Pre-diagnosis blood glucose and prognosis in women with breast cancer.

BACKGROUND: The effect of moderately elevated blood glucose levels among non-diabetic subjects on cancer prognosis is not well described. The goal of this study was to examine the association of elevated random blood glucose (RBG) levels in non-diabetic breast cancer patients with overall survival (OS) and time to tumor recurrence (TTR). RESULTS: Forty-nine deaths and 32 recurrences occurred among 148 eligible study subjects during 855.44 person-years of follow-up, with median follow-up of 5.97 years. We observed that patients with elevated RBG levels experienced significantly shorter OS (hazard ratio [HR], 3.01; 95 % confidence interval [CI] (1.70-5.33); P < 0.001) and shorter TTR (HR, 2.08; CI (1.04-4.16); P = 0.04) as compared to patients with non-elevated RBG levels. After controlling for tumor grade, tumor stage, race, and BMI, elevated RBG continued to display high and statistically significant association with shorter OS (HR, 3.50; CI (1.87-6.54); P < 0.001). Adjustment for age, race, and BMI strengthened HR of RBG for TTR. The association of RGB with TTR lost its borderline statistical significance upon controlling for both tumor grade and stage. CONCLUSIONS: The data suggest that elevated blood glucose is associated with poor prognosis of breast cancer patients. Given the potential clinical implication, these findings warrant further investigation.

CHST11 gene expression and DNA methylation in breast cancer.

Our previously published data link P-selectin-reactive chondroitin sulfate structures on the surface of breast cancer cells to metastatic behavior of cells. We have shown that a particular sulfation pattern mediated by the expression of carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) correlates with P-selectin binding and aggressiveness of human breast cancer cell lines. The present study was performed to evaluate the prognostic value of CHST11 expression and determine whether aberrant DNA methylation controls CHST11 expression in breast cancer. Publicly available datasets were used to examine the association of CHST11 expression to aggressiveness and progression of breast cancer. Methylation status was analyzed using bisulfite genomic sequencing. 5-aza-2'-deoxycytidine (5AzadC) was used for DNA demethylation. Reduced representation bisulfite sequencing was performed in the CpG island of CHST11 with a minimum coverage of 10. Quantitative real-time RT-PCR was employed to confirm the expression profile of CHST11 in breast cancer cell lines. Flow cytometry was also used to confirm the expression of the CHST11 product, chondroitin sulfate A (CS-A). The expression of CHST11 was significantly higher in basal-like and Her2-amplified cell lines compared to luminal cell lines. CHST11 was also highly expressed in cancer tissues compared to normal tissues and the expression levels were significantly associated with tumor progression. We observed very low levels of DNA methylation in a CpG island of CHST11 in basal-like cells but very high levels in the same region in luminal cells. Treatment of MCF7 cells, a luminal cell line with very low expression of CHST11, with 5AzadC increased the expression of CHST11 and its immediate product, CS-A, in a dose-dependent manner. These results suggest that CHST11 may play a direct role in progression of breast cancer and that its expression is controlled by DNA methylation. Therefore, in addition to CHST11 mRNA levels, the methylation status of this gene also has potential as a prognostic biomarker.

Ethics-in-oncology forums.

BACKGROUND: We developed an ethics curriculum for hematology/oncology fellows who had already learned medical ethics from medical school and residency programs. The goal of the ethics program was to train fellows in ethics issues specific to hematology/oncology; to raise awareness of ethical issues; and to teach fellows to write, edit, and publish reviews in specific ethical issues. METHODS: Fellows learned to summarize expert opinions, to understand diversity in cultural concepts relating to ethics, and to crystallize their approaches to ethical dilemmas to selected oncology patients. Fellows were also trained to write ethics discussions in manuscript format, edit the manuscripts, and submit them for publication. RESULTS: We hypothesized that fellows would learn ethics in oncology by recognizing and choosing an ethical dilemma from among patient population; reviewing the literature for a discussion of relevant ethical issues; presenting the case and facilitating discussion to an ethics-in-oncology committee; hearing faculty and peer input into their cases; and finally writing, editing, and publishing the deliberation. It also increased understanding of health systems management, a new competency required by the Accreditation Council for Graduate Medical Education for board certification. CONCLUSIONS: Fellows' perceptions about the experience were positive. We recommend that other subspecialty programs consider this format for teaching ethics in their subspecialties.

Promoter hypermethylation for molecular nodal staging in non-small cell lung cancer.

CONTEXT: Even among cases of non-small cell lung cancer (NSCLC) in the most favorable stage (IA), the disease-specific mortality is 25% or greater. One plausible explanation implicates the simplistic standard pathologic procedures used to designate lymph node involvement. A more sensitive assessment of the nodal status may improve staging. OBJECTIVE: To determine the prognostic impact of detecting an abnormal molecular event (promoter hypermethylation in a set of relevant genes) in histologically uninvolved lymph nodes in resected NSCLC. DESIGN: In this retrospective analysis of archived material, we examined DNA extracted from lymph nodes of stage I NSCLC (n = 180). Patients underwent surgery between 1991 and 1995 in a single institution. Methylation-specific polymerase chain reaction was used to detect promoter hypermethylation in a panel of 8 genes. Survival data were extracted from the computerized database at the Tumor Registry. RESULTS: Evidence of promoter hypermethylation in at least 1 gene was detected in 67% of these N0 nodes. The most commonly hypermethylated gene was E-cadherin (53%). The hypermethylation frequency for the remaining genes were as follows: APC, 5%; p16, 9%; MGMT, 11%; hMLH1, 15%; RASSF1A, 4%; DAP kinase, 9%; and ATM, 19%. The presence of promoter hypermethylation in 2 or more genes did not influence the overall, median, or 5-year survival rates. CONCLUSIONS: Identifying promoter hypermethylation (in our panel) in N0 lymph nodes in stage I NSCLC cannot be recommended for clinical decision making. Molecular abnormalities, including those found in cancer by qualitative methylation-specific polymerase chain reaction, are not synonymous with established, histologically detectable metastasis.

Editorial clubs as a new teaching tool in postgraduate training.

BACKGROUND: We report an editorial club as a novel method of teaching systems-based competency in a hematology/oncology fellowship program. METHOD: Editorial clubs focus on topics of broad economic, political, and legal ramifications of hematology/oncology and thereby help to develop systems competency as required by the Accreditation Council for Graduate Medical Education. RESULTS: We began our program in 2001 and report on its functioning and outcome in a group of hematology/oncology fellows at the University of Arkansas for Medical Sciences. CONCLUSION: Topics were diverse, fellows and faculty attendance was excellent, and fellows reported improved systems-based competency.

Methylation profiling of archived non-small cell lung cancer: a promising prognostic system.

PURPOSE: Enhanced prognostication power is becoming more desirable in clinical oncology. In this study, we explored the prognostic potential of multigene hypermethylation profiling in non-small-cell lung cancer. EXPERIMENTAL DESIGN: We evaluated a panel of eight genes (p16, APC, ATM, hMLH1, MGMT, DAPK, ECAD, and RASSF1A) using methylation-specific PCR in 105 archived specimens of non-small-cell lung cancer representing all stages of the illness. We analyzed the effect of gene methylation status on outcome individually in a cumulative manner and in a combinatorial approach using recursive partitioning to identify methylation profiles, which affect overall survival. RESULTS: In this data set, tumors harboring promoter hypermethylation at two or more genes exhibit similar survival trends to others in the cohort. Using recursive partitioning, three genes (APC, ATM, and RASSF1A) emerged as determinants of prognostic groups. This designation retained its statistical significance even when disease stage and age were entered into a multivariate analysis. Using this approach, patients whose tumors were hypermethylated at APC and those hypermethylated at only ATM (not also at APC or RASSF1A) enjoyed substantially longer 1- and 2-year survival than patients in the remaining groups. In 32 adjacent histologically normal lung tissue specimens, we detected similar methylation abnormalities. CONCLUSION: Assessment of promoter hypermethylation aberrations may facilitate prognostic profiling of lung tumors, but validation in independent data sets is needed to verify these profiles. This system uses material that is abundantly available with linked outcome data and can be used to generate reliable epigenetic determinants.