The effect of cyclin D1 (CCND1) G870A-polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore

Cyclin D1 (CCND1), an intracellular cell-cycle regulatory protein with checkpoint function, can promote cell proliferation or induce growth arrest and apoptosis depending on the cellular context. We hypothesized that the direction of the association between the (CCND1) G870A-polymorphism and breast cancer risk may be modified by dietary and genetic factors influencing the oxidant-antioxidant balance, such as a dietary pattern with a high intake of n-6 fatty acids and a low intake of n-3 fatty acids, or a genetic profile that is deficient in glutathione S-transferases. We tested our hypothesis in a case-control study nested into the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63 000 Chinese men and women. Genomic DNA collected from 258 incident cases of breast cancer and 670 female cohort controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 genes using fluorogenic 5′-nuclease assay. Unconditional logistic regression models were used to assess the effects with adjustment for potential confounders. All statistical tests were two-sided. The heterozygous CCND1 GA genotype significantly reduced the breast cancer risk in all subjects (OR = 0.67, 95% CI 0.45-0.99) when compared with the GG genotype. The association was restricted to women with a high (above median value) intake level of n-6 fatty acids (OR = 0.51, 95% CI 0.30-0.87), a low (below median value) intake level of the antagonistic marine n-3 fatty acids (OR = 0.54, 95% CI 0.32-0.93) or a total lack of the antioxidative GSTM1 (OR = 0.44, 95% CI 0.25-0.80) or GSTT1 genes (OR = 0.46, 95% CI 0.24-0.87). The effects were consistently stronger in cases with advanced disease. The AA genotype did not affect breast cancer risk. The results of this study are compatible with the hypothesis that the oxidant-antioxidant balance in cells is an important determinant of the direction of the cyclin D1 effect, leading either to cell proliferation or cell deat

The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothiocyanate intake in the Singapore Chinese Health Study

Cyclin D1 (CCND1) regulates cellular decision between proliferation and growth arrest. Despite the functional relevance of the CCND1 A870G single nucleotide polymorphism (SNP) published results on its association with colorectal cancer (CRC) were inconsistent. We examined the association between this CCND1 genotype and CRC in the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63 000 Chinese men and women. We explored the hypothesis that inconsistency regarding the CCND1/CRC association may be attributable to the modifying effect of additional CRC risk factors. Since GSTM1/GSTT1 genotype and dietary isothiocyanate (ITC) intake had previously been identified as CRC risk factors in this cohort, we now explored if they influenced the CCND1/CRC association. In a nested case-control study within the Singapore Cohort, genomic DNA collected from 300 incident CRC cases and 1169 controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 polymorphisms. Unconditional logistic regression was used to assess genotype effects on cancer risk. No main effect of CCND1 was observed, yet the CCND1 effect was influenced by ITC intake and GST genotypes. The presence of at least one CCND1 A-allele was associated with increased risk among low dietary ITC consumers (intake below median value for the cohort) with a high-activity GST profile (≥2 of the 3 GST genotypes classified non-null or high-activity) [odds ratio (OR) = 2.05; 95% confidence interval (CI), 1.10-3.82]. In contrast, the presence of at least one A-allele was associated with a decreased risk among all remaining subjects (OR = 0.56; 0.36-0.86) (P for interaction = 0.01). Recent studies indicate that ITCs inhibit cell proliferation and cause apoptosis through pro-oxidant properties. The results of our current study on CRC and those of our previous breast cancer study are compatible with the notion of oxidative stress in target cells as important determinant of direction and magnitude of the CCND1 effec

Late Effects in Survivors of Hodgkin and Non-Hodgkin Lymphoma Treated with Autologous Hematopoietic Cell Transplantation: A Report from the Bone Marrow Transplant Survivor Study

AbstractWe determined the prevalence of self-reported late-effects in survivors of autologous hematopoietic cell transplantation (HCT) for Hodgkin lymphoma (HL, n = 92) and non-Hodgkin lymphoma (NHL, n = 184) using a 255-item questionnaire and compared them to 319 sibling controls in the Bone Marrow Transplant Survivor Study. Median age at HCT was 39 years (range: 13-69) and median posttransplant follow-up was 6 years (range: 2-17). Median age at survey was 46 years (range: 21-73) for survivors and 44 years (range: 19-79) for siblings. Compared to siblings, HCT survivors reported a significantly higher frequency of cataracts, dry mouth, hypothyroidism, bone impairments (osteoporosis and avascular necrosis), congestive heart failure, exercise-induced shortness of breath, neurosensory impairments, inability to attend work or school, and poor overall health. Compared to those receiving no total-body irradiation (TBI), patients treated with TBI-based conditioning had higher risks of cataracts (odds-ratio [OR] 4.9, 95% confidence interval [CI] 1.5-15.5) and dry mouth (OR 3.4, 95% CI 1.1-10.4). Females had a greater likelihood of reporting osteoporosis (OR 8.7, 95% CI: 1.8-41.7), congestive heart failure (OR 4.3, 95% CI 1.1-17.2), and abnormal balance, tremor, or weakness (OR 2.4, 95% CI 1.0-5.5). HL and NHL survivors of autologous HCT have a high prevalence of long-term health-related complications and require continued monitoring for late effects of transplantation

Second Primary Malignancies after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

AbstractRecent studies demonstrate an increased risk of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving maintenance lenalidomide after autologous stem cell transplantation (ASCT). We explored the possibility of other risk factors driving post-ASCT SPMs in patients with MM through analysis of our large transplantation database in conjunction with our Long-Term Follow-Up Program. We conducted a retrospective cohort study of 841 consecutive patients with MM who underwent ASCT at City of Hope between 1989 and 2009, as well as a nested case-control analysis evaluating the role of all therapeutic exposures before, during, and after ASCT. Median duration of follow-up for the entire cohort was 3.4 years (range, 0.3-19.9 years). Sixty cases with a total of 70 SPMs were identified. The overall cumulative incidence of SPMs was 7.4% at 5 years and 15.9% at 10 years when nonmelanoma skin cancers (NMSCs) were included and 5.3% at 5 years and 11.2% at 10 years when NMSCs were excluded. Multivariate analysis of the entire cohort revealed associations of both older age (≥55 years; relative risk, 2.3; P < .004) and race (non-Hispanic white; relative risk, 2.4; P = .01) with an increased risk of SPM. Furthermore, thalidomide exposure demonstrated a trend toward increased risk (odds ratio, 3.5; P = .15); however, an insufficient number of patients were treated with lenalidomide to allow us to accurately assess the risk of this agent. Exclusion of NMSCs retained the association with these variables but was accompanied by loss of statistical significance. This large single-institution analysis identified associations between race and older age and increased risk of developing SPM. The trend toward increased risk with thalidomide exposure suggests a class effect from immunomodulatory drugs that might not be restricted to lenalidomide

Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer

Older adults are at increased risk for chemotherapy toxicity, and standard oncology assessment measures cannot identify those at risk. A predictive model for chemotherapy toxicity was developed (N = 500) that consisted of geriatric assessment questions and other clinical variables. This study aims to externally validate this model in an independent cohort (N = 250)

Gray matter density reduction associated with adjuvant chemotherapy in older women with breast cancer

PURPOSE: The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer. METHODS: We recruited 16 women aged ≥ 60 years with stage I-III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry. RESULTS: The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (pFWE(family-wise error)-corrected < 0.05). The baseline GMD in left insula was positively correlated with the baseline list-sorting working memory score in the HC group (pFWE-corrected < 0.05). No correlation was observed for the changes in GMD with the changes in cognitive testing scores from TP1 to TP2 (pFWE-corrected < 0.05). CONCLUSIONS: Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432)

Effect of chemotherapy on hippocampal volume and shape in older long-term breast cancer survivors

PurposeThe objective of this study was to assess changes in hippocampal volume and shape in older long-term breast cancer survivors who were exposed to chemotherapy 5–15 years prior.MethodsThis study recruited female long-term breast cancer survivors aged 65 years or older with a history of chemotherapy (C+), age-matched breast cancer survivors who did not receive chemotherapy (C−), and healthy controls (HC). The participants were recruited 5–15 years after chemotherapy at time point 1 (TP1) and were followed up for 2 years at time point 2 (TP2). Assessments included hippocampal volume and shape from brain MRI scans and neuropsychological (NP) tests.ResultsAt TP1, each of the three groups was comprised of 20 participants. The C+ group exhibited a hippocampal volume loss estimated in proportion with total intracranial volume (ICV) in both the left and right hemispheres from TP1 to TP2. Regarding the hippocampal shape at TP1, the C+ group displayed inward changes compared to the control groups. Within the C+ group, changes in right hippocampal volume adjusted with ICV were positively correlated with crystalized composite scores (R = 0.450, p = 0.044). Additionally, in C+ groups, chronological age was negatively correlated with right hippocampal volume adjusted with ICV (R = −0.585, p = 0.007).ConclusionThe observed hippocampal volume reduction and inward shape deformation within the C+ group may serve as neural basis for cognitive changes in older long-term breast cancer survivors with history of chemotherapy treatment

RETRATO SIN IDENTIFICAR [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

Risk Factors for Hospitalizations Among Older Adults with Gastrointestinal Cancers

Background: Older adults (≥65 years) with gastrointestinal (GI) cancers who receive chemotherapy are at increased risk of hospitalization caused by treatment-related toxicity. Geriatric assessment (GA) has been previously shown to predict risk of toxicity in older adults undergoing chemotherapy. However, studies incorporating the GA specifically in older adults with GI cancers have been limited. This study sought to identify GA-based risk factors for chemotherapy toxicity-related hospitalization among older adults with GI cancers. Patients and methods: We performed a secondary post hoc subgroup analysis of two prospective studies used to develop and validate a GA-based chemotherapy toxicity score. The incidence of unplanned hospitalizations during the course of chemotherapy treatment was determined. Results: This analysis included 199 patients aged ≥65 years with a diagnosis of GI cancer (85 colorectal, 51 gastric/esophageal, and 63 pancreatic/hepatobiliary). Sixty-five (32.7%) patients had ≥1 hospitalization. Univariate analysis identified sex (female), cardiac comorbidity, stage IV disease, low serum albumin, cancer type (gastric/esophageal), hearing deficits, and polypharmacy as risk factors for hospitalization. Multivariable analyses found that patients who had cardiac comorbidity (OR 2.48, 95% CI 1.13-5.42) were significantly more likely to be hospitalized. Conclusion: Cardiac comorbidity may be a risk factor for hospitalization in older adults with GI cancers receiving chemotherapy. Further studies with larger sample sizes are warranted to examine the relationship between GA measures and hospitalization in this vulnerable population

Effects of chemotherapy on aging white matter microstructure: a longitudinal diffusion tensor imaging study

Objective: We aimed to use diffusion tensor imaging (DTI) to detect alterations in white matter microstructure in older patients with breast cancer receiving chemotherapy. Methods: We recruited women age ≥60 years with stage I-III breast cancer (chemotherapy [CT] group; n = 19) to undergo two study assessments: at baseline and within one month after chemotherapy. Each assessment consisted of a brain magnetic resonance imaging scan with DTI and neuropsychological (NP) testing using the National Institutes of Health (NIH) Toolbox Cognition Battery. An age- and sex-matched group of healthy controls (HC, n = 14) underwent the same assessments at matched intervals. Four DTI parameters (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], and radial diffusivity [RD]) were calculated and correlated with NP testing scores. Results: For CT group but not HCs, we detected statistically significant increases in MD and RD in the genu of the corpus callosum from time point 1 to time point 2 at p 0.05). Conclusions: We identified alterations in white matter microstructures in older women with breast cancer undergoing chemotherapy. These findings may potentially serve as neuroimaging biomarkers for identifying cognitive impairment in older adults with cancer