Citations

Abstract Background: Colorectal cancer (CRC) is the third most common incident cancer among women in the United States. Alcohol use has been proposed as a CRC risk factor, but existing observational data remain inconsistent. To date, relatively few studies have examined associations between alcohol use and CRC risk based on molecularly-defined subtypes. Aim: To evaluate associations between alcohol use and incident CRC overall, as well as by molecularly-defined subtypes including microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF mutation status in the prospective, population-based, Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55–69 years at enrollment, in 1986. Women with prevalent cancers or no follow-up were excluded, leaving 38,001 eligible for this study. Alcohol use was obtained from a self-administered food frequency questionnaire at study baseline. Incident CRCs were identified through annual linkage with the State Health Registry of Iowa. Archived, paraffin-embedded tissue specimens were recently requested for incident CRC cases diagnosed through December 31, 2002. In the present study, useable tissue specimens were obtained and molecularly characterized for 563/1,255 cases (45%), whose baseline age, body mass index, physical activity level, total energy intake and alcohol use were similar to non-retrieved cases (p > 0.05 for each comparison). Alcohol use was categorized as never (n=21,464), < 3.4 g/day (n=8,313) and > 3.4 g/day (n=8,224), based on the median split among users. Molecularly-defined CRC subtypes were categorized as MSI-high (MSIH; n=148), MSI-low or microsatellite stable (MSI-L/MSS; n=400); CIMP-positive (n=167) or CIMP-negative (n=368); and BRAF-mutation (n=154) or BRAF-wildtype (n=391). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated for alcohol use compared to never drinkers, using multivariable Cox regression models adjusted for body mass index, waist-to-hip ratio, smoking status, physical activity level, exogenous estrogen use, and daily intakes of total energy, total fat, red meat, sucrose, calcium, folate, methionine and vitamin E. Results: There was no statistically significant association between alcohol use and overall CRC risk (RR=1.00; 95% CI = 0.86–1.15 for < 3.4 g/day versus none; RR=1.06; 95% CI=0.91–1.24 for >3.4 g/day versus none). Further, there were no associations with alcohol use for specific, molecularly-defined CRC subtypes (RRs shown for > 3.4 g/day versus none): MSI-H (RR=1.07; 95% CI=0.70–1.64); MSI-L or MSS (RR=1.12; 95% CI=0.85–1.47); CIMP-positive (RR=0.97; 95% CI=0.64–1.47); CIMP-negative (RR=1.13; 95% CI=0.85–1.50); BRAF-mutation (RR=0.94; 95% CI=0.61–1.45); and BRAF-wildtype (RR=1.20; 95% CI=0.91–1.57). Conclusion: In this cohort of older women, alcohol use did not appear to be a risk factor for incident CRC, overall or by the defined molecular subtypes. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A115.

ABSTRACT Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase‐1 (HO‐1) expression on vaccine response and outcome of influenza infection. HO‐1‐deficient and wild‐type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus ) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adeno‐viral‐based influenza vaccine. A genome‐wide association study evaluated the expression of single‐nucleotide polymorphisms (SNPs) in the HO‐1 gene and the response to influenza vaccination in healthy humans. HO‐1‐deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P =0.016). HO‐1‐deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P =0.02). One SNP in HO‐1 and one SNP in the constitutively expressed isoform HO‐2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers ( P =0.017 and 0.014, respectively). HO‐1 deficient mice were paired with sex‐ and age‐matched WT controls. HO‐1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO‐1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness.—Cummins, N. W., Weaver, E. A., May, S. M., Croatt, A. J., Foreman, O., Kennedy, R. B., Poland, G. A., Barry, M. A., Nath, K. A., Badley, A. D. Heme oxygenase‐1 regulates the immune response to influenza virus infection and vaccination in aged mice. FASEB J. 26, 2911–2918 (2012). www.fasebj.org

SummaryAlthough the incidence rate of acute lymphoblastic leukaemia (ALL) is slightly higher in older than in younger adults, response rates to induction chemotherapy and survival rates are poorer. The contribution of disease‐related versus treatment‐related factors remains unclear. We analysed 100 older patients (aged 55–65 years) treated on the UKALLXII/ECOG2993 trial compared with 1814 younger patients (aged 14–54 years). Baseline characteristics, induction chemotherapy course, infections, drug reductions and survival outcomes were compared. There were more Philadelphia‐positive (Ph+) patients in the older group (28% vs. 17%, P = 0·02), and a trend towards higher combined cytogenetic risk score (46% vs. 35%, P = 0·07). The complete remission rate in older patients was worse (73% vs. 93%, P < 0·0001) as was 5‐year overall survival (21% vs. 41%, P < 0·0001) and event‐free survival (EFS) (19% vs. 37%, P < 0·0001). Older patients had more infections during induction (81% vs. 70%, P = 0·05), and drug reductions (46% vs. 28%, P = 0·0009). Among older patients, Ph+ and cytogenetic risk category as well as infection during induction predicted for worse EFS. Poorer outcomes in these patients are partly due to cytogenetic risk, but there is significant morbidity and mortality during induction chemotherapy with frequent delays and drug reductions. New approaches, including better risk stratification and use of targeted therapies, could improve treatment for these patients.

AbstractPurposePatellofemoral arthroplasty remains controversial, primarily due to the high failure rates reported with early implants. Numerous case series have been published over the years detailing results of various first‐ and second‐generation implants. The purpose of this work is to summarize results published to date and identify common themes regarding implants, surgical techniques, and indications in order to maximize results of future procedures.MethodsA comprehensive review of the MEDLINE database was carried out to identify all clinical studies related to patellofemoral arthroplasty.ResultsFirst‐generation resurfacing implants were associated with relatively high failure rates in the medium term. Second‐generation implants, with femoral cuts based on TKA designs have yielded more promising medium‐term results. Surgical indications are specific and must be carefully followed to minimize poor results. Short‐term complications are generally related to patellar maltracking, while long‐term complications are generally related to progression of osteoarthritis in the tibiofemoral joint. Implant loosening and polyethylene wear are rarely reported. Short‐term results are favourable for new technology including custom implants and computer navigated surgery.ConclusionsOverall, recent improvements in implant design and surgical techniques have resulted in improvements in short‐ and medium‐term results. More work is required to assess the long‐term outcomes of modern implant designs.Level of evidenceIV.

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.