Hsiu-Hsia Lin

Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma

Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0–8) and a score ≥4.5 was used for CRBN positivity (CRBN+) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN+ NDMM patients, CRBN− NDMM patients had more international staging system (ISS) III (26 vs. 61xa0%, respectively; Pu2009=u20090.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN+ patients than CRBN− patients (LD 79 vs. 33xa0%, respectively; Pu2009=u20090.005) (TD 75 vs. 29xa0%, respectively; Pu2009=u20090.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN+ for treatment response was 79 and 67xa0% and 75 and 71xa0%, respectively. Multivariate analysis showed that CRBN+ was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.

Dielectric studies of Cd1−x−yZnxMnyTe crystals

We report on the dielectric properties of Cd1−x−yZnxMnyTe alloys studied by capacitance and dissipation factor measurements at temperature 5u200aK<T<475u200aK and frequency 20u200aHz<f<1u200aMHz. A Debye-like relaxation of dielectric behavior has been observed, which is found to be a thermally activated process. The activation energies obtained from the capacitance and dissipation factor measurements are in excellent agreement. By means of our measurements, it is believed that the dielectric character of the carrier hopping among structural defects is responsible for the observed Debye relaxation. The relationship between the activation energy and Zn concentration has been established. The results are described by the four-center model, in which the number of Zn atoms appearing in the nearest-neighbor sites of a defect can have four possible configurations.We report on the dielectric properties of Cd1−x−yZnxMnyTe alloys studied by capacitance and dissipation factor measurements at temperature 5u200aK<T<475u200aK and frequency 20u200aHz<f<1u200aMHz. A Debye-like relaxation of dielectric behavior has been observed, which is found to be a thermally activated process. The activation energies obtained from the capacitance and dissipation factor measurements are in excellent agreement. By means of our measurements, it is believed that the dielectric character of the carrier hopping among structural defects is responsible for the observed Debye relaxation. The relationship between the activation energy and Zn concentration has been established. The results are described by the four-center model, in which the number of Zn atoms appearing in the nearest-neighbor sites of a defect can have four possible configurations.

Correlation among DCE-MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma†

We investigated correlations among angiogenesis parameters of the lumbar vertebrae measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), microvessel density (MVD) in bone marrow (BM), and extramedullary disease (EMD) in patients with multiple myeloma (MM). Forty-nine MM patients were enrolled. Two semiquantitative parameters, Peak and Slope, were obtained from the DCE-MRI signal-intensity curve; three more quantitative parameters, Amp, Kep, and Kel, were generated from bicompartmental modeling. Apart from Kep, all parameters were found to correlate positively with MVD (r range, 0.323– 0.594; all P < 0.03). Multivariate analysis indicated that the only factors significantly associated with MVD were Amp and plasma cell percentage in BM. Comparing angiogenesis parameters for patients with EMD at the time of DCE-MRI versus those who did not showed a high Amp ( 0.08) as the only significant factor associated with EMD (odds 6.33; P 5 0.045). During follow-up (median, 76 months), 4 more patients developed EMD. Accumulative incidence for developing EMD over time was significantly higher for patients with high Amp than those with low Amp (P 5 0.0254). In conclusion, Amp correlated strongly with MVD in BM and also EMD in patients with MM. Amp measurement might be helpful for identifying MM patients at risk for EMD. Multiple myeloma (MM) is a malignant plasma cell proliferation typically found in bone marrow (BM) [1]. Although MM cells (MCs) depend on the BM microenvironment to provide the signals essential for their growth and survival [2], in a fraction of patients MCs acquire the ability to proliferate in sites outside the BM. Such occurrences appear as extramedullary disease (EMD), indicating that MCs have become independent of the BM microenvironment [1]. The exact mechanism underlying the development of EMD in MM patients is not clear. One hypothesis suggests an alteration in the interaction between MCs and the BM microenvironment [2,3]. Within the BM microenvironment, angiogenesis might play a major role in not only promoting the growth and survival of MCs but also the disease progression itself [2–4]. The interaction between MCs and BM endothelial cells upregulates a number of angiogenic cytokines, such as vascular endothelial growth factor or matrix metalloproteinases. Such cytokines further stimulate BM angiogenesis and myeloma progression [5,6], as well as possible extramedullary dissemination [4]. To date, dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) is one of the most widely used noninvasive methods of measuring the perfusion and permeability of a biological tissue in the body, such as vertebral BM [7]. In MM patients, the angiogenesis parameters generated from DCE-MRI of vertebral BM reportedly correlate strongly with histological grade of infiltration, osteolytic bone involvement, microvessel density (MVD), and serum markers of disease activity [8,9]. However, prior to our study no data were available on the correlation between degree of BM angiogenesis and the development of EMD in MM patients. We thus examined the correlation between angiogenesis parameters generated from DCEMRI of vertebral bodies, together with MVD in BM (obtained from the posterior iliac crest), with the manifestation of EMD in patients with MM. Between September 2004 and April 2006, a total of 49 patients with MM were enrolled. Of this group, 27 (55%) patients had newly diagnosed MM (NDMM), 6 patients (12%) were in a post-treatment plateau (PTRP), and 16 (33%) had progressive disease (PD). This study was approved by our institutional ethics committee, and written informed consent was obtained from all patients in accordance with the Declaration of Helsinki (ClinicalTrials.gov Identifier: NCT00166855). The salient clinical characteristics of the 49 patients at enrollment are listed in Table I. Notably, 19 of the 49 patients (39%) had EMD at the time of their DCE-MRI, among whom 7 patients (37%) had more than one manifestation of EMD. BM samples were obtained from the posterior iliac crest in all 49 patients at approximately the same time as DCE-MRI was performed (median 2 days; range, -3 to 7 days). The mean MVD [vessels/4003 high-power field (HPF)] was 16.7 (range 1.5–40.2), with significant differences being found for patients in different subgroups (P 5 0.006). Patients with NDMM had a mean MVD of 20.3 (95% confidence interval [CI: 15.3–25.2]), patients in the PTRP group had a mean MVD of 3.2 (95% CI: 1.4–5.0), and patients with PD had a mean MVD of 15.7 (95% CI: 9.9–21.5). The time-signal intensity (SI) curve shown in DCE-MRI correlated strongly with tissue MVD, where a high peak and steep slope were associated with high MVD (Fig. 1A,B). By contrast, a lower peak and gentler slope were associated with lower MVD (Fig. 1C,D). Moderate correlations were found between MVD and the two semiquantitative parameters Peak and Slope (r 5 0.540 and 0.502, respectively; both P < 0.001). Amp and Kel, but not Kep, were also moderately correlated with MVD (r 5 0.594 and 0.323, respectively; P < 0.001 and P 5 0.024, respectively). Other salient characteristics significantly correlated with MVD were beta2-microglobulin (r 5 0.305; P 5 0.035), C-reactive protein (r 5 0.348; P 5 0.018), and percentage of MCs in BM (r 5 0.637; P < 0.001). Further multiple linear regression analysis showed that only Amp (r5 45.7; 95% CI: 13.0–78.3; P5 0.007) and percentage of MCs in BM (r5 0.18; 95% CI: 0.06–0.29; P 5 0.003) were independently correlated with MVD. Table II shows the results of our comparison of salient features and angiogenesis parameters between patients with and without EMD at the time of their DCE-MRI. When compared with patients without EMD, patients with EMD displayed significantly greater infiltration of MCs in BM and higher levels of the angiogenesis parameter Amp. Further multivariate analysis using a multiple logistic regression model showed that Amp was the only significant factor associated with EMD (OR 6.33; P 5 0.045). The median follow-up period was 76

Dielectric studies of ZnSe1−xTex epilayers

We present the results of experimental investigations on dielectric properties of ZnSe1−xTex epilayers by capacitance and dissipation factor at temperature 5u200aK<T<475u200aK and frequency 20u200aHz<f<1u200aMHz. A Debye-like relaxation of dielectric behavior has been observed, which is found to be a thermally activated process. The activation energies obtained from capacitance and dissipation factor are in very good agreement. The activation energies decrease with the increase of Se content, and range from 662 to 819 meV. The results are described by means of the four-center model, in which the number of different atoms occupying the nearest-neighbor sites of defects results in a different activation energy.

Higher Decorin Levels in Bone Marrow Plasma Are Associated with Superior Treatment Response to Novel Agent-Based Induction in Patients with Newly Diagnosed Myeloma - A Retrospective Study.

The growth of myeloma cells depends on bone marrow (BM) stroma consisting of stromal cells, secreted cytokines and the extracellular matrix (ECM). Decorin, a small leucine-rich proteoglycan in the ECM, is a signaling ligand and native anti-tumor agent. However, the role of decorin in patients with myeloma is not clear. We evaluated the correlation between the decorin levels measured by enzyme-linked immunosorbent assay in BM plasma from 121 patients with newly diagnosed myeloma based on their clinical features and treatment response. The median decorin levels in the patients and the normal control group were 12.31 ng/mL [standard deviation (SD), 7.50 ng/mL; range, 2.45 to 44.46 ng/mL] and 10.31 ng/mL (SD, 2.42 ng/mL; range, 4.85–15.14 ng/mL), respectively (P < 0.001). Using 15.15 ng/mL as a cut-off, 46 patients (38%) exhibited higher decorin levels (H-DCN), whereas the other patients exhibited normal to lower decorin levels (NL-DCN). Except for the median age, which was significantly younger in the H-DCN than in the NL-DCN group (60.6±14.0 vs. 65.8±12.2 years, respectively; P = 0.034), there were no differences between the two groups. However, in 79 patients who had received novel agent-based induction, the overall response rate was significantly better in the H-DCN than in the NL-DCN (97 vs. 63%, respectively; P < 0.001), as was the depth of responses (P = 0.008), which were not observed in those who had received chemotherapeutic agents alone. Progression-free survival (PFS) was significantly longer in H-DCN than NL-DCN (not reached vs. 19.5 mo, respectively; P = 0.0003). Multivariate analyses indicated that H-DCN, as a significantly independent factor, was associated with better treatment response (odds ratio, 20.014; 95% CI, 2.187–183.150; P = 0.008) and longer PFS (hazard ratio, 0.135; 95% CI, 0.051–0.361; P < 0.001). These findings disclose the potential role of decorin in myeloma and provide a basis for further study on possible synergistic anti-myeloma effects between decorin and the novel agents that target BM stroma.

Soluble PD-L1: A biomarker to predict progression of autologous transplantation in patients with multiple myeloma

Autologous hematopoietic stem cell transplantation (AuHSCT) is standard in treating eligible multiple myeloma (MM) patients. However, the outcome after treatment is highly variable. We used ELISA to analyze the levels of soluble PD-L1 (suPD-L1) in bone marrow (BM) plasma from 61 patients with MM at 100 days after AuHSCT. Patients were classified into high (H) and normal-to-low (NL) groups depending on their suPD-L1 levels. Among patients who had a very good partial response (VGPR) or better after AuHSCT, those in the H-group had a shorter response period (RpSCT) as well as shorter overall survival (OS) than those in the NL-group. Multivariate analyses confirmed that a high suPD-L1 level and high-risk cytogenetic abnormalities are independent factors for RpSCT. Our data suggest that suPD-L1 in the BM plasma of MM patients who have VGPR or better after AuHSCT could be used as a biomarker to predict outcome.

The osteoblastogenesis potential of adipose mesenchymal stem cells in myeloma patients who had received intensive therapy.

Multiple myeloma (MM) is characterized by advanced osteolytic lesions resulting from the activation of osteoclasts (OCs) and inhibition of osteoblasts (OBs). OBs are derived from mesenchymal stem cells (MSCs) from the bone marrow (BM), however the pool and function of BMMSCs in MM patients (MM-BMMSCs) are reduced by myeloma cells (MCs) and cytokines secreted from MCs and related anti-MM treatment. Such reduction in MM-BMMSCs currently cannot be restored by any means. Recently, genetic aberrations of MM-BMMSCs have been noted, which further impaired their differentiation toward OBs. We hypothesize that the MSCs derived from adipose tissue (ADMSCs) can be used as alternative MSC sources to enhance the pool and function of OBs. Therefore, the purpose of this study was to compare the osteogenesis ability of paired ADMSCs and BMMSCs in MM patients who had completed intensive therapy. Fifteen MM patients who had received bortezomib-based induction and autologous transplantation were enrolled. At the third month after the transplant, the paired ADMSCs and BMMSCs were obtained and cultured. Compared with the BMMSCs, the ADMSCs exhibited a significantly higher expansion capacity (100% vs 13%, respectively; Pu200a=u200a.001) and shorter doubling time (28 hours vs 115 hours, respectively; Pu200a=u200a.019). After inducing osteogenic differentiation, although the ALP activity did not differ between the ADMSCs and BMMSCs (0.78 U/µg vs 0.74±0.14 U/µg, respectively; Pu200a=u200a.834), the ADMSCs still exhibited higher calcium mineralization, which was determined using Alizarin red S (1029 nmole vs 341 nmole, respectively; Pu200a=u200a.001) and von Kossa staining (2.6 E+05 µm2 vs 5 E+04 µm2, respectively; Pu200a=u200a.042), than the BMMSCs did. Our results suggested that ADMSCs are a feasible MSC source for enhancing the pool and function of OBs in MM patients who have received intensive therapy.