Showing papers by "Arnon Nagler published in 2007"
TL;DR: PLD with bortzomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma, and the combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.
Abstract: Purpose This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. Patients and Methods Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m2 on day 4. Results Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = ...
596 citations
TL;DR: The results confirm that the clinical benefit of donor lymphocyte infusion in the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation (HSCT) is limited to a minority of patients.
Abstract: Purpose To evaluate the role of donor lymphocyte infusion (DLI) in the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients and Methods We retrospectively analyzed the data of 399 patients with AML in first hematological relapse after HSCT whose treatment did (n = 171) or did not (n = 228) include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed. Results Median follow-up was 27 and 40 months, respectively. Estimated survival at 2 years (± standard deviation) was 21% ± 3% for patients receiving DLI and 9% ± 2% for patients not receiving DLI. After adjustment for differences between the groups, better outcome was associated with age younger than 37 years (P = .008), relapse occurring more than 5 months after HSCT (P < .0001), and use of DLI (P = .04). Among DLI reci...
426 citations
TL;DR: It is reported that immature humanCD34+ cells dynamically expressed dopamine and β2-adrenergic receptors, with higher expression in the primitive CD34+CD38lo population, to identify new functions for neurotransmitters and myeloid cytokines in the direct regulation of human and mouse progenitor cell migration and development.
Abstract: Catecholamines are important regulators of homeostasis, yet their functions in hematopoiesis are poorly understood. Here we report that immature human CD34+ cells dynamically expressed dopamine and beta2-adrenergic receptors, with higher expression in the primitive CD34+CD38(lo) population. The myeloid cytokines G-CSF and GM-CSF upregulated neuronal receptor expression on immature CD34+ cells. Treatment with neurotransmitters increased the motility, proliferation and colony formation of human progenitor cells, correlating with increased polarity, expression of the metalloproteinase MT1-MMP and activity of the metalloproteinase MMP-2. Treatment with catecholamines enhanced human CD34+ cell engraftment of NOD-SCID mice through Wnt signaling activation and increased cell mobilization and bone marrow Sca-1+c-Kit+Lin- cell numbers. Our results identify new functions for neurotransmitters and myeloid cytokines in the direct regulation of human and mouse progenitor cell migration and development.
316 citations
TL;DR: It is found that the CXCR4 antagonist known as 4F‐benzoyl‐TN14003 (T‐140) can induce mobilization of hematopoietic stem cells and progenitors within a few hours post‐treatment in a dose‐dependent manner.
Abstract: An increase in the number of stem cells in blood following mobilization is required to enhance engraftment after high-dose chemotherapy and improve transplantation outcome. Therefore, an approach that improves stem cell mobilization is essential. The interaction between CXCL12 and its receptor, CXCR4, is involved in the retention of stem cells in the bone marrow. Therefore, blocking CXCR4 may result in mobilization of hematopoietic progenitor and stem cells. We have found that the CXCR4 antagonist known as 4F-benzoyl-TN14003 (T-140) can induce mobilization of hematopoietic stem cells and progenitors within a few hours post-treatment in a dose-dependent manner. Furthermore, although T-140 can also increase the number of white blood cells (WBC) in blood, including monocytes, B cells, and T cells, it had no effect on mobilizing natural killer cells. T-140 was found to efficiently synergize with granulocyte colony-stimulating factor (G-CSF) in its ability to mobilize WBC and progenitors, as well as to induce a 660-fold increase in the number of erythroblasts in peripheral blood. Comparison between the CXCR4 antagonists T-140 and AMD3100 showed that T-140 with or without G-CSF was significantly more potent in its ability to mobilize hematopoietic stem cells and progenitors into blood. These results demonstrate that different CXCR4 antagonists may have different therapeutic potentials.
109 citations
TL;DR: There are marked differences in outcome between RIC regimens that are theoretically dose-equivalent; the FM regimen is more myelosuppressive and toxic but controls disease better but was associated with improved survival in patients transplanted in remission.
Abstract: Reduced-intensity conditioning (RIC) regimens are increasingly used in allogeneic stem-cell transplantation (SCT). There are no data whether any of these regimens has advantage and in what setting. We retrospectively analyzed SCT outcomes in 151 patients given fludarabine-based RIC for various hematological malignancies; 72 conditioned with fludarabine and intravenous-busulfan (FB) and 79 with fludarabine and melphalan (FM). FM was more myelosuppressive. Grade III-IV organ toxicity occurred in 31 and 53% of FB and FM recipients (P=0.005) and acute graft-versus-host disease grade II-IV in 33 and 53%, respectively (P=0.01). Non-relapse mortality rate (NRM) was 16 and 40%, respectively (P=0.003). Active disease (HR 2.2, P=0.003) and prior autologous SCT (HR 1.7, P=0.04) predicted inferior overall survival (OS). Among patients transplanted in remission, OS was 72 and 36% after FB and FM, respectively (P=0.03) due to increased NRM with FM. Similarly, patients transplanted in active disease experienced higher NRM with FM, however lower relapse rates resulted in equivalent OS. In conclusion, there are marked differences in outcome between RIC regimens that are theoretically dose-equivalent. The FM regimen is more myelosuppressive and toxic but controls disease better. FB was associated with improved survival in patients transplanted in remission. These observations merit further study in prospective studies.
91 citations
TL;DR: Fertility was restored with ovarian tissue transplantation in a sterilized patient and following fertility treatment in a patient with very low ovarian reserve, and it is recommended that indications and timing of ovarian tissue banking should be individualized.
Abstract: Cryopreservation of ovarian tissue is currently practiced in an attempt to preserve fertility before commencing potentially sterilizing chemotherapy. Clinical and laboratory guidelines are needed to standardize the procedure. Over the last 10 years ovarian tissue was stored in female patients with hematologic malignancies. Patients' records and consultation charts were evaluated, surgical and laboratory reports were revised and ovarian histology was investigated. Fifty-six patients with hematologic malignancies (age 24 +/- 5.5) had cryopreserved ovarian tissue. Thirty-three patients had Hodgkin's disease, 14 non-Hodgkin's lymphoma, 6 acute leukemia, and 3 chronic myelocytic leukemia. Harvesting of ovarian tissue was also performed following previous exposure to chemotherapy (33 patients), 13 of them shortly after the chemotherapy. Partial oophorectomy was the preferred surgical procedure. Fertility was restored with ovarian tissue transplantation in a sterilized patient and following fertility treatment in a patient with very low ovarian reserve. We recommend that indications and timing of ovarian tissue banking should be individualized. Patients previously exposed to chemotherapy can consider ovarian tissue freezing. The extent of tissue removed should take into account the large number of follicles lost and the risk of future sterilization. Tissue handling should enable further investigation of primordial follicles and identification of cancer cells.
73 citations
TL;DR: Although excess nonrelapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved outcome, and standard-risk patients with chemo-sensitive disease may also benefit from ibritumomab tiuxetan-BEAM and ASCT.
72 citations
TL;DR: RIC transplants show encouraging results in this older patient population with de novo AML, and in patients in 1st (CR), fewer relapses were counterbalanced by significantly increased NRM, so there was no survival advantage in this subgroup.
Abstract: We conducted a retrospective registry-based analysis to compare the outcome of 361 allogeneic human leukocyte antigen (HLA)-identical peripheral blood stem cell transplants (PBSCT) with reduced intensity conditioning (RIC) to that of 1369 autologous (auto) PBSCT in patients aged 50 years or older with de novo acute myeloid leukemia (AML), performed from 1997 until 2003 and reported to the European Group for Blood and Marrow Transplantation. Median age was 58 and 57 years in the RIC and auto groups, respectively. RIC patients had more advanced disease at the time of transplant. At a median follow-up of 24 months for RIC and 16 months for auto, multivariate analysis showed a lower risk for relapse (RR 0.77, P=0.013) without increased non-relapse mortality (NRM) in RIC patients (RR 1.26, P=0.28). Moreover, leukemia-free survival (RR 1.22, P=0.02) and overall survival (OS) (RR 1.32, P=0.005) were superior in the RIC group. In patients in 1st (CR), fewer relapses were counterbalanced by significantly increased NRM. Therefore, there was no survival advantage in this subgroup. In patients in 2nd or subsequent CR, LFS and OS were superior in the RIC group. RIC transplants show encouraging results in this older patient population with de novo AML.
54 citations
TL;DR: Results suggest that targeting the fibroblast-to-myofibroblast transition with halofuginone may synergize with low doses of chemotherapy in achieving a significant antitumoral effect, avoiding the need of high-dose chemotherapy and its toxicity without impairing treatment efficacy.
Abstract: Stromal myofibroblasts play an important role in tumor progression. The transition of fibroblasts to myofibroblasts is characterized by expression of smooth muscle genes and profuse synthesis of extracellular matrix proteins. We evaluated the efficacy of targeting fibroblast-to-myofibroblast transition with halofuginone on tumor progression in prostate cancer and Wilms' tumor xenografts. In both xenografts, low doses of halofuginone treatment, independent of the route of administration, resulted in a trend toward inhibition in tumor development. Moreover, halofuginone synergizes with low dose of docetaxel in prostate cancer and vincristine and dactinomycin in Wilms' tumor xenografts, resulting in significant reduction in tumor volume and weight comparable to the effect observed by high doses of the respective chemotherapies. In prostate cancer and Wilms' tumor xenografts, halofuginone, but not the respective chemotherapies, inhibited the synthesis of collagen type I, alpha-smooth muscle actin, transgelin, and cytoglobin, all of which are characteristics of activated myofibroblasts. Halofuginone, as the respective chemotherapies, increased the synthesis of Wilms' tumor suppressor gene product (WT-1) and prostate apoptosis response gene-4 (Par-4), resulting in apoptosis/necrosis. These results suggest that targeting the fibroblast-to-myofibroblast transition with halofuginone may synergize with low doses of chemotherapy in achieving a significant antitumoral effect, avoiding the need of high-dose chemotherapy and its toxicity without impairing treatment efficacy.
54 citations
TL;DR: The role of TGF-β signaling in liver fibrosis and especially its potential for pharmacological intervention is highlighted and halofuginone, which has demonstrated efficacy and tolerance in animals and humans, could become an effective and novel therapy for Liver fibrosis.
Abstract: Hepatic fibrosis is associated with the activation of stellate cells (HSCs), the major source of extracellular matrix (ECM) proteins. Transforming growth factor-β (TGF-β), signaling via Smad3, is the most profibrogenic cytokine and the major promoter of ECM synthesis. Halofuginone, an inhibitor of liver fibrosis, inhibits TGF-β-dependent Smad3 phosphorylation in human HSCs in culture. We have used transcriptional profiling to evaluate the effect of halofuginone on gene expression during the progression of thioacetamide (TAA)-induced liver fibrosis in the rat and have focused on genes that are associated with TGF-β. TAA treatment causes alterations in the expression of 7% of liver genes. Halofuginone treatment prevents the changes in the expression of 41% of these genes and results in the inhibition of HSC activation and collagen synthesis. During the early stages of the disease, halofuginone affects genes involved in alcohol, lipid, protein, and phosphate metabolism and cell adhesion and, at later stages, in the cell cycle (cell development, differentiation, cell proliferation, and apoptosis). The activation of TGF-β-dependent genes, such as tartrate-resistant acid phosphatase, its putative substrate osteopontin, stellate cell activation-association protein, and fibrillin-1, during chemically induced fibrosis is prevented by halofuginone. This study thus highlights the role of TGF-β signaling in liver fibrosis and especially its potential for pharmacological intervention. Halofuginone, which has demonstrated efficacy and tolerance in animals and humans, could become an effective and novel therapy for liver fibrosis.
54 citations
TL;DR: A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci and the contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor necrosis factor alphainduced apoptosis and activation of caspase-8 and -3.
Abstract: 1 Sellick GS, Catovsky D, Houlston RS. Familial chronic lymphocytic leukemia. Semin Oncol (2006); 33: 195–201. 2 Sellick GS, Webb EL, Allinson R, Matutes E, Dyer MJ, Jonsson V et al. A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci. Am J Hum Genet 2005; 77: 420–429. 3 Rosenbauer F, Owens BM, Yu L, Tumang JR, Steidl U, Kutok JL et al. Lymphoid cell growth transformation are suppressed by a key regulatory element of the gene-encoding PU.1. Nat Genet 2006; 38: 27–37. 4 Okuno Y, Huang G, Rosenbauer F, Evans EK, Radomska HS, Iwasaki H et al. Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol Cell Biol 2005; 25: 2832– 2845. 5 Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD et al. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood 2002; 100: 998–1007. 6 Schievella AR, Chen JH, Graham JR, Lin LL. MADD a novel death domain protein that interacts with the type 1 tumor necrosis factor receptor activates mitogen-activated protein kinase. J Biol Chem 1997; 272: 12069–12075. 7 Lim KM, Yeo WS, Chow VT. Antisense abrogation of DENN expression induces apoptosis of leukemia cells in vitro causes tumor regression in vivo alters the transcription of genes involved in apoptosis the cell cycle. Int J Cancer 2004; 109: 24–37. 8 Müller-Hermelink H, Montserrat E, Catovsky D, Harris N. Chronic lymphocytic leukaemia/small lymphocytic lymphoma.In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) World Health Organization classification of tumours: Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press: Lyon, 2001, pp 127–130. 9 Al-Zoubi AM, Efimova EV, Kaithamana S, Martinez O, El-Idrissi Mel A, Dogan RE et al. Contrasting effects of IG20 and its splice isoforms, MADD and DENN-SV, on tumor necrosis factor alphainduced apoptosis and activation of caspase-8 and -3. J Biol Chem 2001; 276: 47202–47211.
TL;DR: GC ameliorates GVHD in both Th1- and Th2-mediated murine models, suggesting it is able to differentially affect the immune system.
Abstract: Background Natural killer T (NKT) lymphocytes play a role in graft-versus-host disease GVHD (GVHD). Glucocerebroside (GC) is a naturally occurring glycolipid that plays a role in the immune modulation of NKT lymphocytes. This study aims to determine the effect of GC in murine models of semiallogeneic/acute and chronic GVHD. Methods Acute and chronic GVHD were generated by fusion of splenocytes from C57BL/6 to (C57BL/6xBalb/c) F1 mice, and from B10.D2 donor mice into Balb/c, respectively. Recipients were treated daily with GC. Histological and immunological parameters of GVHD were assessed. Results Treatment with GC significantly alleviated GVHD in both models The beneficial effect of GC was associated with an increase in the intrahepatic/peripheral NKT lymphocyte ratio in the semiallogeneic/acute model. This ratio was decreased in the chronic GVHD model. A significant increase in intrahepatic CD8+ lymphocyte trapping was noted in the semiallogeneic/acute model, whereas the opposite effect was observed in the chronic GVHD model. Administration of GC led to decreased serum interferon-gamma and increased serum interleukin-4 levels in the Th1-mediated model, whereas the opposite effect was observed in the Th2-mediated models. Conclusions GC ameliorates GVHD in both Th1- and Th2-mediated murine models, suggesting it is able to differentially affect the immune system. GC may alleviate immunologically incongruous disorders, and may be associated with "fine tuning" of immune responses.
TL;DR: The fludarabine/treosulfan regimen can be considered a fully intensive, modified myeloablative regimen with effective antileukemia activity and acceptable toxicity in patients with AML/MDS not eligible for standard myeloablation, and merits further study in larger scale studies.
Abstract: Allogeneic stem-cell transplantation (SCT) is potentially curative treatment for AML and MDS. New conditioning regimens are continuously explored trying to reduce toxicity while maintaining antileukemia effect. Treosulfan is an alkylating agent with in vitro cytotoxicity against leukemia as well as myeloablative and immunosuppressive properties when used in escalated doses. We explored a regimen of fludarabine (30 mg/m(2) x 5) and treosulfan (12 gr/m(2) x 3) in 24 patients, median age 55 years (range, 30-69), with AML (n = 19) or MDS (n = 5), not eligible for standard myeloablation. Donors were HLA-matched siblings (n = 11) or matched-unrelated (n = 13). Twenty-one patients engrafted within a median of 15 days. Extramedullary toxicity was relatively limited. The incidence of acute and chronic GVHD was 15% and 47%, respectively. With median follow-up of 19 months (range, 8 - 34), 16 patients are alive and 8 died (relapse-2, treatment-related-6). Two-year disease-free survival rate was 60% (95% CI, 39-81). The cumulative incidence of relapse was only 15% (95% CI, 5 - 44) while nonrelapse mortality rate was 25% (95% CI, 13-50). The fludarabine/treosulfan regimen can be considered a fully intensive, modified myeloablative regimen with effective antileukemia activity and acceptable toxicity in patients with AML/MDS not eligible for standard myeloablation, and merits further study in larger scale studies.
TL;DR: The data suggest that certain HPSE gene SNPs may contribute to basal heparanase gene expression and that alterations in this gene are an important determinant in the pathogenesis of ALL, AML and MM.
Abstract: Heparanase, endo-beta-D-glucuronidase, degrades heparan sulfate glycosaminoglycans - the principal polysaccharide of the basement membrane and extracellular matrix. Heparanase activity plays a decisive role in biological processes associated with remodeling of the extracellular matrix, such as cancer metastasis, angiogenesis and inflammation. In the hematopoietic system, heparanase is thought to be associated with normal differentiation and function of myeloid cells and platelets. We investigated heparanase polymorphisms in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), Hodgkin's disease (HD) and multiple myeloma (MM). Significant correlation was found between rs11099592 and rs6535455 heparanase gene (HPSE) single nucleotide polymorphisms (SNPs) and ALL (chi2(1d.f.)=4.96, P=0.026). Genotype frequency comparisons revealed a significant association with rs4693602 (chi2(2d.f.)=7.276, P=0.026) in MM patients and rs4364254 (chi2(2d.f.)=6.226, P=0.044) in AML patients. Examination of HPSE gene mRNA expression by real-time RT-PCR indicated a significant low HPSE gene expression level in ALL patients and a high expression level in MM and AML patients, compared to healthy controls. Moreover, statistically significant correlation was found between heparanase mRNA expression level and three HPSE gene SNPs (rs4693608, rs11099592 and rs4364254) among healthy individuals. These data suggest that certain HPSE gene SNPs may contribute to basal heparanase gene expression and that alterations in this gene are an important determinant in the pathogenesis of ALL, AML and MM.
TL;DR: In this phase I dose finding study, patients with imatinib-resistant or -intolerant Philadelphia (Ph+) chromosome-positive leukemias were eligible for treatment with INNO-406 orally at doses ranging from 30 mg once daily (qd) through 480 mg twice daily (bid).
TL;DR: Human umbilical cord blood has established itself as a legitimate source for hematopoeitic stem cell transplantations and is a major alternative, which provide a true chance for cure for a wide variety of diseases.
Abstract: Human umbilical cord blood (CB) has established itself as a legitimate source for hematopoeitic stem cell transplantations. Since the first transplantation was performed in 1988, it is estimated that approximately 4,000 patients, with malignant and non-malignant diseases, were transplanted with CB. Comparing to bone marrow transplants, cord blood's collection is easier and safer. It is also quicker to perform CB transplantation from the time of beginning of donor search. One of the major advantages of it is the naive nature of newborn's immune system. This allows transplantations with less restriction of the HLA system, and with fewer graft versus host disease (GVHD) cases. A true setback of CB transplantations is the slow pace of engraftment. This fact has negative impact on treatment related mortality and is related to the amount of stem cell infused. Since CB has limited nucleated cell dose, transplanting it to heavier patients, namely adults, poses many difficulties. But the skepticism about the possibility that CB might be used in adult hematopoetic stem cell transplantations, can decline after few large scale trials have shown that it is definitely a feasible procedure. Few fields of research might help to improve the outcome of CB transplantations. While some strategies are at different investigational stages, others are at advanced phases of clinical studies. Main strategies are based on expansion of the number of the stem cells in CB grafts, induction of a temporary engraftment with other stem cell sources, or reduction of the toxicity of the conditioning regimens. It is encouraging to witness that the outcome of CB transplantations is improving constantly. Other potential uses of CB are also discussed. It was used for gene transfer for primary immune deficiency, and it was also demonstrated in animal models that its stem cell could serve as regenerative cells in non-hematopoeitic injured tissues. CB has broad spectrum of possible uses, but hematopoeitic stem cell transplantation is still the major indication. In an era where 30-40% of patients will not have a matched related or unrelated donor, CB is a major alternative, which provide a true chance for cure for a wide variety of diseases.
TL;DR: The administration of G-CSF is associated with transient DNA and gene expression modifications in the lymphocytes of normal mobilized donors, and a long-term follow-up of stem cell donors is recommended.
Abstract: Granulocyte colony-stimulating factor (G-CSF) is widely used for the mobilization of hematopoietic stem cells from normal donors. The mechanism of induced mobilization has recently been elucidated. Tr
TL;DR: The introduction of peripheral blood-derived stem cell grafts into allogeneic HCT and the known anti-leukaemic effect of donor lymphocyte infusions paved the way for reduced-intensity conditioning (RIC)allogeneic stem-cell transplantation, which makes transplant in advanced age possible and significantly reduces transplant-related organ toxicity and mortality.
Abstract: Allogeneic haematopoietic cell transplantation (HCT) is the most effective curative therapy in acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Incidence of AML and MDS increases with age, peaking in the seventh decade. Despite improved Ara-C and anthracyclin-based chemotherapy regimens, the prognosis of AML in patients beyond 60 years of age is dismal. The introduction of peripheral blood-derived stem cell grafts into allogeneic HCT and the known anti-leukaemic effect of donor lymphocyte infusions paved the way for reduced-intensity conditioning (RIC) allogeneic stem-cell transplantation, which makes transplant in advanced age possible and significantly reduces transplant-related organ toxicity and mortality. The success of RIC HCT relies on the alloreactivity of the donor immune system and the graft-versus-leukaemia effect. We try to answer the following questions in this paper: who should receive RIC HCT? when and how should the transplant be performed? is there an upper age limit and what is the future of RIC HCT?
TL;DR: The results point to operationally defined conditions for activating neuronal differentiation of HUCBNPs ex vivo and emphasize the crucial role of neuronal CM and NGF in this process.
Abstract: The aim of the study was to isolate and characterize a population of neuronal progenitors in the human umbilical cord blood (HUCB) mononuclear cell (MNC) fraction, for in vitro manipulation towards neuronal differentiation. Selection of the HUCB neuronal progenitors (HUCBNPs) was based on the neuronal prerequisite for adherence to collagen. Populations of collagen-adherent, nestin-positive (94.8 ± 2.9%) progenitors expressing α1/2 integrin receptors, as revealed by Western blot and adhesion assay using selective antagonists, were isolated and survived for more than 14 days. In vitro differentiation of the HUCBNPs was achieved by treatment with 10% human SH-SY5Y neuroblastoma cell-conditioning media (CM) supplemented with 10 ng/ml nerve growth factor (NGF). Some 83 ± 8.2% of the surviving progenitors acquired a neuronal-like morphology, expressed by cellular outgrowths of different lengths. About 35 ± 6% of the HUCBNPs had long outgrowths with a length/cell diameter ratio greater than 2, typical of developing neurons. The majority of these progenitors, analyzed by immunocytochemistry and/or RT-PCR, expressed common neuronal markers such as microtubule-associated protein 2 (MAP-2; 98.5 ± 2%), neurotrophin receptor (TrkA; 98.5 ± 0.06%), neurofillament-160 (NF-160; 94.2 ± 1%), beta-tubulin III (89.8 ± 4.2%) and neuron specific enolase (NSE). Combined CM and NGF treatment induced constitutive activation of the mitogen-activated protein kinases ERK2 (36-fold vs control), p38α (nine-fold vs control) and p38beta (23-fold vs control), most likely related to survival and/or differentiation. The results point to operationally defined conditions for activating neuronal differentiation of HUCBNPs ex vivo and emphasize the crucial role of neuronal CM and NGF in this process.
TL;DR: A characterization of the normally occurring HPSE gene SNPs in different populations is provided for further studies on the linkage between these SNPs and heparanase expression and function in various pathological processes, primarily cancer progression.
Abstract: Heparanase is a mammalian endoglucuronidase responsible for heparan sulfate (HS) degradation. HS is a major constituent of the extracellular matrix (ECM) and HS-degrading activity plays a decisive role in fundamental biological processes associated with remodeling of the ECM, such as cancer metastasis, angiogenesis and inflammation. There is great interest in the prospect of genome-wide association studies to identify genetic factors underlying complex diseases. It is important to establish a detailed description of the heparanase (HPSE) gene single nucleotide polymorphisms (SNPs). In this study, four Israeli Jewish populations (Ashkenazi, North African, Mediterranean and Near Eastern) were examined for 7 HPSE gene SNPs. Four out of 7 SNPs (rs4693608, db11099592, rs4364254, db6856901) were found to be polymorphic. Population comparisons revealed significant differences in SNPs allele frequency between Near Eastern and each of the other three populations. Genotype and allele frequencies in Jewish populations were different from non-Jewish populations, except for a certain similarity to Caucasians. Although the distance between SNPs is relatively small, the db11099592 SNP was in linkage disequilibrium (LD) only with the proximal SNP rs4693608. LD between distal SNPs rs4364254 and db6856901 was found only in Mediterraneans and North Africans. The current study provides a characterization of the normally occurring HPSE gene SNPs in different populations. This information is obligatory for further studies on the linkage between these SNPs and heparanase expression and function in various pathological processes, primarily cancer progression.
TL;DR: The preliminary data are highly promising in terms of conditioning tolerability and patient outcomes following transplant; further phase II studies are now needed to consolidate these data and to investigate specific patient populations and NHL subtypes.
Abstract: Haematopoietic SCT is currently considered a therapeutic option mainly in relapsed or refractory non-Hodgkin's lymphoma (NHL) owing to high post-transplantation relapse rates and significant toxicity of conventional myeloablative conditioning for allogeneic SCT. Radiolabelled immunotherapy combines the benefits of monoclonal antibody targeting with therapeutic doses of radiation, and is a promising advance in the treatment of malignant lymphomas. It is now under investigation as a component of conditioning prior to SCT, with the aim of improving outcomes following SCT without increasing the toxicity of high-dose chemotherapy pre-transplant conditioning. An expert panel met at a European workshop in November 2006 to review the latest data on radiolabelled immunotherapy in the transplant setting, and its potential future directions, with a focus on (90)Y-ibritumomab tiuxetan. They reviewed data on the combination of standard/high/escalating dose (90)Y-ibritumomab tiuxetan with high-dose chemotherapy, and high/escalating dose (90)Y-ibritumomab tiuxetan as the sole myeloablative agent, prior to autologous SCT, and also (90)Y-ibritumomab tiuxetan as a component of reduced intensity conditioning prior to allogeneic SCT. The preliminary data are highly promising in terms of conditioning tolerability and patient outcomes following transplant; further phase II studies are now needed to consolidate these data and to investigate specific patient populations and NHL subtypes.
TL;DR: These prospective multicenter study show excellent outcome of an busulafan/fludarabine based reduced conditioning regimen followed by allogeneic SCT in patients with myelofibrosis, while no impact on survival was seen for cytogenetic abnormalities, JAK2 mutation status and donor (related vs unrelated).
TL;DR: Preliminary results are promising and suggest improved disease control with no added toxicity; however randomized studies are needed to confirm these initial observations.
Abstract: High-dose chemotherapy and autologous stem-cell transplantation (ASCT) have an established therapeutic role in the treatment of chemo-sensitive relapsed aggressive lymphoma, but has limited success in chemo-refractory disease or in heavily pretreated, multiple relapsed patients. Recurrent disease is the major cause of treatment failure in all patient subsets and the majority is not cured. Methods for better eradication of underlying lymphoma are needed to improve outcome. Radioimmunotherapy (RIT) combines radiation delivered by radio-isotopes with the targeting effect of monoclonal antibodies. Two radioimmunoconjugates are currently approved for relapsed/resistant low-grade or transformed lymphoma: iodine-131 tositumomab and yttrium-90 ibritumomab tiuxetan. These agents are also effective in aggressive lymphoma. Radio-labeled antibodies are ideal candidates to combine with high-dose chemotherapy and ASCT. Their major toxicity is myelosuppression, which is easily reversed by ASCT and they can target disease sites with almost no added toxicity to normal tissues. RIT has been used in escalated doses as the sole treatment prior to ASCT or in standard or escalated doses combined with standard high-dose chemotherapy regimens. RIT was also combined with reduced-intensity conditioning and allogeneic SCT. Preliminary results are promising and suggest improved disease control with no added toxicity; however randomized studies are needed to confirm these initial observations.
TL;DR: An updated survival analysis with a median follow up of 11 months is presented for the DOXIL-MMY-3001 study, a large multi-national, phase III, randomized study of patients with previously treated multiple myeloma demonstrating that the combination of pegylated liposomal doxorubicin (PLD) and bortezomib resulted in a 45% risk reduction of experiencing disease progression over bortzomib alone.
Abstract: 8002 Background: Proteasome inhibition with bortezomib is a standard of care for patients with relapsed/refractory multiple myeloma (MM). Recently, we reported the results of an interim analysis fo...
TL;DR: This study has demonstrated mRNA elevation of p53 and apaf1 during CMLblast crisis, indicating that genes and proteins involved in cellular apoptosis might be involved in disease progression/response to therapy.
Abstract: Chronic myelogenous leukemia (CML) is a stem cell disorder that eventually progresses to a blast crisis phase (BC) characterized by distorted apoptotic pathways. The exact mechanism leading to failure in apoptotic pathways during CML progression is unclear. In view of the central role of p53 and apaf1 in the apoptotic machinery we examined six human paired chronic and BC phases samples for their expression. Real-time PCR (RQ-PCR) experiments showed an elevation of p53 mRNA in all patients during transition to BC. However, elevation of apaf1 during BC was observed in five patients only. In contrast, one patient displayed a significant 11.5-fold reduction of apaf1 expression during the transition to BC. No apaf1 promoter methylation was observed. The reduced apaf1 expression was accompanied by a trans-dominant point mutation (H179R) in one p53 allele and the loss of the other. This mutant p53, when tested using functionality assays, was unable to activate apaf1, consequently explaining the reduced expression observed in this patient. Furthermore, the same mutant failed to activate either genes involved in apoptotic or cell cycle arrest pathways, and can be considered as a complete loss of function mutation. This specific mutation was reported in several types of cancer, but was not implicated in CML. To conclude, in this study we have demonstrated mRNA elevation of p53 and apaf1 during CML blast crisis, indicating that genes and proteins involved in cellular apoptosis might be involved in disease progression/response to therapy. Moreover, the mutated p53 discovered in the patient exhibiting lowered apaf1 expression provides, in a clinical case, the first correlation between p53 and apaf1 transcription regulation in humans.
TL;DR: A combination of three abnormalities, i.e., del (13q), loss of IgH and NT, all of potential prognostic significance, can be overlooked unless NT is specifically searched for and ruled out.
TL;DR: Together escBEACOPP-ABVD therapy is well tolerated and may improve the outcome in pts with advanced HL who have high IPS scores, which is comparable with the reported estimated long term survival rates achieved with the poor prognostic subgroup of pts, receiving eight cycles of escBEacOPP in the GHLSG HD9 trial.
TL;DR: It is demonstrated that HF does not significantly affect wound strength, which encourages the possible use of HF as an antifibrotic agent with minimal complications for post-hematopoietic stem cell transplantation complications including radiation toxicity and graft-versus-host disease.
Abstract: It is a major interest in the field of hematopoietic stem cell transplantation to reduce scarring of healing wounds with overdeposition of collagen due to radiation injury or graft-versus-host disease
TL;DR: TTP was comparable for the PLD+bortezomib combination between groups with ≥2 lines of prior therapy vs. 1 prior therapy, as well as patients who were anthracycline-exposed or -naive patients, indicating a consistent therapeutic benefit favoring thePLD+ bortezOMib combination.