There are no accurate prognostic biomarkers specific for rectal cancer. Epigenetic aberrations, in the form of DNA methylation, accumulate early during rectal tumor formation. In a preliminary study, we investigated absolute quantitative methylation changes associated with tumor progression of rectal tissue at multiple genomic methylated-in-tumor (MINT) loci sequences. We then explored in a different clinical patient group whether these epigenetic changes could be correlated with clinical outcome.

Previous analyses of TOP2A and HER2 in the Danish Breast Cancer Coopererative Group (DBCG) trial 89D suggested that TOP2A amplifications and possible also deletions are predictive markers for the effect of adjuvant epirubicin in patients with primary breast cancer. We present an updated and extended statistical analysis, requested for IVD-labeling of TOP2A testing.

We studied the role of TS (5'VNTR, 5'SNP and 3'UTR), XRCC1-399, XPD-751, ERCC1-118 and XRCC3-241 genetic polymorphisms in tailoring fluroropyrimidine/oxaliplatin treatment. For this purpose, 110 XELOX (capecitabine/oxaliplatin)- or FUOX (fluorouracil/oxaliplatin)-treated metastatic colorectal cancer patients were selected prospectively for genotyping. In the FUOX group, TS-3'UTR +6bp/+6bp (hazards ratio, HR=2.62, p=0.007) and ERCC1-118C/T or C/C (HR=1.96, p=0.050) genotypes correlated with a shorter progression-free survival (PFS). When analysed jointly, the higher the number of favourable genotypes (FG) the longer the PFS (6.8m, 9.6m and 25.8m for 0, 1 or 2 FG; p=0.005). Disease-control rate was 100% in patients with 2 FG (87% and 38.5% for 1 or 0 FG; p=0.001). In the multivariate analysis, ERCC1-118 (HR=2.12, p=0.0037) and TS-3'UTR (HR=2.68, p=0.006) were strong independent prognostic factors. According to this, patients harbouring TS-3'UTR +6bp/+6bp and ERCC1-118C/T or C/C genotypes may better receive capecitabine instead of 5FU in an oxaliplatin-based first-line treatment.

Insulin-like growth factor-I (IGF-I) is an important growth factor associated with increased risk of premenopausal breast cancer. We conducted a randomized, placebo-controlled, double-blind, crossover trial to evaluate whether tomato-derived lycopene supplementation (30 mg/day for 2 mo) decreases serum levels of total IGF-I in premenopausal women with 1) a history of breast cancer (n=24) or 2) a high familial breast cancer risk (n=36). Also, IGF binding protein (IGFBP) increasing effects were evaluated. Lycopene supplementation did not significantly alter serum total IGF-I and other IGF system components in the 2 study populations combined. However, statistically significant discordant results were observed between the 2 study populations (i.e., P<0.05 for total IGF-I, free IGF-I, and IGFBP-3). Total IGF-I and IGFBP-3 were increased in the breast cancer survivor population [total IGF-I=7.0%, 95% confidence interval (CI)= -0.2 to 14.3%; IGFBP-3=3.3%, 95% CI=0.7-6.0%), and free IGF-I was decreased in the family history population (-7.6%, 95% CI= -14.6 to -0.6%). This randomized controlled trial shows that 2 mo of lycopene supplementation has no effect on serum total IGF-I in the overall study population. However, lycopene effects were discordant between the 2 study populations showing beneficial effects in high-risk healthy women but not in breast cancer survivors.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Mammary cancer is among the most prevalent of canine tumors frequently resulting in death due to metastatic disease. Most tumors fail to raise an effective immune reaction making improving immune recognition a priority. Hybrid-cell fusion strategies have been employed to load dendritic cell populations with tumor cell antigens to stimulate immune recognition; however, recovery, heterogeneity and quality of primary cells from patients present enormous challenges. We employed allogeneic cell lines to develop an improved hybrid-cell fusion strategy and evaluated immune reactions in normal laboratory beagles. Such a strategy relies on enhanced immune recognition of allogeneic tumor cell antigens by antigen presenting cells. Optimized PEG-promoted fusions between uniquely stained canine mammary tumor CMT12 or CMT28 cells and a dendritic cell-like DH82 cell fusion partner resulted in greater than 40% hybrid-cell fusion populations by flow cytometry and fluorescence microscopy. Hybrid-cell fusions were delivered by direct ultrasound guided injection into popliteal lymph nodes of laboratory beagles. Only hybrid-cell fusions provided statistically significant enhancement of cell-mediated immunity ((51)Cr-release assay) compared to innate reactions in naïve vehicle injected dogs while dogs vaccinated with either single cell component alone did not. Vaccination with hybrid-cell fusions enhanced IFN-gamma expression in sorted CD8+ and CD4+ cells but not in CD4-/CD8- cells consistent with a CTL response. Cell-mediated immune assays revealed strong reactions against matched (vaccine component) CMT cells and unmatched CMT cells indicative of an immune response to mammary cancer antigens common to both cell lines. These results provide proof of principle for development of an allogeneic vaccination strategy against canine mammary cancer.

This study of first-line treatment in advanced-stage follicular lymphoma patients analysed the effects of MCP (mitoxantrone, chlorambucil and prednisolone) chemotherapy alone or in combination with rituximab (R-MCP) on circulating lymphoma cells (CLC) and assessed the prognostic value of a quantitative monitoring of CLC. CLC numbers were determined by quantitative polymerase chain reaction (PCR) for the t(14;18)-translocation or by allele-specific PCR for rearranged immunoglobulin heavy chain genes. We analysed blood samples from 43 patients treated in a randomized trial comparing eight cycles of MCP versus R-MCP. Clearance of CLC at the end of therapy was achieved in 21/25 patients (84%) treated with R-MCP compared with 0/18 after MCP alone (P < 0.0001). A > or = 2 log CLC reduction was associated with a favourable clinical response (P = 0.0004) and prolonged event-free survival (P = 0.02). In R-MCP patients, stable CLC numbers or consistently PCR-negative blood samples were associated with a continuing clinical remission whereas in two patients a relapse was preceded by a > or = 2 log CLC increase. This study demonstrated that R-MCP led to a rapid and sustained eradication of CLC and a > or = 2 log CLC reduction was associated with a superior quality and duration of the clinical response.

To increase accrual among Hispanics to the Cancer Genetics Network national cancer genetics registry.

Polymorphisms in a number of genes encoding for DNA repair enzymes have been associated with altering the function of these enzymes and increasing risk of a number of cancers, including colon cancer. We have investigated the association between a common variant in polynucleotide kinase 3' phosphatase (PNKP), a putative DNA repair enzyme, and risk of adenoma recurrence in the Polyp Prevention Trial participants. We also investigated possible interaction or effect modification between carriage of the variant allele, dietary components and risk of adenoma recurrence. Unconditional logistic regression models were used to calculate the odds ratios and 95% confidence intervals for an association between the G/T polymorphism, PNKP T5644G and risk of adenoma recurrence. We observed no association between carriage of the variant allele and risk of adenoma recurrence. Furthermore, we found no effect modification between genotype, dietary components and risk of adenoma recurrence. The PNKP T5644G variant does not seem to be involved in adenoma recurrence in the Polyp Prevention Trial.

ErbB-2 (human epidermal growth factor receptor 2) overexpression may be predictive of relative resistance and/or sensitivity to specific chemotherapeutic agents. Results from a previous study from the Cancer and Leukemia Group B (CALGB 8541) demonstrated an interaction between ErbB-2 and increasing dose of adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Other studies have suggested that evaluation of the phosphorylated/activated form of ErbB-2 might be more precise in defining the impact of ErbB-2 in breast cancer. We have evaluated tumor tissue sections from CALGB 8541 patients to determine whether the interaction of ErbB-2 with CAF dose is dependent on ErbB-2 activation state, and whether phosphorylated ErbB-2 is an adverse prognostic factor in patients treated with CAF.

To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer.

To assess the safety and tolerability of a standardized 40 mg red clover isoflavone dietary supplement (Promensil, Novogen) in women with a family history of breast cancer to evaluate the feasibility of using the supplement for prevention of breast cancer in healthy women.

In the present study, eighty-four breast cancer patients were randomized to receive a daily supplement of 100 mg co-enzyme Q10, 10 mg riboflavin and 50 mg niacin (CoRN), one dosage per d along with 10 mg tamoxifen twice per d. A significant increase in poly(ADP-ribose) polymerase levels and disappearance of RASSF1A DNA methylation patterns were found in patients treated with supplement therapy along with tamoxifen compared to untreated breast cancer patients and tamoxifen alone-treated patients. An increase in DNA repair enzymes and disappearance of DNA methylation patterns attributes to reduction in tumour burden and may suggest good prognosis and efficacy of the treatment.

Intergroup Radiation Therapy Oncology Group Trial 9402 study, a phase III trial of chemotherapy plus radiotherapy (PCV-plus-RT) vs. radiotherapy alone for pure and mixed anaplastic oligodendroglioma confirmed the prognostic significance of 1p 19q deletion and showed that only progression-free survival (PFS) was prolonged in PCV-plus-RT-treated patients and only in association with 1p 19q deletion. We reviewed tumor histopathology, separating 115 tumors deemed to be classic for oligodendroglioma (CFO) from 132 lacking classic features of oligodendroglioma (NCFO) and evaluated the relationship of histopathology and 1p 19q status to treatment and outcome. The study disclosed: (i) overall survival (OS) of patients with CFO was significantly longer than for patients with NCFO (P < 0.0001) and was not affected by necrosis. Median OS for CFO patients with and without necrosis was 6.6 and 6.3 years (OS log-rank P = not significant), respectively, in contrast to NCFO showing 1.9 and 3.3 years respectively (OS log-rank P = 0.014). (ii) Classic oligodendroglial morphology was highly associated with 1p 19q deletion, present in 80% of CFO and only in 13% of NCFO. (iii) On multivariate analysis, both classic oligodendroglial morphology and 1p 19q deletion remained significantly associated with PFS and OS. (iv) Patients with CFO treated with PCV-plus-RT showed a trend toward increased survival compared with CFO treated with RT (P = 0.08). Median OS was not reached in the PCV-plus-RT group and was 6.3 years in RT group. These findings suggest that classic oligodendroglial morphology combined with 1p 19q deletion may in the future be predictive of chemotherapeutic response and survival.

In comparison to total therapy 1 (TT1), the phase 3 trial total therapy 2 (TT2) evaluated the benefit of up-front administration of thalidomide (THAL); TT2 also introduced post-transplant consolidation chemotherapy. With median follow-up times of 5 and 12 years, respectively, outcome comparisons were made of 668 patient's enrolled on TT2 and 231 patients treated on TT1. Complete response (CR) rates were similar at 40% for TT1 and TT2 without THAL versus 60% on the THAL arm of TT2. CR durations were similar with either TT2 arm and both were superior to results of TT1. Event-free and overall survivals were extended from 2.6 to 5.7 years, respectively, with TT1 to 4.8 and 8.0 years with TT2. TT2's major advance vis-à-vis TT1 pertained to the subgroup without cytogenetic abnormalities (CA), supporting the role of post-transplant consolidation therapy, whereas the improved survival of the CA subgroup on the experimental versus control arm of TT2 attests to the role of THAL in this setting. Adjusting for prognostic variables in multivariate and pair-mate analyses, TT2 was superior to TT1 in terms of CR duration, event-free and overall survival. These results provide a basis for the prospective evaluation of the consolidation strategy in a randomized clinical trial design.

The insulin-resistant state of the polycystic ovary syndrome (PCOS) was found to be associated with a decreased glucose transporter GLUT4 expression in the insulin target tissues. This study was performed to explore whether the well-known clinical, hormonal and metabolic efficacy of metformin or rosiglitazone treatment is reflected in the modulation of adipocyte GLUT4 mRNA expression in patients with PCOS.

To determine the optimal doses of the antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody cetuximab and the EGFR tyrosine kinase inhibitor gefitinib when administered as a combination for patients with advanced/metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy.

Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.

First-degree relatives (FDRs) of people diagnosed with colorectal cancer (CRC) have a two- to threefold increased risk of developing the same disease. Tailored print interventions based on behavior change theories have demonstrated considerable promise in facilitating health-promoting behaviors. This study compared the impact of two mailed print interventions on CRC screening outcomes among FDRs.

Total therapy 3 (TT3), incorporating bortezomib up-front into a tandem transplant regimen for newly diagnosed multiple myeloma (MM), effected 2-year complete response (CR) estimates >90%, which appeared superior to results reported for total therapy 2 (TT2). With median follow-up times of 2 years with TT3 and 5 years with TT2, the clinical outcomes of 303 patients in the former and 668 in the latter trial were compared, including the subset of 607 patients with gene expression profiling (GEP) data. With similar baseline prognostic factors, event-free survival (EFS) (P = 0.0002) and CR duration (P = 0.003) were superior with TT3 vs. TT2 with a strong trend noted also for improved overall survival (OS) (P = 0.16). In the GEP-defined FGFR3 subgroup, TT3 imparted significantly superior OS, EFS and CR duration vis-à-vis TT2. Matching 300 patients each by standard prognostic factors, TT3 yielded superior EFS and CR duration and borderline superior OS. The advantage of TT3 still pertained when the comparison was limited to patients who completed TT2 consolidation rapidly within 24 months. Our data strongly suggest that the addition of bortezomib in TT3 was accountable for its superior performance rather than greater compliance with protocol completion as a result of greater dose-density in TT3 vs. TT2.