Cost-effective approach to the diagnostic workup of B cell lymphoproliferative disorders via optimal integration of flow cytometric data.

INTRODUCTION: The workup of lymphoproliferative disorders (LPDs) involves the combined use of flow cytometry (FC) and immunohistochemistry (IHC). This often results in duplicate immunophenotypic testing and adds costs that may not be eligible for reimbursement based on the Medicare National Correct Coding Initiative. We aimed to establish a cost-effective diagnostic algorithm based on initial FC categorization to reduce repetitive immunophenotyping. METHODS: We retrospectively reviewed 242 cases of suspected LPDs with concurrent FC and IHC testing over a 12-month period. We correlated FC with surgical diagnoses and evaluated the frequency of repeat IHC testing. RESULTS: Repetitive immunophenotyping was common; overall, 85% of cases had at least one marker repeated. Concordant cases were significantly less likely to have markers repeated than discordant cases. Of concordant B cell malignancies, 57% represented recurrent disease; however, repeat marker usage was not decreased as compared to new diagnoses. The most frequently repeated markers were CD3, CD5, CD10, and CD20. CONCLUSIONS: We propose that in concordant cases, CD5 and CD10 should not be repeated by IHC; this would decrease the use of these markers by 80% and 76%, respectively. We developed an algorithmic approach to IHC usage that has improved incorporation of FC data at our institution and may reduce healthcare costs.

Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis.

Hematopoietic cells normally require cell extrinsic signals to maintain metabolism and survival. In contrast, cancer cells can express constitutively active oncogenic kinases such as BCR-Abl that promote these processes independent of extrinsic growth factors. When cells receive insufficient growth signals or when oncogenic kinases are inhibited, glucose metabolism decreases and the self-digestive process of autophagy is elevated to degrade bulk cytoplasm and organelles. Although autophagy has been proposed to provide a cell-intrinsic nutrient supply for mitochondrial oxidative metabolism and to maintain cellular homeostasis through degradation of damaged organelles or protein aggregates, its acute role in growth factor deprivation or inhibition of oncogenic kinases remains poorly understood. We therefore developed a growth factor-dependent hematopoietic cell culture model in which autophagy can be acutely disrupted through conditional Cre-mediated excision of the autophagy-essential gene Atg3. Treated cells rapidly lost their ability to perform autophagy and underwent cell cycle arrest and apoptosis. Although Atg3 was essential for optimal upregulation of mitochondrial oxidative pathways in growth factor withdrawal, this metabolic contribution of autophagy did not appear critical for cell survival, as provision of exogenous pyruvate or lipids could not completely rescue Atg3 deficiency. Instead, autophagy suppressed a stress response that otherwise led to p53 phosphorylation and upregulation of p21 and the pro-apoptotic Bcl-2 family protein Puma. Importantly, BCR-Abl-expressing cells had low basal levels of autophagy, but were highly dependent on this process, and rapidly underwent apoptosis upon disruption of autophagy through Atg3 deletion or treatment with chemical autophagy inhibitors. This dependence on autophagy extended in vivo, as Atg3 deletion also prevented BCR-Abl-mediated leukemogenesis in a cell transfer model. Together these data demonstrate a critical role for autophagy to mitigate cell stress, and that cells expressing the oncogenic kinase BCR-Abl appear particularly dependent on autophagy for cell survival and leukemogenesis.

Summary of findings of the School Health Education Evaluation: health promotion effectiveness, implementation, and costs.

A summary of important findings from the School Health Education Evaluation (SHEE) are reported. This paper focuses on the four principal outcome scores of Overall Knowledge, Attitude, Practice, and Program-Specific Knowledge. The relationship of those scores to measures of program implementation and cost also is described. A consistent pattern of findings emerged across the participating health instruction programs, suggesting that health instruction was effective in meeting program objectives as taught in the study classrooms, and that school health program effectiveness was strongly related to the level of implementation. Significant increases in Overall Knowledge and Program-Specific Knowledge were found for treatment classrooms when compared with control classrooms. Smaller, yet statistically significant, increases were found for attitudes and self-reported practices. Curriculum implementation measures were related to program effectiveness. A higher level of program implementation produced greater increases in all scores, but was most strongly related to improvement in attitudes and self-reported practices. Analysis of cost data revealed wide variation across the program. Implementation costs (those associated directly with the number of classroom instruction hours) accounted for more than 90% of the total costs and were, in turn, related to program effectiveness. Analysis of effects-to-classroom hours revealed that, while relatively few hours of instruction can produce large effects for knowledge, more hours are required for the development of attitude and practice effects, and that stable effects are established for all three domains at about 40-50 classroom hours.

Selecting and recruiting health programs for the School Health Education Evaluation.

The School Health Curriculum Project (SHCP) and three promising health education approaches, Project Prevention, 3 Rs and High Blood Pressure (HBP), and Health Education Curriculum Guide, were the curricula used in the School Health Education Evaluation (SHEE) project. This paper contains program descriptions of each, and a brief description of the process that led to their selection. Inclusion of the School Health Curriculum Project (SHCP) was mandated by the use of government funds to support the SHEE. The three alternative curricula, Project Prevention, 3 Rs and High Blood Pressure, and Health Education Curriculum Guide, were selected on the basis of a protocol devised jointly by contractors, government project officers, and the project advisory panel.