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INTRODUCTION AND OBJECTIVE:Sarcopenia (low skeletal muscle mass) is a poor prognostic factor in patients undergoing nephrectomy for localized renal cancer. However, little is known about the trajec...

AB Introduction: Maintenance of normal weight and higher levels of physical activity are associated with a reduced risk of several types of cancer. Because genomic instability is regarded as a hallmark of cancer development, one proposed mechanism is improvement of DNA repair function. We investigated links between dietary weight loss, exercise, and strand break rejoining in an ancillary study to a randomized-controlled trial. Methods: Overweight/obese postmenopausal women (n = 439) were randomized to the following: a) reduced calorie weight loss diet ("diet," n = 118), b) moderate- to vigorous-intensity aerobic exercise ("exercise," n = 117), c) a combination ("diet + exercise," n = 117), or d) control (n = 87). The reduced calorie diet had a 10% weight loss goal. The exercise intervention consisted of 45 min of moderate to vigorous aerobic activity 5 d[middle dot]wk-1 for 12 months. DNA repair capacity was measured in a subset of 226 women at baseline and 12 months from cryopreserved peripheral mononuclear cells using the comet assay. Anthropometric and body composition measures were performed at baseline and 12 months. Results: DNA repair capacity did not change significantly with any of the 12-month interventions compared with control; there were also no significant changes when stratified by changes in body composition or aerobic fitness (V[spacing dot above]O2max). At baseline, DNA repair capacity was positively associated with weight, body mass index, and fat mass (r = 0.20, P = 0.003; r = 0.19, P = 0.004; r = 0.13, P = 0.04, respectively) and inversely with lean body mass (r = -0.14, P = 0.04). Conclusion: In conclusion, DNA repair capacity in cryopreserved PBMCs (Comet Assay) did not change with dietary weight loss or exercise interventions in postmenopausal women within a period of 12 months. Other assays that capture different facets of DNA repair function may be needed.

Introduction The glutathione S-transferase (GST) enzymes are involved in the detoxification of a range of carcinogenic compounds as well as chemotherapeutic agents. Therefore, genetic variants in the GST genes could influence survival in patients with colorectal cancer (CRC). Results from previous studies have been inconsistent and therefore we investigated the association between the GSTP1 ile105val polymorphism and the copy number variants of the GSTM1 and GSTT1 genes and survival in CRC patients treated with adjuvant/palliative chemotherapy. Patients and methods We included 755 CRC patients with stage II-IV disease from two population-based studies carried out in Germany. Genotyping of the GSTP1 polymorphism was carried out using fluorescence-based melting curve analysis and copy number variants were determined using a multiplex PCR. Survival analysis was carried out using the Cox regression model, adjusting for age, sex, UICC stage, cancer site, and radiation therapy. Results Compared with noncarriers, CRC patients who were homozygote carriers of GSTM1 had significantly poorer survival after treatment with oxaliplatin [hazard ratio (HR) 2.25, 95% confidence interval (CI) 0.93-5.44] than those not treated with oxaliplatin (HR 0.64, 95% CI 0.30-1.34; P for heterogeneity=0.031). The association was significant in metastatic CRC patients treated with oxaliplatin (HR 3.59, 95% CI 1.29-10.03). Neither the GSTP1 105val allele nor the GSTT1 deletion was significantly associated with CRC survival. Conclusion Our data suggest that GSTM1 may be a predictive marker for oxaliplatin therapy; however, independent large studies are warranted to confirm these results.

Family history of cancer (FHC) is important in the context of cancer prevention and risk counselling, but there is a lack of information about its consideration in medical routine. We aimed to characterize how FHC is assessed and taken into account in the primary care setting in Germany. We conducted a mail survey among 285 office-based physicians in south-west Germany. We sent a questionnaire to randomly selected general practitioners, dermatologists, gastroenterologists, gynaecologists, urologists and pulmonologists, asking about collection of information on FHC and implications for preventive counselling. A total of 207 physicians returned the questionnaire (response rate 73%), of whom 71% reported asking for FHC routinely, 17% reported using a standardized tool to collect the information and 35% reported regularly updating it. Implications of a positive FHC for counselling were heterogeneous, with priority on recommendations for screening. Referral to genetic counselling was considered by 34% of physicians, mainly gastroenterologists and gynaecologists. In the primary care setting in Germany, FHC is considered an important topic, but there is a lack of standardization in collecting the information and heterogeneity on the implications for counselling. Options to improve this situation, such as the implementation of standardized tools or centralized counselling systems, are needed.

AB Purpose: This study aimed to evaluate the safety, feasibility, and effects of an 8-wk combined resistance and endurance exercise program in patients with advanced non-small cell lung cancer (NSCLC) during in- and outpatient care. Methods: In this intervention study, 40 patients with predominantly advanced NSCLC receiving simultaneous or sequential radiochemotherapy or chemotherapy alone were enrolled. For a period of 8 wk, patients were instructed to exercise at least five times per week during the inpatient setting and at least three times per week in the outpatient setting. Physical performance status (endurance capacity: 6-min walk test; strength capacity: handheld dynamometry), quality-of-life (Functional Assessment of Cancer Therapy-Lung), fatigue (Multidimensional Fatigue Inventory), and depression (Patient Health Questionnaire) were assessed at baseline (T0), after the exercise intervention (T1), and at a follow-up time point 8 wk later (T2). The primary end point was adequate adherence (feasibility) defined as completing at least two training sessions per week during a minimum of 6 wk. Results: Of 40 patients, 31 (77.5%) completed the postexercise assessment (T1) and 22 (55%) completed follow-up (T2). The stages were IIA (5%), IIIA (8%), IIIB (20%), and IV (67%), and the median age was 63 yr (range = 22-75 yr). Overall, adherence was 82% for those patients who completed T1, and 55% of the 40 participating patients fulfilled the adequate adherence criterion. Those who completed the intervention showed a significant improvement in the 6-min walk distance and in knee, elbow, and hip muscle strength after the intervention (T1). Quality of life, fatigue, and depression scores remained stable or declined slightly. Significant improvements in knee-muscle strength were also observed at T2. Conclusions: Exercise training is feasible in advanced and metastatic NSCLC patients during anticancer treatment. In this pilot study, endurance and strength capacity improved over time, indicating the rehabilitative importance of the applied intervention. To investigate the potential impact of exercise training in this patient group, a larger randomized trial is warranted

This study examined the effect of a yearlong exercise intervention on F2-isoprostane, a specific marker of lipid peroxidation and a general marker of oxidative stress.In a randomized, controlled trial, 173 overweight or obese, postmenopausal, sedentary women were randomized either to an aerobic exercise intervention (60%-75% observed maximal HR) foror =45 min.d-1, 5 d.wk-1 (n = 87), or to a stretching control group (n = 86), on an intent-to-treat basis. Baseline and 12-month measures included urinary F2-isoprostane, maximal O2 uptake, body weight, body fat percentage, waist circumference, and intra-abdominal fat surface area. Urine samples were available from 172 and 168 women at baseline and 12 months, respectively.During the 12-month study, controls minimally changed maximal O2 uptake (+0.2%) and body weight (+0.1 kg), whereas exercisers increased maximal O2 uptake (+13.6%; P0.0001 vs controls) and decreased body weight (-1.3 kg; P = 0.007 vs controls). F2-isoprostane increased slightly among controls (+3.3%) and decreased in exercisers (-6.2%), although the effect was not statistically significant (P = 0.26). In planned subgroup analyses, F2-isoprostane decreased linearly with gain in maximal O2 uptake (Ptrend = 0.005) relative to controls; exercisers who increased maximal O2 uptake by15% decreased F2-isoprostane by 14.1% (P = 0.005 vs controls). A borderline statistically significant trend was observed between decreased waist circumference and F2-isoprostane (P = 0.06). Similar subgroup analyses by 12-month changes in body fat percentage, weight, and intra-abdominal fat were not statistically significant.These findings suggest that aerobic exercise, when accompanied by relatively marked gains in aerobic fitness, decreases oxidative stress among previously sedentary older women and that these effects occur with minimal change in mass or body composition.

Purpose: To investigate the effect of a yearlong moderate-intensity aerobic exercise intervention on C-reactive protein (CRP), serum amyloid A (SAA), and interleukin 6 (IL-6) among overweight or obese postmenopausal women. Methods: In a randomized controlled trial, 115 postmenopausal, overweight or obese, sedentary women, aged 50-75 yr were randomized to an aerobic exercise intervention of moderate-intensity (60%-75% observed maximal HR), for >=45 min[middle dot]d-1, 5 d[middle dot]wk-1 (n = 53), or to a 1-d[middle dot]wk-1 stretching control (n = 62), on an intent-to-treat basis. CRP, SAA, and IL-6 were measured at baseline, at 3 months, and at 12 months. Results: From baseline to 12 months, CRP decreased 10% in exercisers and increased 12% in controls (P = 0.01); no effects were observed for SAA and IL-6. Among participants at baseline who were obese (body mass index (BMI) >= 30 kg[middle dot]m-2) or had abdominal obesity (waist circumference (WC) >= 88 cm), exercise resulted in a more pronounced reduction in CRP (BMI >= 30 kg[middle dot]m-2, P = 0.002; WC >= 88 cm, P = 30 kg[middle dot]m-2, P = 0.08; WC >= 88 cm, P = 0.04); no intervention effects were observed among women who did not have these characteristics. Overall, weight loss was minimal in the exercise intervention (~1.8 kg). Linear trends were observed between CRP and 12-month changes in aerobic fitness (Ptrend = 0.006), exercise adherence (Ptrend = 0.004), percentage body fat (Ptrend = 0.002), body weight (Ptrend = 0.002), WC (Ptrend = 0.02), and intra-abdominal fat (Ptrend = 0.03). Conclusions: A moderate-intensity exercise intervention reduced CRP for 12 months among women who were obese at baseline. These findings support the role of exercise in modulating inflammatory processes that are related to increased risk of chronic disease among obese women.

C-reactive protein (CRP) is a nonspecific marker of inflammation linked to cardiovascular disease and possibly colon cancer. Polymorphisms in CRP have been associated with differential CRP concentrations among healthy adults, with some evidence for functional effects on CRP expression.A linkage disequilibrium-based tag single nucleotide polymorphism (SNP)-selection algorithm identified six tagSNPs for Europeans (-821AG, -390CT/A, 90AT, 838GC, 2043GA, and 4363CA), defining six haplotypes with more than 1% frequency. In a case-control study of adenomatous (n=491) or hyperplastic (n=184) polyps versus polyp-free controls (n=583) we investigated these SNPs in relation to colorectal polyp risk.Individuals with 838 GC or CC genotypes had a modestly, although not statistically significantly, increased risk of adenomas (odds ratio: 1.4 95% confidence interval: 0.9-2.1) and a nearly 2-fold increased risk of concurrent adenomas and hyperplastic polyps (odds ratio: 2.0 95% confidence interval: 1.1-3.6). Increased risk for concurrent adenomas and hyperplastic polyps was also observed for haplotype ACACAC. No other main associations were detected. Risk of adenomas associated with 2043GA differed with nonsteroidal anti-inflammatory drug (NSAID) use. Among NSAID nonusers, there was a suggestion that the GA or AA genotypes were associated with decreased risk of adenomas; this was not seen among NSAID users (P interaction=0.03). We also observed interactions between UGT1A1 [TA](7) promoter repeat polymorphism and CRP tagSNPs -390CT/A and 90AT, in which only the homozygous variant CRP genotype was associated with increased risk of adenoma among those with the UGT1A1 6rpt/6rpt genotype (P interaction=0.02 and 0.04 for -390CT/A and 90AT, respectively).These results provide limited support for associations between genetic variation in CRP and colorectal polyp risk. The observed interactions should be evaluated further.

Prostaglandin synthesis is the primary target of aspirin and other nonsteroidal antiinflammatory drugs, and thus is a pathway of major interest to pharmacology, pharmacogenetics, and epidemiology. Several lines of evidence implicate prostaglandin E2 in carcinogenesis; this study aimed to identify genetic variants in genes related to prostaglandin E2 synthesis and signaling.We resequenced the coding regions of human prostaglandin E2 synthase (PGES), and prostaglandin E2 receptors EP1, EP2, and EP4 in 48 African-Americans and 47 Caucasians.We identified 23 variants, 6 of which cause amino acid changes. The non-synonymous polymorphisms in PGES, EP1, and EP2 were present only among African-Americans; both populations carried non-synonymous polymorphisms in EP4. We used two sequence homology-based programs, SIFT and PolyPhen, to predict the impact of these polymorphisms. These programs predicted that the amino-acid changes p.Phe119Val in EP1, p.Ala44Glu in EP2, and possibly p.Val7Glu in PGES, p.Thr176Ile in EP4 and p.Gly420Asp in EP4 are likely to affect protein function. Thus, these variants may be relevant for inflammatory conditions, carcinogenesis, and pharmacogenetics.

Mutations in the mismatch repair (MMR) enzymes hMLH1 and hMSH6 are known causes of hereditary nonpolyposis colorectal cancer and act by inducing a mutator phenotype characterized by microsatellite instability. The aim of our study was to determine if polymorphisms in the DNA MMR genes hMLH1 and hMSH6 are associated with an increased risk of colorectal polyps, and to evaluate interactions with exposures known to cause DNA damage.In a Minnesota-based case-control study of individuals with adenomas (N=401), hyperplastic polyps (N=195), or both adenomas and hyperplastic polyps (N=123) versus polyp-free controls (N=624), we investigated the role of hMLH1-93GA, hMLH1 I219V, and hMSH6 G39E polymorphisms in increasing the risk of colorectal polyps. Polytomous multivariate logistic regression analysis was used, adjusting for age, sex, body mass index, postmenopausal hormone use, aspirin use, and NSAID use.Overall, no evidence of an association between any of the three polymorphisms or hMLH1 haplotypes and colorectal polyps was observed. However, risk associated with the hMLH1-93A variant differed by smoking: smoking-associated risks were stronger among those with variant -93AA or -93AG genotypes, showing a twofold greater risk of adenoma with25 pack-years of smoking compared with nonsmokers, and a corresponding eightfold greater risk of hyperplastic polyps (genotype smoking: p-interaction=0.02 for hyperplastic polyps and p-interaction=0.08 for adenomas).These data are consistent with the observation that smoking is associated with MMR in colorectal neoplasia and suggest that the risk increase with smoking may differ by hMLH1-93GA genotype.

Introduction: This analysis was conducted to study the effect of a 1-yr moderate-intensity aerobic exercise program on serum lipoproteins among overweight/obese postmenopausal women. Methods: We randomized 173 sedentary (mean [latin capital V with dot above]O2max = 20.2 mL[middle dot]kg-1[middle dot]min-1), overweight/obese women (body mass index (BMI) 25.0-42.0 kg[middle dot]m-2 or body fat > 33% if BMI 24.0-25.0) aged 50-75 yr, not using hormone therapy, living in the Seattle area, to an exercise intervention or stretching control group. The exercise intervention included facility and home-based exercise (45 min, 5 d[middle dot]wk-1 of moderate-intensity sports or recreational exercise). Total cholesterol (TC), triglycerides, and high-density lipoprotein (HDL) were determined by chemical assay; low-density lipoprotein (LDL) was then calculated. Results: Of the 173 women, 170 (98.3%) completed the study with exercisers averaging 176 (SD 91) min[middle dot]wk-1 of moderate- to vigorous-intensity (60%-75% HRmax) exercise, expending approximately 3828 kJ[middle dot]wk-1 (SD 2053). Exercisers, compared with stretchers, significantly increased their [latin capital V with dot above]O2max (+11%, P