The bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with and patients without osteolytic lesion is that the latter have fewer and less active osteoblasts. Hepatocyte growth factor (HGF) is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. IntroductionAlmost all patients with multiple myeloma develop osteolytic lesions and/or diffuse osteopenia. The presence of myeloma cells in the bone marrow leads to both increased number and activity of osteoclasts as well as reduced number and dysfunction of osteoblasts. 1,2 During the early stages of the disease, enhanced osteoclast activation is at least partly compensated by an increase in bone formation. As the disease progresses, the osteoblasts are fewer and less active, so that bone resorption is uncoupled from bone formation. 3 Recently, several factors have been proposed to be involved in the dysregulation of osteoblastogenesis in multiple myeloma. [4][5][6][7] However, the mechanisms for reduced bone formation in patients with myeloma are still not completely understood.We have shown that myeloma cells produce hepatocyte growth factor (HGF). 8 Others have shown that HGF is among the most upregulated genes in myeloma cells as compared with normal plasma cells. 9 High serum concentration of HGF is associated with poor prognosis in patients with myeloma, 10 and HGF has been shown to play several roles in disease progression. [11][12][13][14][15][16] Furthermore, we have shown that HGF is found at high concentrations in bone marrow plasma from patients with myeloma. 17 In a mouse model of multiple myeloma developed in our laboratory, a prominent feature was the complete lack of osteoblasts. 18 In this model, JJN3 cells, which produce high levels of HGF, were injected into severe combined immunodeficient (SCID) mice. The concentration of HGF in the bone marrow plasma of the mice was high; in some mice the concentration exceeded 5 g/mL. 18 We therefore hypothesized that HGF can interfere with osteoblastogenesis, and thereby be a factor responsible for the reduced number and reduced activity of osteoblasts in patients with multiple myeloma. Materials and methods Cells and cell culture conditionsC2C12 cells (ATTC, Rockville, MD) were routinely maintained in Dulbecco modified Eagle medium (DMEM; Gibco, Carlsbad, CA) with 15% heat inactivated fetal calf serum (FCS; EuroClone, Pero, Italy) in a humidified atmosphere containing 5% CO 2 at 37°C. Cells were not allowed to reach confluence, and were used before they completed 8 passages. Human mesenchymal stem cells (hMSCs) were purchased from Cambrex Bio Science and routinely maintained in human mesenchymal stem cells growth media (MSCGM; Cambrex Bio Science, East Rutherford, NJ) according to the manufacturer's instructions. hMSCs were used before they completed 8 passages. Osteoblast differentiationhMSCs were seeded at 4000 cells/cm 2 and cultured until they reached 70% co...

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Our results indicate that the performance of the UTE method as implemented in VB20P is close to the theoretical maximum of such an MRAC method in the brain, while it does not perform satisfactorily in the neck or face/nasal area. Further improvement of the UTE MRAC or other available methods for more accurate segmentation of bone should be incorporated.

ABSTRACT

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rearrangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P < .0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P < .0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.