Expression of the CD117 Antigen on Multiple Myeloma and Its Significance.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4867-4867
Author(s):  
Juan Li ◽  
Shaokai Luo ◽  
Guocai Zhang ◽  
Wende Hong ◽  
Xiuzhen Tong
Keyword(s):  
Multiple Myeloma ◽  
Tyrosine Kinase ◽  
Selective Inhibitors ◽  
Differentiation Antigen ◽  
Color Flow ◽  
Myeloma Cells ◽  
Significant Difference ◽  
Theoretical Evidence ◽  
Highly Correlated

Abstract BACKGROUND & OBJECTIVE: Leukocyte differentiation antigen CD117 is one of the targets that tyrosine kinase selective inhibitors work on. CD117, whether the cell surface is expressed and the quality of its expression, is highly correlated with the tyrosine kinase selective inhibitors. And whether Multiple myeloma (MM) cells express CD117 and its expression quality is not reported domestic yet but only several reported overseas. In this study, CD117 expressed in MM cells is evaluated, which provide an theoretical evidence for tyrosine kinase selective inhibitors used in the MM, meanwhile, the value of the CD117 expressed in MM cells is estimated. METHODS:CD117,CD56,CD54 were measured by three -color flow cytometry with CD45/SSC gating strategy. RESULTS:Of 48 patients with MM, 17(35.5%) CD117 expression was positive in myeloma cells, and CD56, CD54 expression was positive in 39(81.2%), 48(100.0%), respectively. CD117 expression in myeloma cells was low compared with CD56, CD54 in 48 patients with MM; CD117 positive expression showed a positive correlation with myeloma cells in the bone marrow; CD117 positive in IgG type of MM was 64%, higher than other types such as light chain or IgA.CD117 positive showed no significant difference in different stage, untreated, relapsed and refractory patients (P>0.05, P>0.01); In untreated MM patient, chemotherapy of VAD in CD117 positive patient, the effectiveness was 71.4%, compared with the reaction rate 66.7% in CD117 negative, showed no significant difference (P>0.05). CONCLUSIONS:CD117 </SU

What Is Important Factor of Bone Disease in Multiple Myeloma?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4855-4855
Author(s):  
Shoso Munemasa ◽  
Akira Sakai ◽  
Yoshiko Okikawa ◽  
Yoshiaki Kuroda ◽  
Yuta Katayama ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cyclin D1 ◽  
Bone Disease ◽  
Tissue Growth ◽  
Good Survival ◽  
Bone Lesions ◽  
Rt Pcr ◽  
Myeloma Cells ◽  
Significant Difference ◽  
Chromosome 13Q

Abstract New International Prognostic Index (IPI) staging system of multiple myeloma (MM) is a combination of the level of serum β2-microglobulin and serum albumin. Particularly, good survival (median survival >5 years) is associated with absence of chromosome 13q deletion. Recently, correlations between molecular subtypes and prognosis have been identified as a good prognosis with t(11;14) and a poor prognosis with t(4;14) and t(14;16) besides chromosome 13 abnormalities. We have reported that some MM cases with cyclin D1 overexpression detected by competitive RT-PCR were not caused by t(11;14)(q13;q32) or extra copies of 11q13 (In J Oncol, in press). A recent report revealed that subtypes of MM cases with the translocation of cyclin D showed a close correlation with bone disease and high level of DKK1. We also have been studing about the correlation between bone disease and bone morphogenetic protein (BMP) 2, or connective tissue growth factor (CTGF) that is supposed to inhibit the VEGF binding to its receptor or modulate cell signaling by BMP. First, we analyzed IPI staging in 91 MM cases, and then analyzed the relation between IPI staging and existence of cyclin D1 overexpression, or t(11;14)(q13;q32) and extra copies of 11q13. Competitive RT-PCR was performed in 77 cases, and cyclin D1 overexpression was detected in 40/77 (52%). Deletion of chromosome 13q was detected in 32/87 (37%), and t(11;14)(q13;q32) or extra copies of 11q13 was detected in 11/50 (22%) and 7/50 (14%), respectively. There were no significant differences of those factors among IPI staging. And we analyzed the scale of bone lesion by bone x-ray in 81 cases. We could not detect the relation between bone disease and cyclin D1 overexpression or translocation of 11q13. Furthermore, we analyzed the expression of BMP2 and CTGF by quantitative real time-PCR in purified myeloma cells or in bone marrow mononuclear cells (BMMNC) reduced myeloma cells less than 5%. We have gotten results that MM cases have a tendency to show higher CTGF expression in BMMNC compared with that of normal BM, but there was no significant difference of BMP2 expression in BMMNC between them. And there was no correlation between cyclin D1 overexpression and BMP2 or CTGF expression. So far a cause of bone lesions in MM is supposed to be the activity of osteoclast, however, our preliminary examination by TRAP staining revealed that osteoclast differentiation from BMMNC in MM cases by adding M-CSF (25 ng/ml) and RANKL (50 ng/ml) decreased compared with that in normal BM, and osteoblast diffentiation also decreased in MM by cytochemical staining for alkaline phosphatase (AP). We guess that both osteoclast and osteobalst differentiation are suppressed in MM and CTGF is a candidate for the suppressor of osteoblast differentiation. We will be able to show the result of AP activity of osteoblast and the effect of recombinant CTGF on osteoblast in meeting.

Angiopoietin-1 and Osteopontin Expression by CD138+ Myeloma Cells Rather Than VEGF and CD45 Correlates with Bone Marrow Angiogenesis in Multiple Myeloma Patients at the Diagnosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2501-2501
Author(s):  
Nicola Giuliani ◽  
Simona Colla ◽  
Francesca Morandi ◽  
Sabrina Bonomini ◽  
Mirca Lazzaretti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Linear Trend ◽  
The Other ◽  
Vegf Mrna ◽  
Myeloma Cells ◽  
Other Hand ◽  
Significant Difference ◽  
Angiopoietin 1

Abstract Bone marrow (BM) angiogenesis is increased in Multiple Myeloma (MM) patients and correlates with disease progression and patient survival. Myeloma cells secrete the main endothelial growth factor VEGF. In mouse models VEGF secretion as well as the angiogenic properties of MM cells correlate with the lack of CD45 expression by MM cells. However, recent data indicate that VEGF plasma cell expression is similar between MGUS and MM patients suggesting that other molecules could be involved. In line with this hypothesis we have recently demonstrated that myeloma cells may also produce factors with angiogenic properties as angiopoietin-1 (ANG-1) and osteopontin (OPN) that are involved in myeloma induced angiogenesis in vitro. In order to identify which factors correlate with BM angiogenesis in MM patients, we have investigated in a cohort of 121 newly diagnosed MM patients (stage I–III) the expression of the angiogenic molecules VEGF, ANG-1 and OPN and their correlation with bone marrow (BM) angiogenesis and CD45 expression by MM cells. We found that 90% of CD138+ MM cells tested were positive for VEGF mRNA. On the other hand we found that 50% and 40 % of MM patients were positive for ANG-1 and OPN mRNA respectively. Using the previously published cut off for CD45 expression we found that 61 out of 121 MM patients were positive for CD45 and 60 out of 121 were negative for CD45 expression. Any correlation was not observed between VEGF expression and BM angiogenesis in MM patients (p=0.5), whereas the number of microvessels X field was higher in Ang-1 positive patients in comparison with Ang-1 negative ones (mean±SE: 6.23±0.2 vs. 2.94±0.1, median: 6.21 vs. 2.79; p=0.001,) and the microvascular density (MVD) was significantly increased (32.98±1.7 vs. 14.55±1.3, median: 34.69 vs. 13.04; p<0.01; capillaries: 26.73±1.3 vs. 10.42±0.8, median: 24.06 vs. 9.04; p<0.01, small venules: 9.56 ±0.5 vs. 4.14±0.5, median: 10.60 vs. 3.65; p<0.01). Furthermore a significantly positive correlation between Ang-1 expression and MVD was found (Pearson Chi-square: p=0.036, Cochran’s Linear Trend: p=0.01). A significantly higher MVD was also observed in the group of patients positive for OPN, (mean±SE: 29.1±0.7 vs. 17.55±0.37; p<0.01) and similarly, the number of microvessels per field was higher in OPN positive patients in comparison with OPN negative ones (mean±SE: 6.7±0.15 vs. 4.28±0.04; p=0.05). On the other hand, any significant difference was not observed between CD45 positive and CD45 negative patients for the expression of VEGF (p=0.4), ANG-1 (p=0.3) and OPN (p=0.09). Consistently we did not find any significant difference in both MVD and number of vessels X field between CD45 positive patients as compared with CD45 negative ones (p=0.5 and p=0.4, respectively). Finally, a multivariate analysis confirmed that VEGF and CD45 did not correlate with the BM angiogenesis showing that ANG-1 expression by MM cells was more tightly correlated with MVD and the number of vessels X field as compared to OPN. Our data indicate that ANG-1 and in part OPN rather than VEGF and CD45 expression by MM cells are the critical determinants correlated with the increase of BM angiogenesis that occurs in MM patients at the diagnosis.

CHIR258, a Novel Multi-Targeted Tyrosine Kinase Inhibitor, for the Treatment of t(4;14) Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 641-641 ◽  
Author(s):  
Suzanne Trudel ◽  
Zhi Hua Li ◽  
Ellen Wei ◽  
Marion Wiesmann ◽  
Katherine Rendahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Myeloma Cells

Abstract The t(4;14) translocation that occurs uniquely in a subset (15%) of multiple myeloma (MM) patients results in the ectopic expression of the receptor tyrosine kinase, Fibroblast Growth Factor Receptor3 (FGFR3). Wild-type FGFR3 induces proliferative signals in myeloma cells and appears to be weakly transforming in a hematopoeitic mouse model. The subsequent acquisition of FGFR3 activating mutations in some MM is associated with disease progression and is strongly transforming in several experimental models. The clinical impact of t(4;14) translocations has been demonstrated in several retrospective studies each reporting a marked reduction in overall survival. We have previously shown that inhibition of activated FGFR3 causes morphologic differentiation followed by apoptosis of FGFR3 expressing MM cell lines, validating activated FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these poor-prognosis patients. CHIR258 is a small molecule kinase inhibitor that targets Class III–V RTKs and inhibits FGFR3 with an IC50 of 5 nM in an in vitro kinase assay. Potent anti-tumor and anti-angiogenic activity has been demonstrated in vitro and in vivo. We employed the IL-6 dependent cell line, B9 that has been engineered to express wild-type FGFR3 or active mutants of FGFR3 (Y373C, K650E, G384D and 807C), to screen CHIR258 for activity against FGFR3. CHIR258 differentially inhibited FGF-mediated growth of B9 expressing wild-type and mutant receptors found in MM, with an IC50 of 25 nM and 80 nM respectively as determined by MTT proliferation assay. Growth of these cells could be rescued by IL-6 demonstrating selectivity of CHIR258 for FGFR3. We then confirmed the activity of CHIR258 against FGFR3 expressing myeloma cells. CHIR258 inhibited the viability of FGFR3 expressing KMS11 (Y373C), KMS18 (G384D) and OPM-2 (K650E) cell lines with an IC50 of 100 nM, 250 nM and 80 nM, respectively. Importantly, inhibition with CHIR258 was still observed in the presence of IL-6, a potent growth factors for MM cells. U266 cells, which lack FGFR3 expression, displayed minimal growth inhibition demonstrating that at effective concentrations, CHIR258 exhibits minimal nonspecific cytotoxicity on MM cells. Further characterization of this finding demonstrated that inhibition of cell growth corresponded to G0/G1 cell cycle arrest and dose-dependent inhibition of downstream ERK phosphorylation. In responsive cell lines, CHIR258 induced apoptosis via caspase 3. In vitro combination analysis of CHIR258 and dexamethasone applied simultaneously to KMS11 cells indicated a synergistic interaction. In vivo studies demonstrated that CHIR258 induced tumor regression and inhibited growth of FGFR3 tumors in a plasmacytoma xenograft mouse model. Finally, CHIR258 produced cytotoxic responses in 4/5 primary myeloma samples derived from patients harboring a t(4;14) translocation. These data indicate that the small molecule inhibitor, CHIR258 potently inhibits FGFR3 and has activity against human MM cells setting the stage for a Phase I clinical trial of this compound in t(4;14) myeloma.

In-Vitro and in-Vivo Synergistic Effect of Melphalan and Dual DNA Repair Inhibition in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3301-3301
Author(s):  
Pritesh R. Patel ◽  
Annie L. Oh ◽  
Vitalyi Senyuk ◽  
Dolores Mahmud ◽  
Nadim Mahmud ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Repair ◽  
Combination Index ◽  
Fold Increase ◽  
High Dose ◽  
Myeloma Cells ◽  
Synergistic Cytotoxicity ◽  
Significant Difference

Abstract High dose melphalan is commonly used in patients with multiple myeloma (MM). Resistance to melphalan has been linked to the ability to repair DNA damage. To test whether DNA repair inhibitors overcome resistance to melphalan and and also have a direct anti-MM effect, we tested MM cell lines RPMI8226 and U266 in-vitro and in-vivo, using a NOD/SCID/ gamma null (NSG) xenograft model. RPMI8226 and U266 cells were initially treated in-vitro with the PARP inhibitor ABT-888. Using a proliferative assay, myeloma cells appeared sensitive to ABT-888 with low GI50 values (8.7μM for RPMI8226 cells, 49μM for U266 cells) and increased γH2AX foci, which persisted at 24 hours after treatment. This was confirmed in methycellulose colony assay where ABT-888 treatment reduced RPMI8226 colonies by 35% (p=0.002). Next we showed synergistic cytotoxicity between ABT-888 and melphalan. In both RPMI8226 and U266 cells strong synergy was displayed with a combination index (CI) less than 1 in proliferative assays (CI 0.5 and 0.3 at 50% proliferation respectively). Combination ABT-888 and melphalan treated cells underwent accelerated senescence compared to cells treated by melphalan alone (27% versus 51% βGal+ staining at 24 hours, p=0.02). This was confirmed by upregulation of senescence related genes p16 (1.6 fold increase) and p21 (1.5 fold increase). We did not find significant difference in apoptosis by Annexin V/ PI staining. Given that increased non-homologous end joining (NHEJ) activity has been shown to lead to resistance to melphalan, we tested whether an inhibitor of NHEJ could be synergistic with PARP inhibition and melphalan. Treatment with the DNA-PK inhibitor NU7026 at 10μM in addition to ABT-888 at 4μM resulted in 46% reduction in proliferation in RPMI8226 cells and 52% in U266 cells. When used in combination with melphalan chemotherapy, the dual DNA repair inhibitor therapy showed marked synergy in RPMI8226 cells with a combination index of 0.39. Finally we tested the ability of the combination of ABT-888 and melphalan to treat myeloma in-vivo. NSG mice were injected via tail vein with 5x106 RPMI8226 cells. Control (untreated) mice subsequently developed myeloma infiltrating the marrow, spleen and axial skeleton, with hind limb paralysis occurring at a median of 42 days. Treated mice received intraperitoneal injections of ABT-888 (3 times a week), or melphalan (weekly) or a combination of both agents starting on day 28 post-injection of MM cells for a total of 3 weeks. Using ABT-888, melphalan and a combination of both agents, median survival of mice was progressively prolonged (44 vs. 67 vs. 107 days, respectively) (p=0.02). Here we show that PARP and DNA-PK inhibition synergizes with melphalan in myeloma cells lines, providing a rationale for the addition of these agents to conditioning chemotherapy. In addition, we also show a direct anti-myeloma activity of these agents without the use of alkylator chemotherapy. Disclosures No relevant conflicts of interest to declare.

Milk quality in Merino and Corriedale ewes

1966 ◽  
Vol 17 (2) ◽  
pp. 201 ◽  
Author(s):  
RW Moore
Keyword(s):  
Milk Quality ◽  
Lactation Period ◽  
Fat Percentage ◽  
Genetic Groups ◽  
Breed Difference ◽  
Whole Milk ◽  
Significant Difference ◽  
The Difference ◽  
Highly Correlated

Comparisons have been made of the milk quality of ewes of two strains of Merino, strong-wool (S) and medium-wool Peppin (B), and of two breeds, strong-wool Merino and Corriedale (C). The strains were compared in two ways – for ewes suckling single lambs and for ewes suckling a pair of twins containing one lamb of each strain, and the breeds were compared for ewes suckling single lambs. The strain comparisons were made in 1960–61 and the breed comparison in 1961–62. Ewes of the S and B strains during the first 10 weeks of lactation had milk with mean fat percentages of 6.0 and 6.5 respectively when suckling singles, and 6.4 and 7.2 when suckling twins. The corresponding percentages for solids-not-fat (S.N.F.) for the period 45–72 days after parturition were 9.5 and 9.3 for singles, 9.9 and 10.2 for twins. The C breed and the S strain yielded milk with respective mean fat percentages of 8.6 and 9.4, and mean S.N.F. of 10.1 and 10.6, during the first 20 days of lactation. The only statistically significant difference among these breed and strain comparisons was the breed difference in S.N.F. In Merino ewes suckling twins the fat percentage was higher than in those suckling singles over 10 weeks of lactation (6.8 v. 6.2), while the percentage of S.N.F. for the period 45–72 days after parturition was also higher (10.1 v. 9.4). The difference in fat was not significant, but the difference in S.N.F. was. When adjusted for the higher amount of whole milk produced by ewes suckling twins, the relative amounts of fat and S.N.F. secreted become 116 : 100 and 112 : 100. There is thus a suggestion that the extra sucking stimulus which leads to a greater production of whole milk also increases the secretion of fat and S.N.F. When the 10-week lactation period was divided into three subperiods, the fat percentages showed a significant increase with time since parturition for Merino ewes suckling singles (5.7 : 5.8 : 7.2) or twins (5.7 : 6.8 : 7.9). Even when these figures were adjusted for amount of whole milk, the relative total amounts of fat secreted were 100 : 105 : 102 and 100 : 111 : 104. Lamb growth rate was no more highly correlated with the constituents of milk quality than with the total amount of whole milk. No important differences in milk quality were found between the genetic groups examined, but these were all related, the Corriedale breed being half Merino. The possibility remains that breeds differing more widely in their genetic background might also differ in milk quality.

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1405-1412 ◽  
Author(s):  
Anders Waage ◽  
Peter Gimsing ◽  
Peter Fayers ◽  
Niels Abildgaard ◽  
Lucia Ahlberg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Controlled Study ◽  
Plateau Phase ◽  
Life Outcomes ◽  
Double Blind ◽  
Skin Reactions ◽  
Significant Difference ◽  
To Receive

Abstract In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

VP111 Referral Center For Multiple Myeloma Patient Care

2017 ◽  
Vol 33 (S1) ◽  
pp. 201-201
Author(s):  
Indara Saccilotto ◽  
Rosane Bittencourt ◽  
Camila Fischer ◽  
Amanda Quevedo ◽  
Vania Hirakata ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Outcome Measure ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Care Facilities

INTRODUCTION:Within the Brazilian Health System, Referral Centers (RCs) are care facilities that provide specialized services. The objective of this study was to evaluate the efficacy of care provided to patients with multiple myeloma (MM) at a specialized Referral Centers (Hospital de Clínicas de Porto Alegre Referral Center for Multiple Myeloma, CRMM-HCPA) and to compare quality of life between patients with MM treated at CRMM-HCPA and those treated at non-RC facilities.METHODS:A 6-month cohort study was conducted in patients with MM receiving thalidomide from the State Health Department and treated at CRMM-HCPA, and patients receiving treatment at other non-RC facilities. Thirty-two patients were included in the study, nineteen from CRMM-HCPA and thirteen from other institutions. To analyze the efficacy of care provided at CRMM-HCPA, the main outcome measure was the time from diagnosis to referral for autologous hematopoietic stem cell transplantation.This outcome measure was assessed using questionnaires specifically designed for this study. Quality of life was also assessed, using the Short-Form 36 Item Health Survey (SF-36) questionnaire.RESULTS:Time from MM diagnosis to referral for autologous hematopoietic stem cell transplantation in each group was measured only in patients aged 65 years (n = 25); of these, 15 were recruited from CRMM-HCPA and 10 from other institutions. In this analysis, there was a significant difference (p = .036) in time elapsed between diagnosis and referral for autologous hematopoietic stem cell transplantation, which was significantly shorter for patients treated at CRMM-HCPA (median, 9 months; Interquartile Range, IQR, 8.5–14.5) than for those treated elsewhere (median, 24 months; IQR, 16–24). On quality of life analysis, there was a significant difference in the Social Functioning, which relates to performance of social activities (p = .02).CONCLUSIONS:The Referral Centers model provided seems to be a more efficient treatment strategy as compared with other health care facilities, as it enabled a reduction in time to transplantation. Patients treated at CRMM-HCPA demonstrated greater ease in performing social activities, with less interference from physical or emotional problems.

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