Comparison of a Mediterranean to a low-fat diet intervention in adults with type 1 diabetes and metabolic syndrome: A 6-month randomized trial.

BACKGROUND AND AIMS: The metabolic syndrome (MS) is an emerging complication in patients with type 1 diabetes (T1D), with no preventive or therapeutic treatment reported yet. We wanted to compare the impact of two 6-month nutritional interventions, based on a Mediterranean (MED) or a low-fat diet, on waist circumference, anthropometric and metabolic outcomes in patients with both T1D and the MS. METHODS AND RESULTS: Participants were randomized into 2 intervention groups: 1) MED-diet or 2) low-fat diet. The 6-month study included 9 teaching sessions with a registered dietitian. Anthropometric (primary outcome: waist circumference), metabolic and nutritional assessments were performed at inclusion, 3 and 6-month. We used mixed effects models to assess the effects of both interventions. 28 participants were included (50.9 ± 10.3 years old) with a mean BMI of 30.7 ± 3.3 kg/m2 and a waist circumference of 105.5 ± 8.9 cm at inclusion. A trend towards a greater reduction of dietary fat intakes in the low-fat diet group was observed (P-interaction = 0.09). Waist circumference was reduced at 6-month in both groups (-3.5 cm low-fat; -1.5 cm MED-diet) with no significant difference between groups (P-interaction = 0.43). Body mass index also significantly decreased in both groups (-0.7 kg/m2 low-fat; -1.1 kg/m2 MED-diet; P-interaction = 0.56). No significant differences between groups were observed for other metabolic parameters. CONCLUSIONS: This study suggests that a 6-month non-restrictive dietary intervention in patients with T1D and MS could contribute to weight management, without significant differences between interventions for anthropometric and metabolic parameters. Further studies should investigate the long-term benefits of these diets. CLINICAL TRIAL REGISTRY: NCT02821585 (https://clinicaltrials.gov/).

Validation of the omega-3 fatty acid intake measured by a web-based food frequency questionnaire against omega-3 fatty acids in red blood cells in men with prostate cancer.

BACKGROUND/OBJECTIVES: The objective of this study was to evaluate the ability of a web-based self-administered food frequency questionnaire (web-FFQ) to assess the omega-3 (ω-3) fatty acids (FAs) intake of men affected with prostate cancer (PCa) against a biomarker. SUBJECTS/METHODS: The study presented herein is a sub-study from a phase II clinical trial. Enrolled patients afflicted with PCa were included in the sub-study analysis if the FA profiles from the red blood cell (RBC) membranes and FA intakes at baseline were both determined at the time of the data analysis (n=60). Spearman's correlation coefficients were calculated to estimate the correlations between FA intakes and their proportions in the RBC membranes. RESULTS: Intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were highly correlated with their respective proportions in the RBC membranes (both rs=0.593, P<0.0001). Correlation between alpha-linolenic acid (ALA) intake and its proportion in RBC was not significant (rs=0.130, P=0.332). Correlations were observed between fatty fish intake and total ω-3 FAs (rs=0.304, P=0.02), total long-chain ω-3 FAs (rs=0.290, P=0.03) and DHA (rs=0.328, P=0.01) in RBC membranes. CONCLUSIONS: This study has shown that the web-FFQ is an accurate tool to assess total long-chain ω-3 FAs, EPA and DHA but not ALA intake in clinical trials and epidemiological studies carried out in men with PCa.

Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer.

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer.

Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR-restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556-10.421, P=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, 95% CI 1.194-3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.

Quality of diet is associated with insulin resistance in the Cree (Eeyouch) indigenous population of northern Québec.

BACKGROUND AND AIMS: Indigenous people worldwide have a greater disease burden than their non-aboriginal counterparts with health challenges that include increased obesity and higher prevalence of diabetes. We investigate the relationships of dietary patterns with nutritional biomarkers, selected environmental contaminants and measures of insulin resistance in the Cree (Eeyouch) of northern Québec Canada. METHODS AND RESULTS: The cross-sectional 'Nituuchischaayihitaau Aschii: A Multi-Community Environment-and-Health Study in Eeyou Istchee' recruited 835 adult participants (≥18 y) from 7 communities in the James Bay region of northern Québec. The three dietary patterns identified by principal component analysis (PCA) were: inland and coastal patterns with loadings on traditional foods, and a junk food pattern with high-fat and high-sugar foods. We investigated dietary patterns scores (in quantiles) in relation with nutritional biomarkers, environmental contaminants, anthropometry, blood pressure, fasting plasma glucose and insulin, and insulin resistance. Homeostatic model assessment (HOMA-IR) was used as surrogate markers of insulin resistance. ANCOVA ascertained relationships between dietary patterns relationship and outcomes. Greater scores for the traditional patterns were associated with higher levels of n-3 fatty acids, mercury and polychlorinated biphenyls (PCBs) (P trend <0.001). Higher scores for the junk food pattern were associated with lower levels of PCBs and Vitamin D, but higher fasting plasma insulin and HOMA-IR. CONCLUSION: Our results suggest that poor diet quality accompanied greater insulin resistance. Impacts of diet quality on insulin resistance, as a sign of metabolism perturbation, deserve more attention in this indigenous population with high rates of obesity and diabetes.

Docosahexaenoic acid-enriched canola oil increases adiponectin concentrations: a randomized crossover controlled intervention trial.

BACKGROUND AND AIMS: Little is known about the effect of various dietary fatty acids on pro- and anti-inflammatory processes. We investigated the effect of 5 oils containing various amounts of alpha-linolenic acid (ALA), linoleic acid (LA), oleic acid (OA) and docosahexaenoic acid (DHA) on plasma inflammatory biomarkers and expression levels of key inflammatory genes and transcription factors in whole blood cells. METHODS AND RESULTS: In a randomized, crossover controlled nutrition intervention, 114 adult men and women with abdominal obesity and at least one other criterion for the metabolic syndrome consumed 5 experimental isoenergetic diets for 4 weeks each, separated by 4-week washout periods. Each diet provided 60 g/3000 kcal of different oils: 1) control corn/safflower oil blend (CornSaff; LA-rich), 2) flax/safflower oil blend (FlaxSaff; ALA-rich), 3) conventional canola oil (Canola; OA-rich), 4) high oleic canola oil (CanolaOleic; highest OA content), 5) DHA-enriched high oleic canola oil (CanolaDHA; OA- and DHA-rich). Gene expression in whole blood cells was assessed in a subset of 62 subjects. CanolaDHA increased plasma adiponectin concentrations compared with the control CornSaff oil treatment (+4.5%, P = 0.04) and FlaxSaff (+6.9%, P = 0.0008). CanolaDHA also reduced relative expression levels of interleukin (IL)1B compared with CornSaff and Canola (-11% and -13%, respectively, both P = 0.03). High-sensitivity C-reactive protein concentrations were lower after Canola than after FlaxSaff (-17.8%, P = 0.047). CONCLUSION: DHA-enriched canola oil exerts anti-inflammatory effects compared with polyunsaturated fatty acids from plant sources.

Association of red blood cell n-3 polyunsaturated fatty acids with plasma inflammatory biomarkers among the Quebec Cree population.

BACKGROUND/OBJECTIVES: We examined the prevalence of elevated plasma high-sensitivity C-reactive protein (hs-CRP) concentrations and associations with red blood cell (RBC) long-chain n-3 polyunsaturated fatty acids (LCn-3PUFA) in the James Bay Cree population from the province of Quebec (Canada). SUBJECTS/METHODS: A total of 744 Cree adults (18-91 years) from seven communities of Eastern James Bay were included in these cross-sectional analyses. Associations between RBC LCn-3PUFA and proinflammatory markers (hs-CRP, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)) were assessed by using multivariate general linear models with adjustment for sex, age and waist circumference. An arbitrary inflammation score was defined based on the sum of the quartiles of hs-CRP, IL-6 and TNF-α concentrations (range=3-12). RESULTS: Elevated hs-CRP concentrations (>3 mg/l) were present in 46.9% (95% confidence interval (CI) 43.3-50.5) of the James Bay Cree population. RBC docosapentaenoic acid (DPAn-3; C22:5n-3) was inversely associated with hs-CRP, TNF-α and the inflammation score (all P trend<0.02), whereas eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3) in RBC were not associated with inflammation (all P trend>0.18). Among participants with RBC DPAn-3 levels above the median of the population, odds ratio of having an elevated inflammation score (≥9) was 0.67 (95% CI, 0.48-0.93) compared with participants below the median. CONCLUSIONS: RESULTS indicate that low-grade systemic inflammation is highly prevalent and that higher RBC DPAn-3 levels are associated with a lower risk of systemic inflammation in the James Bay Cree population.

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy.

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

Association of common gene variants in the WNT/ß-catenin pathway with colon cancer recurrence.

Wnt/ß-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/ß-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/ß-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.

Gender-specific profiling in SCN1A polymorphisms and time-to-recurrence in patients with stage II/III colorectal cancer treated with adjuvant 5-fluoruracil chemotherapy.

This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.

Is a small muscle mass index really detrimental for insulin sensitivity in postmenopausal women of various body composition status?

OBJECTIVES: We sought to determine if a small muscle mass index (MMI) is actually detrimental for insulin sensitivity when studying a large group of postmenopausal women displaying various body composition statuses and when age and visceral fat mass (VFM) are taken into account. METHODS: A cross-sectional study was conducted in 99 healthy postmenopausal women with a BMI of 28±4 kg/m(2). Fat mass and total fat-free mass (FFM) were obtained from DXA and VFM and MMI were estimated respectively by the equation of Bertin and by: Total FFM (kg)/height (m)(2). Fasting plasma insulin and glucose were obtained to calculate QUICKI and HOMA as an insulin sensitivity index. RESULTS: Total MMI and VFM were both significantly inversely correlated with QUICKI and positively with HOMA even when adjusted for VFM. A stepwise linear regression confirmed Total MMI and VFM as independent predictors of HOMA and plasma insulin level. CONCLUSIONS: A small muscle mass might not be detrimental for the maintenance of insulin sensitivity and could even be beneficial in sedentary postmenopausal women. The impact of muscle mass loss on insulin sensitivity in older adults needs to be further investigated.

Selecting the best targeted agent in first-line treatment of unresectable liver metastases from colorectal cancer: does the bench have the answers?

For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micrometastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent (anti-EGFR or anti-VEGF) to reach these goals. Therefore, a priori molecular identification of patients that could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the currently approved targeted therapies for metastatic colorectal cancer) is of critical importance. In this setting, the KRAS mutation status was the first identified predictive marker of response to anti-EGFR therapy. Since it has been demonstrated that tumors with KRAS mutation do not respond to anti-EGFR therapy, KRAS status must be determined prior to treatment. Thus, for KRAS wild-type patients, the choices that remain are either anti-VEGF or anti-EGFR. In this review, we present the most updated data from translational research programs dealing with the identification of biomarkers for response to targeted therapies.

Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of death in the United States. Increased level of interleukin-8 (IL-8) and CXCR2 on tumours and in the tumour microenvironment has been associated with CRC growth, progression and recurrence in patients. Here, we aimed to evaluate the effects of tissue microenvironment-encoded IL-8 and CXCR2 on colon cancer progression and metastasis. METHODS: A novel immunodeficient, skin-specific IL-8-expressing transgenic model was generated to evaluate colon cancer growth and metastasis. Syngeneic mouse colon cancer cells were grafted in CXCR2 knockout (KO) mice to study the contribution of CXCR2 in the microenvironment to cancer growth. RESULTS: Elevated levels of IL-8 in the serum and tumour microenvironment profoundly enhanced the growth of human and mouse colon cancer cells with increased peri-tumoural angiogenesis, and also promoted the extravasation of the cancer cells into the lung and liver. The tumour growth was inhibited in CXCR2 KO mice with significantly reduced tumour angiogenesis and increased tumour necrosis. CONCLUSION: Increased expression of IL-8 in the tumour microenvironment enhanced colon cancer growth and metastasis. Moreover, the absence of its receptor CXCR2 in the tumour microenvironment prevented colon cancer cell growth. Together, our study demonstrates the critical roles of the tumour microenvironment-encoded IL-8/CXCR2 in colon cancer pathogenesis, validating the pathway as an important therapeutic target.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer.

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination. PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate. RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92). CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Validity and reproducibility of a web-based, self-administered food frequency questionnaire.

BACKGROUND/OBJECTIVES: To assess the validity and the reproducibility of a newly developed web-based, self-administered food frequency questionnaire (web-FFQ). SUBJECTS/METHODS: A total of 74 healthy subjects (34 men and 40 women) from the Québec City metropolitan area were asked to complete, in random order, the web-FFQ, a validated interviewer-administered FFQ (IA-FFQ) and a 3-day food record (3-day FR). RESULTS: Mean intakes of 17/22 nutrients assessed between the web-FFQ and the 3-day FR were not significantly different (differences <10%, P≥0.11). Sex and energy-adjusted de-attenuated Pearson correlation coefficients for each nutrient varied from 0.12-0.98 (mean R=0.55, 95% confidence interval 0.46; 0.63) between the web-FFQ and the 3-day FR. All correlations were significant (P≤0.01) and above 0.34 (mean R=0.59, 95% confidence interval 0.54; 0.65) between the web-FFQ and the IA-FFQ, except for sodium (R=0.17, P=0.14). Cross-classification analysis revealed that on average, 77% of subjects were classified in the same or adjacent quartile of nutrient intake between the web-FFQ and the 3-day FR. Correlation coefficients for reproducibility of the web-FFQ tested 4-6 weeks apart in the same individuals were all equal or above 0.48 (P≤0.0001; mean R=0.72, 95% confidence interval 0.68; 0.76). More than 90% of the subjects were classified in the same or adjacent quartile between the two administrations of the web-FFQ, while only 0.8% was misclassified. CONCLUSIONS: These data demonstrate that the newly developed web-based FFQ appears to have reasonable validity and good reproducibility for assessing nutrient intakes at the group and individual levels in a population of healthy adults.

Combined effect of antioxidant supplementation and resistance training on oxidative stress markers, muscle and body composition in an elderly population.

This study was aimed to examine the effect of vitamin C/E intake alone or combined with resistance training on antioxidant/pro-oxidant status, muscle strength and body composition in an elderly population. Fifty-seven men and women with a mean age of 65.6 ± 3.8 years were recruited and randomized in a double-blind fashion into four groups: control-placebo; resistance training (RT); vitamins C/E supplementation (AS); AS+RT. Oxidative stress status and metabolic and lipid profiles were determined at baseline and after six months. Fat-free mass and fat mass measured by DXA were similar at baseline for all groups. At six month, there was a significant difference among the groups as a function of vitamin E supplementation. Moreover, although there was no effect on pro-oxidative parameters, a significant effect on body composition was noted, but no difference was noted on strength gain. The combination of RT+AS had a positive effect on the plasma antioxidant profile but not on the pro-oxidant status.

A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy.

PURPOSE: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy. PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique. RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes. CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

Effect of antioxidants combined to resistance training on BMD in elderly women: a pilot study.

SUMMARY: We determined the effect of antioxidants and resistance training on bone mineral density of postmenopausal women. After 6 months, we observed a significant decrease in the lumbar spine BMD of the placebo group while other groups remained stable. Antioxidants may offer protection against bone loss such as resistance training. INTRODUCTION: The purpose of this pilot study was to determine the effects of antioxidant supplements combined to resistance training on bone mineral density (BMD) in healthy elderly women. METHODS: Thirty-four postmenopausal women (66.1 +/- 3.3 years) were randomized in four groups (placebo, n = 7; antioxidants, n = 8; exercise and placebo, n = 11; and exercise and antioxidants, n = 8). The 6-month intervention consisted in antioxidant supplements (600 mg vitamin E and 1,000 mg vitamin C daily) or resistance exercise (3x/week). Femoral neck and lumbar spine BMD (DXA) and dietary intakes (3-day food record) were measured before and after the intervention. A repeated measure ANOVA and non-parametric Mann-Whitney U tests were used. RESULTS: We observed a significant decrease in the placebo group for lumbar spine BMD (pre, 1.01 +/- 0.17 g/cm(2); post, 1.00 +/- 0.16 g/cm(2); P < 0.05 respectively) while it remained stable in all other groups. No changes were observed for femoral neck BMD. CONCLUSIONS: Antioxidant vitamins may offer some protection against bone loss in the same extent as resistance exercise although combining both does not seem to produce additional effects. Our results suggest to further investigate the impact of antioxidant supplements on the prevention of osteoporosis.

Dietary animal protein intake: association with muscle mass index in older women.

BACKGROUND: Aging is associated with reductions in muscle mass and strength, so-called sarcopenia, and is generally characterized using muscle mass index (MMI = FFM (kg)/height (m)2). It is believed that adequate nutrition especially regarding protein intake, can delay this progression and enhance the quality of life of elders. OBJECTIVES: We examined whether the predominant source of protein consumed (animal or vegetal) by older women was associated with MMI. DESIGN: Thirty-eight healthy, normal weight, sedentary women, aged between 57-75 years (mean age: 66 +/- 5 years old), and taking no medication that could influence metabolism were recruited. Body composition was measured by dual-energy X-ray absorptiometry; muscle protein content was measured by the use of creatinine excretion. Physical activity metabolism was obtained by the use of accelerometry, and indirect calorimetry. Finally, protein intake was measured with a 3-day dietary record. RESULTS: Significant correlations were observed between MMI and body mass index, fat-free mass, muscle protein content, total protein intake, animal protein intake, fat mass, visceral fat and daily energy expenditure. However, a stepwise regression analysis showed animal protein intake to be the only independent predictor of MMI (r2=0.19; p=0.008). CONCLUSIONS: Our results suggest that protein intake, especially from animal sources, may be associated with a better preservation of MMI. However, more research is needed to confirm our results.