Short term e-bicycle riding results in favorable cardiometabolic shifts in moderately active adults.

PURPOSE: Electric bikes (EB) are a form of active transportation with demonstrated health benefits. The purpose of this study was to determine the influence of riding an EB for one week on indices of cardiometabolic health in middle-aged adults. METHODS: Adults (n = 22; age = 57.1 ± 11.3 year; BMI = 27.7 ± 4.9) participated in a 2 week study. During Week 1, participants were instructed to continue regular activities. Starting Week 2 participants were provided an EB to ride at least 3 days for a minimum of 30 min·day-1. Physical activity (PA) and glucose were measured continuously. Body composition, blood lipids, glucose, insulin, hemoglobin A1c (HbA1c), plasma endothelin-1 (ET-1), and carotid-femoral pulse wave velocity (cf-PWV) were measured on days 1 and 14.Data and Statistical analyses or Statistics. Each participant served as their own control. Paired t-tests compared dependent variables between week 1 (without EB) and week 2 (with EB). RESULTS: When provided an EB for one week, moderate to vigorous PA increased by 6-9 min·day-1 (P < 0.05) and sedentary time decreased by ~ 77 min·day-1 (P < 0.05). Data from 24 h continuous glucose monitoring showed the percentage of time in healthy range (70-120 mg·dl-1 glucose) increased (P < 0.05) from week 1 to week 2. Compared to day 1, cf-PWV was lower at day 14 (P < 0.05) following one week of riding an EB. CONCLUSION: Moderately-active, middleaged adults showed improved continuous glucose regulation and lower central arterial stiffness following one week of riding an EB.

NSABP FC-6: Surgical conversion rate in colorectal cancer patients with unresectable, KRAS wild-type liver metastases receiving mFOLFOX7 plus cetuximab.

PURPOSE: This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment. METHODS: Twenty patients were enrolled. None had prior adjuvant chemotherapy. Cetuximab was added to a FOLFOX7 backbone and administered at 500 mg/m2 every 14 days with dose reductions to 400 and 300 mg/m2 in the event of toxicity. In the absence of toxicity, dose-escalations to 600, 700, and 800 mg/m2 were allowed. The mean dose of cetuximab (mg/m2 /week) throughout the study was 289 mg/m2 . Paired samples were collected for correlative studies, where feasible. RESULTS: We assessed the conversion rates from unresectable to resectable in hepatic-only, KRAS exon 2 WT mCRC. Seventeen of 20 patients undergoing chemotherapy were considered resectable by imaging criteria; R0 resection was achieved in 15/20 patients. Molecular profiling revealed heterogeneity between patients at the gene-expression, pathway signaling, and immune-profile levels. CONCLUSIONS: Although 15/20 (75%) converted to R0 resection, by 2 years, 10/15 R0 resections had recurred. Therefore, chemotherapy plus cetuximab is of limited long-term benefit in this setting. ctDNA analysis may guide additional therapy including immunotherapy.

Assessing the Quality of Rectal Cancer Pathology Reports in National Surgical Adjuvant Breast and Bowel Project Protocol R-04/NRG Oncology.

BACKGROUND: Accurate and comprehensive surgical pathology reports are integral to the quality of cancer care. Despite guidelines from the College of American Pathologists, variations in reporting quality continue to exist. OBJECTIVE: The aim of this study was to evaluate the quality of rectal cancer pathology reports and to identify areas of deficiency and potential sources of reporting variations. DESIGN: This is a retrospective analysis of prospectively obtained pathology reports. SETTING: This study is based at the hospitals participating in the National Surgical Adjuvant Breast and Bowel Project Protocol R-04 study. PATIENTS: Patients with rectal cancer undergoing surgical resection between July 2004 and August 2010 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the adherence to the College of American Pathologists guidelines and the impact of synoptic reporting, academic status, rural/urban setting, and hospital bed size on reporting quality. RESULTS: We identified 1004 surgical pathology reports for rectal cancer surgery from 383 hospitals and 755 pathologists. The overall adherence rate to the College of American Pathologists guidelines was 73.3%. Notable reporting deficiencies were found in several key pathology characteristics, including tumor histologic grade (reporting rate 77.8%), radial margin (84.6%), distance from the closest margin (47.9%), treatment effect (47.1%), and lymphovascular (73.1%)/perineural invasions (35.4%). Synoptic reporting use and urban hospital settings were associated with better adherence rates, whereas academic status and hospital bed size had no impact. Reporting variations existed not only between institutions, but also within individual hospitals and pathologists. There was a trend for improved adherence over time (2005 = 65.7% vs 2010 = 82.3%, p < 0.001), which coincided with the increased adoption of synoptic reporting by pathologists (2005 vs 2010, 9.4% vs 25.3%, p < 0.001). LIMITATIONS: Data were obtained from a restricted setting (ie, hospitals participating in a randomized clinical trial). CONCLUSIONS: Wide variations in the quality of pathology reporting are observed for rectal cancer. The National Accreditation Program for Rectal Cancer mandates that programs meet strict quality standards for surgical pathology reporting. Further improvement is needed in this key aspect of oncology care for patients with rectal cancer. See Video Abstract at http://links.lww.com/DCR/B238.ClinicalTrials.gov registration: NCT00058 EVALUACIÓN DE LA CALIDAD DE LOS INFORMES DE PATOLOGÍA QUIRÚRGICA EN CASOS DE CÁNCER DE RECTO DEL NSABP R-04/ ONCOLOGÍA DEL NRG: Un informe de patología quirúrgica preciso y completo es fundamental en la calidad de atención de pacientes con cáncer. A pesar de las normas establecidas por el Colegio Americano de Patología, la variabilidad en la calidad de los informes es evidente.Evaluar la calidad de los informes de patología en casos de cáncer de recto para así identificar las áreas con deficiencias y las posibles fuentes variables en los mencionados informes.Análisis retrospectivo de informes de patología quirúrgica obtenidos prospectivamente.Hospitales que participan del Protocolo del Estudio Nacional R-04 como Adyuvantes Quirúrgicos de Mama e Intestino.Todos aquellos pacientes con cáncer de recto sometidos a resección quirúrgica entre Julio 2004 y Agosto 2010.Cumplimiento de las normas del Colegio Americano de Patología, del impacto de los informes sinópticos, del estado académico, del entorno rural / urbano y el número de camas hospitalarias en en la calidad de los informes.Identificamos 1,004 informes de patología quirúrgica en casos de cirugía en cáncer de recto en 383 hospitales y 755 patólogos. La tasa general de adherencia a las directivas del Colegio Americano de Patología fue del 73.3%. Se encontraron deficiencias notables en los informes en varias características patológicas clave incluidos, el grado histológico del tumor (tasa de informe 77.8%), margenes radiales (84.6%), distancia del margen más cercano (47.9%), efecto del tratamiento (47.1%) invasión linfovascular (73.1 %) / invasion perineural (35.4%). El uso de informes sinópticos y los entornos hospitalarios urbanos se asociaron con mejores tasas de adherencia, mientras que el estado académico y el número de camas hospitalarias no tuvieron ningún impacto. Hubo variaciones en los informes no solo entre instituciones, sino también dentro de hospitales y patólogos individuales. Hubo una tendencia a una mejor adherencia a lo largo del tiempo (2005 = 65.7% v 2010 = 82.3%, p < 0.001), que coincidió con la mayor adopción de informes sinópticos por parte de los patólogos (2005 v 2010, 9.4% v 25.3%, p < 0.001)Datos obtenidos de un entorno restringido (es decir, hospitales que participan en un ensayo clínico aleatorizado).Se observaron grandes variaciones en la calidad de los informes de patología quirúrgica en casos de cáncer de recto. El Programa Nacional de Acreditación para Cáncer de Recto exige que los programas cumplan con estrictos estándares de calidad para los informes de patología quirúrgica. Se necesita una mejoría adicional en este aspecto clave de la atención oncológica para pacientes con cáncer de recto. Video Resumen en http://links.lww.com/DCR/B238.Registro de Clinical Trials.gov: NCT00058.

Linked matrix factorization.

Several recent methods address the dimension reduction and decomposition of linked high-content data matrices. Typically, these methods consider one dimension, rows or columns, that is shared among the matrices. This shared dimension may represent common features measured for different sample sets (horizontal integration) or a common sample set with features from different platforms (vertical integration). We introduce an approach for simultaneous horizontal and vertical integration, Linked Matrix Factorization (LMF), for the general case where some matrices share rows (e.g., features) and some share columns (e.g., samples). Our motivating application is a cytotoxicity study with accompanying genomic and molecular chemical attribute data. The toxicity matrix (cell lines × chemicals) shares samples with a genotype matrix (cell lines × SNPs) and shares features with a molecular attribute matrix (chemicals × attributes). LMF gives a unified low-rank factorization of these three matrices, which allows for the decomposition of systematic variation that is shared and systematic variation that is specific to each matrix. This allows for efficient dimension reduction, exploratory visualization, and the imputation of missing data even when entire rows or columns are missing. We present theoretical results concerning the uniqueness, identifiability, and minimal parametrization of LMF, and evaluate it with extensive simulation studies.

Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience.

This study examines the long-term OS of relapsed AML patients who were enrolled to 9 successive ECOG-ACRIN trials for newly diagnosed AML, during 1984-2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long-term OS after relapse. A total of 3012 patients were enrolled, 1779 (59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow-up was 9.7 years. The median OS from relapse was 0.5 years and the 5-year OS was 10 (±1)%. These results were similar even for the most recent studies. A multivariate model showed that age, cytogenetics at diagnosis, duration of CR1 and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age < 40 and CR1 > 12 months, there was no significant OS difference between the studies. In conclusion, this large cohort appears to confirm that the survival of AML patients postrelapse continues to be dismal and has not improved during the past quarter of a century.

R.JIVE for exploration of multi-source molecular data.

UNLABELLED: : The integrative analysis of multiple high-throughput data sources that are available for a common sample set is an increasingly common goal in biomedical research. Joint and individual variation explained (JIVE) is a tool for exploratory dimension reduction that decomposes a multi-source dataset into three terms: a low-rank approximation capturing joint variation across sources, low-rank approximations for structured variation individual to each source and residual noise. JIVE has been used to explore multi-source data for a variety of application areas but its accessibility was previously limited. We introduce R.JIVE, an intuitive R package to perform JIVE and visualize the results. We discuss several improvements and extensions of the JIVE methodology that are included. We illustrate the package with an application to multi-source breast tumor data from The Cancer Genome Atlas. AVAILABILITY AND IMPLEMENTATION: R.JIVE is available via the Comprehensive R Archive Network (CRAN) under the GPLv3 license: https://cran.r-project.org/web/packages/r.jive/ CONTACT: elock@umn.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials.

BACKGROUND: Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer. Adjuvant capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin has not been directly compared; therefore, we aimed to analyse the efficacy and safety of these treatments using individual patient data pooled from four randomised controlled trials. We also assessed post-relapse survival, which has been postulated to be worse in patients receiving adjuvant oxaliplatin. METHODS: Patients with resected stage III colon cancer who were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from four randomised controlled trials (NSABP C-08, XELOXA, X-ACT, and AVANT; 8734 patients in total) were pooled and analysed. The treatment regimens included in our analyses were: XELOX (oxaliplatin and capecitabine); leucovorin and fluorouracil; capecitabine; FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin); and modified FOLFOX-6 (mFOLFOX-6). Disease-free survival was the primary endpoint for all trials that supplied patients for this analysis. Here, we compared disease-free, relapse-free, and overall survival between the patient groups who received capecitabine with or without oxaliplatin and those who received leucovorin and fluorouracil with or without oxaliplatin. Post-relapse survival was compared between the combined XELOX and FOLFOX groups, and the leucovorin and fluorouracil groups. Post-relapse survival was also compared between the capecitabine with or without oxaliplatin and leucovorin and fluorouracil with or without oxaliplatin groups. FINDINGS: Disease-free survival did not differ significantly between patients who received leucovorin and fluorouracil versus those who received capecitabine in adjusted analyses (hazard ratio [HR] 1·02 [0·93-1·11; p=0·72]) or in unadjusted analyses (HR 1·01 [95% CI 0·92-1·10; p=0·86]). Relapse-free survival was similar (adjusted HR 1·02 [0·93-1·12; p=0·72] and unadjusted HR 1·01 [95% CI 0·92-1·11; p=0·86]), as was overall survival (adjusted HR 1·04 [95% CI 0·93-1·15; p=0·50] and unadjusted HR 1·02 [0·92-1·14]; p=0·65). For overall survival, a significant interaction between oxaliplatin and fluoropyrimidine was recorded in the multiple Cox regression analysis (p=0·014). Post-relapse survival was similar in adjusted (p=0·23) and unadjusted analyses (p=0·33) for the comparison of XELOX or FOLFOX versus leucovorin and fluorouracil, and was also similar for capecitabine-based regimens versus leucovorin and fluorouracil-based regimens (unadjusted p=0·26). INTERPRETATION: Combination therapy with oxaliplatin provided consistently improved outcomes without adversely affecting post-relapse survival in the adjuvant treatment of stage III colon cancer, irrespective of whether the fluoropyrimidine backbone was capecitabine or leucovorin and fluorouracil. These data add to the existing evidence that oxaliplatin plus capecitabine or leucovorin and fluorouracil is the standard of care for the adjuvant treatment of stage III colon cancer, and offers physicians flexibility to treat patients according to the patients' overall physical performance and preference. FUNDING: Genentech Inc.

Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy.

BACKGROUND: Although obesity is an established risk factor for developing colon cancer, its prognostic impact and relation to patient sex in colon cancer survivors remains unclear. METHODS: The authors examined the prognostic and predictive impact of the body mass index (BMI) in patients with stage II and III colon carcinoma (N = 25,291) within the Adjuvant Colon Cancer Endpoints (ACCENT) database. BMI was measured at enrollment in randomized trials of 5-fluorouracil-based adjuvant chemotherapy. Association of BMI with the time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were determined using Cox regression models. Statistical tests were 2-sided. RESULTS: During a median follow-up of 7.8 years, obese and underweight patients had significantly poorer survival compared with overweight and normal-weight patients. In a multivariable analysis, the adverse prognostic impact of BMI was observed among men but not among women (Pinteraction = .0129). Men with class 2 and 3 obesity (BMI ≥ 35.0 kg/m(2) ) had a statistically significant reduction in DFS (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.01-1.33; P = .0297) compared with normal-weight patients. Underweight patients had a significantly shorter TTR and reduced DFS (HR, 1.18; 95% CI, 1.09-1.28; P < .0001) that was more significant among men (HR, 1.31; 95% CI, 1.15-1.50; P < .0001) than among women (HR, 1.11; 95% CI, 1.01-1.23; P = .0362; Pinteraction = .0340). BMI was not predictive of a benefit from adjuvant treatment. CONCLUSIONS: Obesity and underweight status were associated independently with inferior outcomes in patients with colon cancer who received treatment in adjuvant chemotherapy trials.

KOMPUTE: imputing summary statistics of missing phenotypes in high-throughput model organism data.

Motivation: The International Mouse Phenotyping Consortium (IMPC) is striving to build a comprehensive functional catalog of mammalian protein-coding genes by systematically producing and phenotyping gene-knockout mice for almost every protein-coding gene in the mouse genome and by testing associations between gene loss-of-function and phenotype. To date, the IMPC has identified over 90 000 gene-phenotype associations, but many phenotypes have not yet been measured for each gene, resulting in largely incomplete data; ∼75.6% of association summary statistics are still missing in the latest IMPC summary statistics dataset (IMPC release version 16). Results: To overcome these challenges, we propose KOMPUTE, a novel method for imputing missing summary statistics in the IMPC dataset. Using conditional distribution properties of multivariate normal, KOMPUTE estimates the association Z-scores of unmeasured phenotypes for a particular gene as a conditional expectation given the Z-scores of measured phenotypes. Our evaluation of the method using simulated and real-world datasets demonstrates its superiority over the singular value decomposition matrix completion method in various scenarios. Availability and implementation: An R package for KOMPUTE is publicly available at https://github.com/statsleelab/kompute, along with usage examples and results for different phenotype domains at https://statsleelab.github.io/komputeExamples.

Lens Epithelial Explants Treated with Vitreous Humor Undergo Alterations in Chromatin Landscape with Concurrent Activation of Genes Associated with Fiber Cell Differentiation and Innate Immune Response.

Lens epithelial explants are comprised of lens epithelial cells cultured in vitro on their native basement membrane, the lens capsule. Biologists have used lens epithelial explants to study many different cellular processes including lens fiber cell differentiation. In these studies, fiber differentiation is typically measured by cellular elongation and the expression of a few proteins characteristically expressed by lens fiber cells in situ. Chromatin and RNA was collected from lens epithelial explants cultured in either un-supplemented media or media containing 50% bovine vitreous humor for one or five days. Chromatin for ATAC-sequencing and RNA for RNA-sequencing was prepared from explants to assess regions of accessible chromatin and to quantitatively measure gene expression, respectively. Vitreous humor increased chromatin accessibility in promoter regions of genes associated with fiber differentiation and, surprisingly, an immune response, and this was associated with increased transcript levels for these genes. In contrast, vitreous had little effect on the accessibility of the genes highly expressed in the lens epithelium despite dramatic reductions in their mRNA transcripts. An unbiased analysis of differentially accessible regions revealed an enrichment of cis-regulatory motifs for RUNX, SOX and TEAD transcription factors that may drive differential gene expression in response to vitreous.

Prognostic web-based models for stage II and III colon cancer: A population and clinical trials-based validation of numeracy and adjuvant! online.

BACKGROUND: Numeracy and Adjuvant! are 2 web-based calculators that are used widely to estimate the prognosis and potential benefit of adjuvant 5-fluorouracil (5-FU)-based therapy for patients with stage II and III colon cancer. In this study, the authors compared the predicted survival estimates from these models with the actual observed estimates in independent datasets that were derived from a population cohort and from clinical trials. METHODS: The population cohort was derived from the British Columbia Colorectal Cancer Outcomes Unit database, which identified referred patients with stage II and III colon cancer from 1995 to 1996 and from 1999 to 2003. Patients who were enrolled in North Central Cancer Trials Group (NCCTG) trials NCCTG 94651 and NCCTG 914653 were included in the trials dataset. Patient and disease data were used to predict 5-year relapse-free and overall survival using both tools. RESULTS: In the population-based dataset (N = 2033), Adjuvant! offered more reliable predictions of prognosis for patients who underwent surgery alone, but it had reliability similar to that of Numeracy for predicting the prognosis for patients who received adjuvant 5-FU. Both models tended to overestimate survival for patients with stage II disease who received 5-FU. In the trials dataset of patients who underwent and received 5-FU (N = 1729), Numeracy and Adjuvant! demonstrated similar performance and improved correctness. CONCLUSIONS: This independent validation analysis demonstrated that both Numeracy and Adjuvant! had similar predictive performance and acceptable reliability for patients with stage III disease. Survival outcomes of patients with stage II colon cancer who received adjuvant 5-FU were slightly lower than estimated by either model.

Long-term follow-up and individual item analysis of quality of life assessments related to laparoscopic-assisted colectomy in the COST trial 93-46-53 (INT 0146).

BACKGROUND: Postoperative outcomes of patients undergoing laparoscopic-assisted colectomy (LAC) have shown modest improvements in recovery but only minimal differences in quality of life (QOL) compared with open colectomy. We therefore sought to assess the effect of LAC on QOL in the short and long term, using individual item analysis of multi-item QOL assessments. METHODS: QOL variables were analyzed in 449 randomized patients from the COST trial 93-46-53 (INT 0146). Both cross-sectional single-time and change from baseline assessments were run at day 2, week 2, month 2, and month 18 postoperatively in an intention-to-treat analysis using Wilcoxon rank-sum tests. Stepwise regression models were used to determine predictors of QOL. RESULTS: Of 449 colon cancer patients, 230 underwent LAC and 219 underwent open colectomy. Subdomain analysis revealed a clinically moderate improvement from baseline for LAC in total QOL index at 18 months (P = 0.02) as well as other small symptomatic improvements. Poor preoperative QOL as indicated by a rating scale of ≤ 50 was an independent predictor of poor QOL at 2 months postoperatively. QOL variables related to survival were baseline support (P = 0.001) and baseline outlook (P = 0.01). CONCLUSIONS: Eighteen months after surgery, any differences in quality of life between patients randomized to LAC or open colectomy favored LAC. However, the magnitude of the benefits was small. Patients with poor preoperative QOL appear to be at higher risk for difficult postoperative courses, and may be candidates for enhanced ancillary services to address their particular needs.

Sex and Adverse Events of Adjuvant Chemotherapy in Colon Cancer: An Analysis of 34 640 Patients in the ACCENT Database.

BACKGROUND: Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. METHODS: The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). RESULTS: Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. CONCLUSIONS: Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Long-term survivors of metastatic colorectal cancer treated with systemic chemotherapy alone: a North Central Cancer Treatment Group review of 3811 patients, N0144.

BACKGROUND: Although systemic chemotherapy in patients with unresectable metastatic colorectal cancer (mCRC) is palliative in nature, some patients experience long-term remission beyond 5 years consequent to treatment with chemotherapy alone. PATIENTS AND METHODS: We reviewed clinical data from 32 prospective North Central Cancer Treatment Group chemotherapy trials in mCRC that enrolled patients from 1972 to 1995. Metastatic CRC was verified histologically. Excluded from analyses were patients who withdrew consent to the study, enrolled in > 1 study, were ineligible, or had major protocol violations. We defined patients with survival beyond 5 years from the initiation of systemic treatment of mCRC as long-term survivors (LTS). RESULTS: A total of 36 of 3407 (1.1%) patients were LTS. A total of 13 patients (0.4%) are without evidence of disease or disease progression > 5 years from cessation of last chemotherapy, with a median follow-up of 10.6 years (minimum, 7.6 years). Long-term survivors were more likely to have received 5-fluorouracil (5-FU)-based treatment (33 of 2503 [1.3%]) as opposed to other, less effective therapy (3 of 904 [0.3%]), suggesting that the chemotherapy played an important role among LTS (P = .01). Clinical characteristics of LTS were similar to the overall population in terms of age, sex, performance status, and tumor grade. CONCLUSION: This study establishes a baseline for long-term outcomes of mCRC in the era when effective treatment was limited to 5-FU. With the development of improved systemic therapy for mCRC, cure without salvage surgery might be possible for a small, but important number of patients. Clinical trials should follow patients for > 5 years to document the long-term outcomes.

Prognostic impact of bim, puma, and noxa expression in human colon carcinomas.

PURPOSE: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates. EXPERIMENTAL DESIGN: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates. RESULTS: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011). CONCLUSIONS: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil-based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.

The half century of clinical trials of the National Surgical Adjuvant Breast And Bowel Project.

The supplanting of radical mastectomy by simple mastectomy and then by lumpectomy plus radiation, the use of adjuvant therapy to alter the natural course of breast and colorectal cancer, the use of tamoxifen for the prevention of breast cancer, and the dramatic improvement in survival demonstrated with the use of the monoclonal antibody trastuzumab in women with HER2-positive breast cancer are all the direct results of research that has been carried out over the past 50 years by the National Surgical Adjuvant Breast and Bowel Project (NSABP). This National Cancer Institute-supported clinical cooperative trials group based in Pittsburgh, PA, currently has 200 member institutions and 700 satellite centers located throughout the United States, Canada, Puerto Rico, and Ireland. The NSABP's mandate is to conduct large randomized phase III trials to evaluate therapies designed to improve the treatment and prevention of breast and colorectal cancer. Over the past half century, the NSABP has entered more than 150,000 patients and participants into clinical studies that have changed the treatment of colorectal cancer and have revolutionized the treatment and prevention of breast cancer.

FOLFOX and FLOX regimens for the adjuvant treatment of resected stage II and III colon cancer.

The MOSAIC trial showed that the use of adjuvant oxaliplatin and an infusional regimen of 5-FU/LV in the treatment of stage II/III colon cancer improved disease-free survival (DFS). The NSABP's C-07 trial evaluated the addition of oxaliplatin to a weekly Roswell Park regimen of bolus 5-FU/LV and found a similar improvement in DFS. The benefit of oxaliplatin appears to be independent of the 5-FU/LV regimen used. This paper reviews the efficacy and toxicities of these two regimens and is meant to serve as a guide for clinical practice.

State Agency Support of Weight-Related School Policy Implementation.

BACKGROUND: In this study, we describe state agency strategies to support weight-related policy implementation in schools, and examine the association among state support, obesity prevalence, and strength of state policies governing school nutrition and physical education. METHODS: The 2012 School Health Policies and Practices Study describes prevalence of implementation support state agencies provided to schools/districts. Implementation support items were analyzed by weight-related policy area (eg, advertising, wellness policy) and by type of support (eg, technical assistance). Results were summed to create a total weight-related policy support score. Linear regression was used to examine associations between policy support and state youth obesity prevalence (2011-2012 National Survey for Children's Health), overall and stratified by state policy strength (2012 Classification of Laws Associated with School Students). RESULTS: States provided support most commonly for school meals and wellness policies (89% and 81%, respectively) and least often for after-school PE (26%). Most states (80%) provided technical assistance. The total weight-related policy support score had a significant positive association with state-level youth overweight/obesity prevalence (p = .03). CONCLUSION: State agencies appear to be responding to their youth obesity prevalence with technical support. Schools and state agencies should work in collaboration to provide a healthy school environment for all students.

Dealing with a deluge of data: an assessment of adverse event data on North Central Cancer Treatment Group trials.

PURPOSE: Adverse events (AEs) are monitored in clinical trials for patient safety, to satisfy reporting requirements, and develop safety profiles. Recently, much attention has been placed on the reporting of serious AEs (SAEs) that are either life threatening or lethal in clinical trials. However, SAEs comprise a small subset of all AE data collected for trials; the majority of AE data collected are routine AEs (RAEs) regarding non-life-threatening events. We assessed the utility of the RAE data collected, relative to the volume. PATIENTS AND METHODS: We surveyed the RAE data from 26 North Central Cancer Treatment Group coordinated trials. RESULTS: A total of 8,318 (11%) of 75,598 of RAEs required queries. Of these, 86% were protocol-required RAEs, 83% of RAEs required per protocol were within normal limits (eg, platelets) or not present, and 61% of extra AEs were mild. One fifth of RAEs were considered unlikely to be related or unrelated to treatment. Overall, 3% of events were severe, life threatening, or caused death. Only 1% of RAE data reported required expedited reporting (eg, via Adverse Event Expedited Reporting System). Results indicate that 72% of RAEs would be eliminated if only the maximum severity per patient and type were required. These results were validated in a large phase III trial. CONCLUSION: The majority of RAEs identified, transcribed, and entered are not clinically important. Our data suggest that reducing the number of AEs monitored will affect substantially neither overall patient safety nor compromise evaluation of regimens undergoing testing. We present several considerations for such a reduction in data collection, as well as a policy that we have used to address the deluge of RAE data.

Diverticular disease in patients with colon cancer: subgroup analysis of national surgical adjuvant breast and bowel project protocol C-06.

BACKGROUND: Similar epidemiologic characteristics suggest a common etiology for colon cancer (CC) and diverticular disease of the colon (DD). The relationship between the 2 diseases is still unclear, and the impact of DD in patients diagnosed with CC on disease-free survival (DFS) and overall survival (OS) is unknown. National Surgical Adjuvant Breast and Bowel Project (NASBP) protocol C-06 is a clinical trial comparing oral uracil/tegafur/leucovorin with 5-fluorouracil/leucovorin in patients with resected stage II/III carcinoma of the colon. PATIENTS AND METHODS: The NASBP enrolled 1,608 patients who had undergone potentially curative resection for stage II/III colon cancer from 256 medical sites between February 14, 1997, and March 31, 1999. RESULTS: Pathology reports from 1561 eligible patients retrospectively reviewed for the presence of DD revealed that 160 (10.2%) had this disease. The median ages of patients with CC and DD and without DD were 67 and 61 years, respectively (P < 0.05). The majority of patients were white, and Hispanic patients were better represented in the group with DD (P < 0.05). Colon cancer was located in the rectosigmoid in 46.88% of patients with DD and in 31.92% of patients without DD (P < 0.05). A baseline diagnosis of DD made no significant contribution to DFS or OS without adjustment for confoundin factors (P = 0.2 and P = 0.32, respectively) or adjusted for Dukes classification and age (P = 0.49 and P = 0.68, respectively). CONCLUSION: The prevalence of DD in patients diagnosed and treated for CC was 10.2%. Patients with CC with and without DD differed from each other with respect to age, tumor location, and ethnicity. There was no negative impact of having DD on DFS and OS in patients treated for stage II/III CC.