Individual Factors Contributing to Nausea in First-Time Chemotherapy Patients: A Prospective Cohort Study.

OBJECTIVE: The expectation of developing side effects can enhance the likelihood to develop them - a phenomenon referred to as nocebo effect. Whether nocebo effects can be reduced by lowering negative expectancies, is not clear. The aim of this prospective study was to learn more about the factors contributing to nausea expectancy and their potential role in actual occurrence of nausea in patients undergoing chemotherapy for the first time in their life. METHODS: Patients scheduled for moderately emetogenic chemotherapeutic regimens filled in questionnaires to assess state anxiety and quality of life and to rate the expectancy of nausea as a side effect of chemotherapy. Patient diaries were used to monitor the severity of post-chemotherapy nausea in the 4 days following chemotherapy administration. Bivariate analyses complemented by multiple regression analyses were performed to identify the relationship between nausea expectation and nausea occurrence. RESULTS: 121 female patients (mean age 53 years) with completed questionnaires were included in the analyses. The majority of the patients had a diagnosis of breast cancer (86%). The two main sources for nausea expectancy were positive history of nausea in other situations and state anxiety. Patients with high expectancy levels (first quartile) experienced greater nausea than those with lower expectancy levels. Bivariate analyses revealed a weak but non-significant association between nausea expectation and post-chemotherapy nausea. When controlling for age, type of cancer, history of nausea, state and trait anxiety, and global quality of life, positive history of nausea (OR = 2.592; 95% CI, 1.0 to 6.67; p < 0.05), younger age (OR = 0.95; 95% CI, 0.92 to 0.99; p < 0.05), and a lower quality of life (OR = 0.97; 95% CI, 0.94 to 1.0; p < 0.05), but not nausea expectancy (OR = 1.014; 95% CI, 0.51 to 2.02; p = 0.969), predicted the occurrence of post-chemotherapy nausea. CONCLUSION: In this female cohort, younger patients with lower initial quality of life and a positive history of nausea were at higher risk to develop nausea after first time chemotherapy. These patients may benefit from psychological co-interventions that aim to enhance quality of life.

Diagnostic relevance of plasma DNA and DNA integrity for breast cancer.

Levels of ALU 115, ALU 247, DNA integrity ([1, 2]) and of the tumour markers CA 15-3 and CEA were analysed in the blood of 152 patients. Plasma levels of ALU 115 and ALU 247 were significantly higher in patients with locally confined (LBC; N = 65), metastatic breast cancer (MBC; N = 47), and benign diseases (N = 12) than in healthy controls (p < 0.001 for all comparisons). DNA integrity, CEA, and CA 15-3 were significantly higher in MBC than in benign controls and LBC but could not identify LBCs. The best discrimination of LBC from healthy controls was achieved by ALU 115 and ALU 247 (AUC 95.4 and 95.5 %) and of MBC from all control groups by CA 15-3 and CEA (AUC 83.2 and 79.1 %). Plasma DNA is valuable for the detection of LBC, while established tumour markers are most informative in MBC.

Circulating plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, biomarkers for predicting response to therapy are urgently required. PATIENTS AND METHODS: In 65 patients with locally confined breast cancer who had completed the course of chemotherapy until surgery, plasma DNA biomarkers obtained before and during therapy were evaluated concerning (early) estimation of therapy response. Levels of repetitive ALU 115 and ALU 247 elements as well as DNA integrity calculated according the formulas of Umetani (1) and Wang (2) were correlated with changes in histopathological staging at surgery and compared with conventional tumor markers CEA and CA 15-3. RESULTS: At surgery, 13 patients presented complete remission (CR), 32 partial remission (PR) and 20 no change of disease (NC). Pretherapeutic Her2/neu status was positively correlated with therapy response (p=0.019). DNA biomarkers before onset of therapy cycles 1, 2 and 6 did not indicate outcome after therapy. However, kinetics of ALU 115 from cycle 1 to 6 showed decreases in CR patients, while in NC patients, an increase was observed (p=0.033). Similar tendencies were found for ALU 247 fragments. DNA integrity index as well as CEA and CA 15-3 were not informative for therapy outcome. CONCLUSION: Kinetics of plasma DNA (ALU 115) is associated with response to neoadjuvant chemotherapy in patients with locally confined breast cancer.

Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity.

Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4(+) T cells have been described to be highly important for tumour elimination although TCR derived from CD4(+) T cells with anti-tumour reactivity have been only rarely described. In this study we aimed to isolate MHC class-II-restricted CD4(+) T cells and TCR with specificity for leukaemia antigens. We used professional antigen-presenting cells pulsed with the leukaemia-associated and tumour-associated antigen FMNL1 for stimulation of autologous T cells in vitro. We isolated two CD4(+) HLA-DR-restricted T-cell clones and T-cell-derived TCR with so far unknown specificity but high reactivity against lymphoma cells and native malignant cells derived from HLA-matched patients with diverse leukaemias. Moreover, characterization of the TCR after TCR gene transfer revealed that specific characteristics of isolated TCR as reactivity in response to Toll-like receptors were transferable on effector cells. Our results have a major impact on the development of novel immunotherapies. They demonstrate that TCR with potent HLA-DR-restricted anti-leukaemic reactivity against so far undefined self-restricted antigens can be isolated from the healthy autorestricted CD4(+) T-cell repertoire and these TCR are highly interesting candidate tools for novel immunotherapies.

Methods for isolation of cell-free plasma DNA strongly affect DNA yield.

Extracellular nucleic acids are present in plasma, serum, and other body fluids and their analysis has gained increasing attention during recent years. Because of the small quantity and highly fragmented nature of cell-free DNA in plasma and serum, a fast, efficient, and reliable isolation method is still a problem and so far there is no agreement on a standardized method. We used spin columns from commercial suppliers (QIAamp DNA Blood Midi Kit from Qiagen; NucleoSpin Kit from Macherey-Nagel; MagNA Pure isolation system from Roche Diagnostics) to isolate DNA from 44 plasma samples in parallel at laboratories in Berlin and Munich. DNA in all samples was quantified by real-time PCR on a LightCycler 480 using three different targets (GAPDH, ß-globin, ERV). The quantities of cell-free DNA for the different isolation methods and genes varied between medians of 1.6 ng/mL and 28.1 ng/mL. This considerable variation of absolute DNA values was mainly caused by the use of different isolation methods (p<0.0001). Comparable results were achieved by the use of the genes GAPDH and ERV while higher values were obtained by use of ß-globin. The laboratory site had only minor influence on DNA yield when manual extraction methods were used.