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Patients undergoing allo-HCT often experience a substantial loss in physical performance. We have recently published the general effectiveness of an exercise intervention in 105 allo-HCT patients on physical performance and psychosocial well-being. However, predictor variables for differentiated treatment response remained unclear. To determine the impact of basic physical performance on treatment response, we assessed muscle strength and endurance performance at four assessment points before and after allo-HCT. The exercise group started training 2 weeks before admission and ended 6–8 weeks after discharge. Comparing initially fit with unfit classified patients, the fit patients lost 31% of the strength of the knee-extensors, whereas the unfit patients lost only 1% ( P <0.05). For endurance capacity, fit patients lost 4% of their walking capability, whereas unfit patients gained 13% ( P <0.05). The individual percent change was statistically different at the 0.05 level in all measures of physical performance. Individual training response in allo-HCT patients strongly depends on the initial physical performance level. Unfit patients can be trained safely and may benefit more from this exercise intervention than fit patients. This result is of major clinical relevance and should encourage hematologists to promote exercise even more in impaired/unfit allo-HCT patients.

Background:Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA.Methods:A study was conducted to examine whether MLH1 (-93G>A and Ile219Val) and MSH6 (Gly39Glu) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity.Results:The MSH6 39Glu allele was associated with increased risk of colon cancer among men (Gly/Glu or Glu/Glu vs Gly/Gly, OR 1.27; 95% CI 1.04 to 1.54). Neither MLH1 polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the MLH1 -93A allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (AA vs GG, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: MLH1 -93G>A and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and MLH1 Ile219Val and Western diet (p value interaction: 0.03).Conclusions:The MSH6 Gly39Glu and MLH1 -93G>A polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Hyperinsulinaemia and hyperglycaemia are two possible risk factors for colorectal cancer, which constitutes the third leading cause of cancer death in Western countries. Molecular evidence as well as animal models provide support for these associations: Insulin has been shown to be an important growth factor for colonic carcinoma cells, and both insulin and insulin-like growth factor-1 receptors have been detected in colon cancer tissue. The insulin-signal transduction pathway is involved in the regulation of gene expression and apoptosis. The role of hyperglycaemia in carcinogenesis could include pathways via luminal factors (related to fecal bile acid concentrations, stool bulk, and prolonged transit time) or circulatory factors (via glucose as the only energy source for neoplastic cells). This review summarizes the epidemiologic literature with respect to hyperinsulinaemia and hyperglycaemia as risk factors for colorectal cancer, and aims to integrate the biological and epidemiological evidence. Epidemiologic findings to date indicate a slightly increased risk of colorectal cancer for diabetic patients; however, there are some inconsistencies. Possible explanations for these inconsistencies include inadequate information about patients' diabetic disease and treatment states. We suggest that future studies should take medical history, staging and treatment for hyperinsulinaemia and hyperglycaemia into account to further our understanding of the role of hyperglycaemia and hyperinsulinaemia in colorectal carcinogenesis.

Objective: To investigate cross-sectional and longitudinal relationships among exercise, sleep, ghrelin and leptin. Methods: We randomly assigned 173 post-menopausal sedentary overweight (body mass index greater than or equal to 24.0 kg/m2 and > 33% body fat) women aged 50-75 years living in western Washington State to either a facility- and home-based moderate-intensity physical activity intervention or a stretching control group. Fasting plasma ghrelin, leptin, measured height, weight and self-reported sleep were assessed at baseline and 12 months. Results: There were no consistent cross-sectional patterns between self-reported sleep measures and ghrelin or leptin at baseline. The weight loss differences between exercisers and stretchers were greater for those who slept less at follow-up than at baseline compared to those whose sleep duration did not change (-3.2 kg, 95% confidence interval (CI) -5.8, -0.5). Improvements in sleep quality were associated with significantly greater differences between exercisers and stretchers for ghrelin increases (improved vs same sleep quality: +115 pg/ml, 95% CI +25, +206) and leptin decreases (improved vs worsened sleep quality: -5.7 ng/ml, 95% CI -9.5, -1.5). Conclusion: There was only limited evidence that changes in sleep duration or quality modified exercise-induced changes in weight, ghrelin or leptin. Moreover, the observed differences were not in the directions hypothesized. Future longitudinal studies including population-based samples using objective measures of sleep and long follow-up may help to clarify these relationships.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective chemopreventive agents for colorectal neoplasia. Polymorphisms in NSAID targets or metabolizing enzymes may affect NSAID efficacy or toxicity. We conducted a literature review to summarize current evidence of gene–drug interactions between NSAID use and polymorphisms in COX1 , COX2 , ODC , UGT1A6 and CYP2C9 on risk of colorectal neoplasia by searching OVID and PubMed. Of 134 relevant search results, thirteen investigated an interaction. One study reported a significant interaction between NSAID use and the COX1 Pro17Leu polymorphism ( P =0.03) whereby the risk reduction associated with NSAID use among homozygous wild-type genotypes was not observed among NSAID users with variant alleles. Recent pharmacodynamic data support the potential for gene–drug interactions for COX1 Pro17Leu. Statistically significant interactions have also been reported for ODC (315G>A), UGT1A6 (Thr181Ala+Arg184Ser or Arg184Ser alone), and CYP2C9 ( * 2/ * 3). No statistically significant interactions have been reported for polymorphisms in COX2 ; however, an interaction with COX2 −765G>C approached significance ( P =0.07) in one study. Among seven remaining studies, reported interactions were not statistically significant for COX1 , COX2 and ODC gene polymorphisms. Most studies were of limited sample size. Definitions of NSAID use differed substantially between studies. The literature on NSAID–gene interactions to date is limited. Reliable detection of gene–NSAID interactions will require greater sample sizes, consistent definitions of NSAID use and evaluation of clinical trial subjects of chemoprevention studies.

Methotrexate (MTX) is used as an immunosuppressive agent for acute graft-versus-host disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT). Concerns that folate intake may impair MTX effectiveness or selectively rescue leukemic cells have led to variations in clinical practice regarding supplemental folic acid during MTX administration. A retrospective, observational study was undertaken to determine the association between folic acid intake (days 0-18 post transplant) and MTX toxicity and efficacy following HCT. The study population consisted of 311 adult patients who received a myeloablative HCT for chronic myelogenous leukemia, all four scheduled doses of MTX, and did not require leucovorin rescue. Multiple linear regression models were used to assess the relationships between folic acid intake (days 0-18 post-HCT) and oral mucositis index (OMI) scores, time to engraftment and risk of detectable acute GVHD. No statistically significant differences in mean OMI scores, time to engraftment, risk of acute GVHD, days to acute GVHD, risk of relapse or survival were observed when comparing patients taking, on average, <400 (14%), 400 (58%) or >400 microg (28%) folic acid per day. Our results suggest that concurrent folic acid supplementation does not change MTX effectiveness or toxicity in this patient population.

Oxaliplatin-based chemotherapy exerts its effects through generating DNA damage. Hence, genetic variants in DNA repair pathways could modulate treatment response. We used a prospective cohort of 623 colorectal cancer patients with stage II–IV disease treated with adjuvant/palliative chemotherapy to comprehensively investigate 1727 genetic variants in the DNA repair pathways as potential predictive markers for oxaliplatin treatment. Single nucleotide polymorphisms (SNP) associations with overall survival and recurrence-free survival were assessed using a Cox regression model. Pathway analysis was performed using the gamma method. Patients carrying variant alleles of rs3783819 ( MNAT1 ) and rs1043953 ( XPC ) experienced a longer overall survival after treatment with oxaliplatin than patients who did not carry the variant allele, while the opposite association was found in patients who were not treated with oxaliplatin (false discovery rate-adjusted P -values for heterogeneity 0.0047 and 0.0237, respectively). The nucleotide excision repair (NER) pathway was found to be most likely associated with overall survival in patients who received oxaliplatin ( P -value=0.002). Our data show that genetic variants in the NER pathway are potentially predictive of treatment response to oxaliplatin.

The cyclooxygenase (COX) activity of prostaglandin H synthase-2 (PGHS-2) is implicated in colorectal cancer and is targeted by nonsteroidal anti-inflammatory drugs (NSAIDs) and dietary n −3 fatty acids. We used purified, recombinant proteins to evaluate the functional impacts of the R228H, E488G, V511A and G587R PGHS-2 polymorphisms on COX activity, fatty acid selectivity and NSAID actions. Compared to wild-type PGHS-2, COX activity with arachidonate was ∼20% lower in 488G and ∼20% higher in 511A. All variants showed time-dependent inhibition by the COX-2-specific inhibitor (coxib) nimesulide, but 488G and 511A had 30–60% higher residual COX activity; 511A also showed up to 70% higher residual activity with other time-dependent inhibitors. In addition, 488G and 511A differed significantly from wild type in V max values with the two fatty acids: 488G showed ∼20% less and 511A showed ∼20% more discrimination against eicosapentaenoic acid. The V max value for eicosapentaenoate was not affected in 228H or 587R, nor were the K m values or the COX activation efficiency (with arachidonate) significantly altered in any variant. Thus, the E488G and V511A PGHS-2 polymorphisms may predict who will most likely benefit from interventions with some NSAIDs or n −3 fatty acids.