Several risk factors have been associated with OM, but the relationship between OM and race/ethnicity remains controversial. We sought to define the relationship between OM diagnosis and race/ethnicity in infants. METHODS: By multivariable logistic regression, we evaluated the association between OM diagnosis and race/ethnicity in 11,349 non-low-birthweight infants who were participants in a prospective cohort study of infant care practices. RESULTS: As in previous studies, breastfeeding was associated with a decreased risk of OM diagnosis while other factors were independently associated with a substantially increased risk of OM diagnosis: out-of-home daycare, multiple children living in the home, and mother's multiparity. Daycare was associated with a "dose effect" in that the risk of OM diagnosis increased with an increasing number of children in the daycare. While the crude analysis suggested little relation of OM diagnosis and race/ethnicity, the association was confounded by several covariates including maternal marital status, number of children living in the home, breastfeeding status, and maternal age. After adjustment for relevant confounders, Black (OR 0.74; 95% CI 0.61-0.89) and Asian infants (OR 0.77; 95% CI 0.57-1.0]) were less likely to be diagnosed with OM than White infants. CONCLUSIONS: This large prospective study confirms previous risk factors for OM and demonstrates a strong "dose effect" of the size of daycare centers on OM. The study also demonstrates that the association between race/ethnicity and OM diagnosis is confounded by social factors. After adjusting for such factors, Black and Asian infants are less likely to be diagnosed with OM than White infants. The reason for this racial disparity remains unknown.

The safety of ibuprofen suspension in children.

This paper describes two studies in children with fever in which the safety of ibuprofen was compared with that of paracetamol. The Boston University Fever Study aimed to assess the risk of rare but serious adverse events in febrile children. There were 795 admissions among 84,192 children during the study. There were no significant differences between the drugs in the risk of admission or the risk of secondary endpoints (admissions for asthma or cellulitis, or physician visits for abdominal pain or dyspepsia) and no evidence of clinically significant impairment of renal function. However, ibuprofen was associated with a significantly lower risk of physician visits for asthma: the incidence associated with ibuprofen was 3.0% (CI95% 2.1, 4.1) compared with 5.1% (CI95% 3.5, 7.1) for paracetamol (P = 0.02). The second study was a case control study to investigate a possible association between antipyretic medication, varicella infection and necrotising fasciitis. We identified 52 children aged under 19 years who were admitted to hospital with varicella and Group A streptococcal infection and 172 matched controls with uncomplicated varicella. The risk of invasive Group A streptococcal infection was associated with demographic and environmental factors and persistent high fever. There was no association with the use of ibuprofen or paracetamol alone, but the use of both agents was significantly associated with streptococcal infection. These studies demonstrate that children with fever tolerate treatment with ibuprofen as well as treatment with paracetamol. Neither agent is associated with an increased risk of necrotising soft tissue infections.

Predictors of acute kidney injury in geriatric patients undergoing total knee replacement surgery.

BACKGROUND: Few studies have focused on patients' characteristics that affects acute kidney injury (AKI) after total knee replacement surgery (TKR). OBJECTIVES: The primary objective of this retrospective study was to identify patients' characteristics associated with AKI after TKR. PATIENTS AND METHODS: Between January 2008 and December 2009, 659 patients with a mean age of 67.1 years (range, 39-99) underwent TKA at Regional Hospital Knee and Hip Institute. Retrospective chart review was done to identify patients' characteristics that were associated with AKI after TKR. Logistic regression was used to evaluate AKI. RESULTS: AKI occurred in 21.9% of patients. AKI risk decreased between 2008 and 2009 (odds ratio, 0.55; 95% CI, -0.37 to 0.82) but increased with age (P < 0.001), diabetes mellitus (DM), and angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) use (OR, -1.6; 95% CI, -1.0 to 2.5; and OR, -1.5, 95% CI, -1.0 to 2.3, respectively). However, the effects of DM and ACEI/ARB use were not independent; when both were included in the regression model, neither was statistically significant, and both ORs were smaller than combined OR. CONCLUSIONS: When examined separately, both DM and preoperative ACEI/ARB use increased the risk of AKI; however these factors were correlated and were not independent predictors of significantly increased risk. Patients with DM have higher tendency to develop AKI and hence, preoperative renal risk stratification should be done in all patients with DM.

Association of dietary and supplemental iron and colorectal cancer in a population-based study.

We evaluated the role of dietary iron, heme iron, and supplemental iron on colorectal cancer (CRC) risk in a population-based case-control study in Pennsylvania, including 1005 incident cases and 1062 controls. Diet was assessed through a modified food frequency questionnaire that included supplement use and a meat-specific module. Cases reported intakes for the year before diagnosis, whereas controls reported intakes for the year before interview. Heme iron intake was calculated using a new heme database developed by the US National Cancer Institute. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. After multivariate adjustment, there were no significant associations between heme iron or total iron intake and CRC incidence. Dietary iron intake was inversely associated with CRC among women (OR Q5 vs. Q1=0.45; 95% CI=0.22-0.92), but not among men. Supplemental iron intake of more than 18 mg/day versus none was positively associated with CRC incidence (OR=2.31; 95% CI=1.48-3.59; P-trend<0.001), an effect that was observed in both men (OR=2.56; 95% CI=1.30-5.05) and women (OR=2.46; 95% CI=1.34-4.52). These findings suggest that consumption of more than 18 mg/day of supplemental iron may increase risk for CRC.

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance.

The HER2-targeted therapy trastuzumab is widely used for the treatment of patients with metastatic breast tumors overexpressing HER2. However, an objective response is observed in only 12% to 24% of patients treated with trastuzumab as a single agent and initial responders regress in <6 months (1-3). The reason for the clinical failure of trastuzumab in this setting remains unclear. Here we show that local lymph node-positive disease progression in 89% of breast cancer patients with HER2-positive tumors involves the HER2 oncogenic variant HER2Delta16. We further show that ectopic expression of HER2Delta16, but not wild-type HER2, promotes receptor dimerization, cell invasion, and trastuzumab resistance of NIH3T3 and MCF-7 tumor cell lines. The potentiated metastatic and oncogenic properties of HER2Delta16 were mediated through direct coupling of HER2Delta16 to Src kinase. Cotargeting of HER2Delta16 and Src kinase with the single-agent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, destabilization of HER2Delta16, and suppressed tumorigenicity. Activated Src kinase was also observed in 44% of HER2Delta16-expressing breast carcinomas underscoring the potential clinical implications of coupled HER2Delta16 and Src signaling. Our results suggest that HER2Delta16 expression is an important genetic event driving trastuzumab-refractory breast cancer. We propose that successful targeted therapeutics for intervention of aggressive HER2-positive breast cancers will require a strategy to suppress HER2Delta16 oncogenic signaling. One possibility involves a therapeutic strategy employing single-agent tyrosine kinase inhibitors to disengage the functionally coupled oncogenic HER2Delta16 and Src tyrosine kinase pathways.

Identifying cluster subtypes for intentions to have colorectal cancer screening among non-compliant intermediate-risk siblings of individuals with colorectal cancer.

Although first-degree relatives of colorectal cancer (CRC) patients diagnosed at an early age are at increased risk for CRC, their compliance with colorectal cancer screening (CRCS) is not high. Relatively little is known about why these intermediate-risk family members do not comply with CRCS. Study aims were to identify subgroups of siblings of individuals diagnosed with CRC prior to age 61 who were not compliant with CRCS using cluster analysis and to identify demographical, medical and attitudinal correlates of cluster membership. A total of 421 siblings completed measures of pros, cons, processes of change, CRCS knowledge, physician and family CRCS support, CRC risk, severity, preventability, curability, closeness with the affected sibling, distress about the sibling's cancer and screening intentions. Three clusters characterized as 'Positive about Screening', 'Uncertain about Screening' and 'Negative about Screening' were identified. External validation revealed that those in the Positive about Screening cluster reported significantly stronger CRCS intentions than those who are Uncertain about Screening and Negative about Screening clusters. Results provide an empirical typology for understanding motivations for CRCS among at-risk family members and may lead to the development of more effective interventions to improve screening uptake.