Citations

Abstract Steady-state hematopoiesis is sustained through differentiation balanced with proliferation and self-renewal of hematopoietic stem cells (HSCs). Disruption of this balance can lead to hematopoietic failure, as hematopoietic differentiation without self-renewal leads to loss of the HSC pool. We find that conditional knockout mice that delete the transcriptional repressor NKAP in HSCs and all hematopoietic lineages during embryonic development exhibit perinatal lethality and abrogation of hematopoiesis as demonstrated by multilineage defects in lymphocyte, granulocyte, erythrocyte and megakaryocyte development. Inducible deletion of NKAP in adult mice leads to lethality within 2 weeks, at which point hematopoiesis in the bone marrow has halted and HSCs have disappeared. This hematopoietic failure and lethality is cell intrinsic, as radiation chimeras reconstituted with inducible Mx1-cre NKAP conditional knockout bone marrow also succumb with a similar time course. Even in the context of a completely normal bone marrow environment using mixed radiation chimeras, NKAP deletion results in HSC failure. NKAP deletion leads to decreased proliferation and increased apoptosis of HSCs, which is likely due to increased expression of the cyclin-dependent kinase inhibitors p21Cip1/Waf1 and p19Ink4d. These data establish NKAP as one of a very small number of transcriptional regulators that is absolutely required for adult HSC maintenance and survival.

Purpose Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia. Patients and Methods The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years. Results Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not. Conclusion The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.

Purpose The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children. Patients and Methods Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC). Results Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination. Conclusion In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Abstract Malignant cells are capable of influencing the microenvironment in a manner that facilitates tumor cell survival. Bidirectional crosstalk between chronic lymphocytic leukemic (CLL) cells and marrow-derived mesenchymal stromal cells (MSCs) activates both cell types. In this study, we observed that the conditioned medium (CM) obtained from CLL cells was able to induce Akt activation in MSC. Subsequent studies investigated the mechanism of MSC activation mediated by CLL-CM. Platelet-derived growth factor receptors (PDGFRs) were selectively activated in MSCs by CLL-CM and found to be critical receptors for CLL-CM–driven MSC proliferation and MSC Akt activation. The known ligands of PDGFR, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), were detected in CLL-CM, but PDGF was the predominant ligand involved in the CM-mediated PDGFR activation. Both PDGF and VEGF were found to be elevated in the plasma of CLL patients with a positive association for high-risk factors and more advanced stage. Finally, we demonstrated that PDGF induced MSC VEGF production through a phosphatidylinositol 3-kinase (PI3K)–dependent mechanism. These results show that PDGF-PDGFR signaling influences at least the MSC in the microenvironment of CLL and may play a role in the induction of an angiogenic switch known to be permissive for disease progression.

Purpose The appropriate treatment for MSCC is controversial. A small randomized trial showed that decompressive surgery followed by radiotherapy was superior to radiotherapy alone. That study was limited to highly selected patients. Additional studies comparing surgery plus radiotherapy to radiotherapy could better clarify the role of surgery. Methods Data from 108 patients receiving surgery plus radiotherapy were matched to 216 patients (1:2) receiving radiotherapy alone. Groups were matched for 11 potential prognostic factors and compared for post-treatment motor function, ambulatory status, regaining ambulatory status, local control, and survival. Subgroup analyses were performed for patients receiving adequate surgery (direct decompressive surgery plus stabilization of involved vertebrae), patients receiving laminectomy, patients with solid tumors, patients with solid tumors receiving adequate surgery, and patients with solid tumors receiving laminectomy. Results Improvement of motor function occurred in 27% of patients after surgery plus radiotherapy and 26% after radiotherapy alone (P = .92). Post-treatment ambulatory rates were 69% after surgery plus radiotherapy and 68% after radiotherapy alone (P = .99). Of the nonambulatory patients, 30% and 26%, respectively, (P = .86) regained ambulatory status after treatment. One-year local control rates were 90% after surgery plus radiotherapy and 91% after radiotherapy alone (P = .48). One-year overall survival rates were 47% and 40%, respectively (P = .50). The subgroup analyses did not show significant differences between both groups. Surgery-related complications occurred in 11% of patients. Conclusion In this study, the outcomes of the end points evaluated after radiotherapy alone appeared similar to those of surgery plus radiotherapy. A new randomized trial comparing both treatments is justified.