Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function.

Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.

LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.

B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.

Magnetic field exposure assessment in a case-control study of childhood leukemia.

Epidemiologic evaluation of the relation between magnetic field exposures and cancer depends critically on study design, particularly the methods used for exposure assessment. We incorporated a complex magnetic field exposure assessment protocol into a large incident case-control study of childhood leukemia. We measured residential magnetic fields using a standard protocol in current and former homes of 638 cases and 620 controls and determined wire codes for 414 case-control pairs. We chose a time-weighted average of magnetic field measurements in each eligible home, weighted by the time the subject lived in each home as the main exposure metric for each subject. We found that 24-hour bedroom magnetic field measurements adequately characterize children's residential exposure and that measuring other rooms contributes only slightly to the estimate of average residential exposure to magnetic fields. Front door measured fields provide useful exposure information when interior measurements are missing. If feasible, measuring multiple homes in which the subject has resided is preferable to measuring a single home. A similar distribution of wire codes for controls agreeing or refusing to participate in our study implies that risk estimates derived from wire code data will not be influenced by response bias.

Residential exposure to magnetic fields and acute lymphoblastic leukemia in children.

BACKGROUND: Previous studies found associations between childhood leukemia and surrogate indicators of exposure to magnetic fields (the power-line classification since known as "wire coding"), but not between childhood leukemia and measurements of 60-Hz residential magnetic fields. METHODS: We enrolled 638 children with acute lymphoblastic leukemia (ALL) who were under 15 years of age and were registered with the Children's Cancer Group and 620 controls in a study of residential exposure to magnetic fields generated by nearby power lines. In the subjects' current and former homes, data collectors measured magnetic fields for 24 hours in the child's bedroom and for 30 seconds in three or four other rooms and outside the front door. A computer algorithm assigned wire-code categories; based on the distance and configuration of nearby power lines, to the subjects' main residences (for 416 case patients and 416 controls) and to those where the family had lived during the mother's pregnancy with the subject (for 230 case patients and 230 controls). RESULTS: The risk of childhood ALL was not linked to summary time-weighted average residential magnetic-field levels, categorized according to a priori criteria. The odds ratio for ALL was 1.24 (95 percent confidence interval, 0.86 to 1.79) at exposures of 0.200 mu T or greater as compared with less than 0.065 mu T. The risk of ALL was not increased among children whose main residences were in the highest wire-code category (odds ratio as compared with the lowest category, 0.88; 95 percent confidence interval, 0.48 to 1.63). Furthermore, the risk was not significantly associated with either residential magnetic-field levels or the wire codes of the homes mothers resided in when pregnant with the subjects. CONCLUSIONS: Our results provide little evidence that living in homes characterized by high measured time-weighted average magnetic-field levels or by the highest wire-code category increases the risk of ALL in children.

Childhood exposure to magnetic fields: residential area measurements compared to personal dosimetry.

We examined the relation between area measurements of residential magnetic fields and personal dosimetry measurements among 64 control children age 2-14 years from the National Cancer Institute-Children's Cancer Group's nine-state case-control study of childhood leukemia. During a typical weekday, an activity diary was completed, and a 24-hour measurement was obtained in each child's bedroom. According to the activity diaries, children spent more than 40% of the 24 hours in their bedrooms, and 68% of their time at home. We found that at-home personal dosimetry levels were highly correlated with total personal dosimetry levels in children under 9 years (Spearman correlation coefficient, R = 0.94), whereas the correlation was lower in older children (R = 0.59). For all children combined, bedroom 24-hour measurements correlated well with at-home personal dosimetry levels (R = 0.76). The 24-hour bedroom measurement was a useful predictor of both at-home and total personal dosimetry measurements. Particularly for younger children, our data suggest that in-home area measurements predict both current residential and current total magnetic field exposures. This information will be valuable for assessing the validity of exposure assessment in previous and ongoing studies and for developing measurement protocols for future studies.

Case-control evaluation of breast cancer screening efficacy.

The feasibility and validity of using case-control methods to evaluate the efficacy of breast cancer screening were investigated using data from the Health Insurance Plan of Greater New York Breast Cancer Screening Trial. Women who died of breast cancer were compared with individually matched controls of the same age who had equal or greater survival times. To minimize the effects of self-selection bias, most analyses focused on the 95 cases and 380 matched controls who had been screened at least once and for whom covariate data were available. A statistically significant effect for being screened more than once versus being screened once, uncorrected for healthy-screenee bias, was found (odds ratio = 0.13, p less than 0.001). After correction for healthy-screenee bias, the effect was not statistically significant (odds ratio = 0.54, p = 0.15). Possible explanations for this statistical nonsignificance are: 1) correction for healthy-screenee bias entails loss of power and 2) the correction procedure used may, under some circumstances, result in bias toward the null hypothesis. Further research into means of eliminating healthy-screenee bias is needed to improve the applicability of case-control methods to the evaluation of screening efficacy.

Breast cancer detection centers and case-control studies of the efficacy of screening.

Case-control studies of screening efficacy have been proposed as a cost- and time-efficient alternative to randomized controlled trials. Possible source populations for such retrospective studies of breast cancer screening are considered, including women from (i) pre-existing randomized trials, (ii) non-experimental population-based studies and (iii) detection centers. On practical grounds women attending detection centers are seen to comprise the most readily accessible source of adequate numbers of cases and controls. Potential biases are addressed, involving incomplete case ascertainment, self-selection, and different screening recommendations. Data from the Guttman Breast Diagnostic Institute are used for illustration.

Psychosocial adjustment of familial polyposis patients and participation in a chemoprevention trial.

Psychological and social adjustment was assessed in eighty-nine individuals with familial polyposis, a genetically transmitted disease placing one at high risk for colon cancer. Three illness-related concerns were identified: fear about future health due to the high risk for cancer; guilt about transmitting a genetic disease to one's children; and concern about physical disfigurement resulting from surgery. Well-being scores were generally positive, although somewhat lower than those reported in a community sample. Two factors in particular influenced well-being scores: those with higher levels of concern about disfigurement reported lower well-being, and those with accurate information about the disease reported higher well-being. Of the eighty-nine individuals included in this study, sixty-one were participating in a clinical trial and twenty-eight had been invited but declined entry. Demographic and psychosocial factors were examined for their relationship to participation. Only three of these variables, length of time since diagnosis, religious affiliation, and geographic location distinguished participants from nonparticipants.