bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Novel Receptors on Myeloma Cells and Monocytes That Contribute to Myeloma Tumor Proliferation and Angiogenesis.
Authors: Gordon Melinda S. , Lee Hee Jin , Campbell Richard A. , Chen Haiming , Bonavida Benjamin , Berenson James R. 
Published: April 2020

Abstract
Hyper-activation of multiple cell signaling pathways, including Akt, IRS-1, JAK/ STAT3, NF-kB, Wnt and MAPK, contribute to myeloma cell survival and/or proliferation, and myeloma tumor vascularization. We discovered the novel expression of two cell surface receptors that are able to activate these cell signals but were not previously known to be expressed by hematopoietic cells or to be involved in hematological malignancies. We analyzed bone marrow (BM) and peripheral blood (PB) mononuclear cells (MCs) from multiple myeloma (MM) patients and normal donors for the expression of new surface receptors by flow cytometry. We found that the malignant cells from myeloma patients (N = 10) and the MM cell lines RPMI 8226 and U266 express the receptor protein tyrosine phosphatase b/z (RPTPb/z). RPTPb/z contributes to the growth of solid tumors, including glioblastoma, neuroblastoma and melanoma by aberrant accumulation of b-catenin, leading to activation of Wnt, NF-kB and Akt-mediated cell signals. We interfered with RPTPb/z stimulation by its ligand, pleiotrophin (PTN), using specific anti-PTN antibody and showed significant inhibition of MM proliferation in vitro by MTT assay. Importantly, when this antibody was administered to MM tumor-bearing mice in vivo a significant decrease in tumor volume was detected. We have also discovered that peripheral blood monocytes from MM patients (N = 9) and normal donors (N = 7), and a monocytic cell line (THP-1), display untranslocated anaplastic lymphoma kinase (ALK) on the cell surface. Dysregulated ALK expression on a variety of solid tumors is associated with tumor growth, vascularization and metastasis. ALK+ monocytes and THP-1 cells, but not ALK− peripheral B or T lymphocytes or the ALK− monocytic cell line U937, respond to ALK stimulation by modulating hematopoietic genes and inducing the expression of endothelial genes as well as exhibiting changes in morphology typical of early vascular endothelial cells (Chen et al, 2004, Blood104: 1472). ALK cross-linking leads to activation of the signaling intermediates IRS-1, PI3′K/Akt, STAT3 and MAPK, that are known to play key roles in angiogenesis. Thus RPTPb/z and ALK, or their downstream signal mediators, could be important new molecular targets for anti-myeloma (RPTPb/z) or anti-angiogenic (ALK) therapy. We are defining the signaling pathway(s) leading from RPTPb/z stimulation to MM cellular proliferation and survival, and from ALK to tumor vascularization via monocytic transdifferentiation. These studies provide potential new targets that should lead to new therapeutic strategies for treating MM.
Serum Total-RANKL Is Elevated in Patients with Multiple Myeloma, Increases with ISS Stage and Decreases after Induction Therapy.
Authors: Jakob Christian , Sterz Jan , Kleeberg Lorenz , Zavrski Ivana , Kaiser Martin , Eucker Jan , Heider Ulrike , Possinger Kurt , Sezer Orhan 
Published: April 2020

Abstract
Enhanced osteolytic bone resorption is a hallmark of multiple myeloma. Several studies demonstrated an elevation of RANKL levels in the bone marrow microenvironment in multiple myeloma, but serum levels of soluble RANKL (sRANKL) revealed controversial results. One study reported elevated sRANKL in serum in myeloma patients, but using the same test, the levels in the majority of the patients were below the detection limit in the hand of other groups. Thus, a novel test was developed which measures both soluble and OPG-bound RANKL (total-RANKL, tRANKL). The objective of the present study was to investigate the clinical significance of circulating levels of tRANKL in monoclonal gammopathies of undetermined significance (MGUS) or multiple myeloma (MM). Serum levels of tRANKL were analyzed by ELISA in 128 individuals: 20 healthy donors, 20 with MGUS and 88 newly diagnosed patients with multiple myeloma. Multiple myeloma patients had significantly (P&lt;0.001) higher serum tRANKL values (median 7.01 μmol/L, range &lt; 2 – 57.6) than healthy controls (median &lt; 2 μmol/L) and individuals with MGUS (median &lt; 2 μmol/L). Serum tRANKL levels increased significantly (P&lt;0.001) from Durie & Salmon stage I to stage III (median values: stage I = 2.98, stage II = 4.61, stage III = 10.45 μmol/L) und from ISS stage I to stage III (median values: stage I = 4.64, stage II = 7.98, stage III = 23.12 μmol/L). Furthermore the serum tRANKL concentrations were significantly elevated in MM Durie & Salmon stage I versus MGUS (P=0.01). Multiple myeloma patients with osteolytic bone lesions in conventional radiography had significantly higher tRANKL levels than those without bone lesions (median 8.34 vs. 4.02 μmol/L, P=0.01). In 32 patients with multiple myeloma in stages II and III, who received chemotherapy and a monthly bisphosphonate treatment with zoledronic acid or pamidronate additional serum samples after 3 months were available. There was a significant (P&lt;0.001) decrease from pre- to post-treatment tRANKL concentrations after three months of treatment. Our study shows that serum tRANKL levels are detectable in the majority of myeloma patients using this novel ELISA test. Advanced disease stages and osteolytic bone lesions in multiple myeloma patients are associated with increased serum tRANKL levels. The decrease of tRANKL after 3 months of induction therapy and bisphosphonates suggest a positive effect of anti-myeloma treatment on RANK ligand expression in multiple myeloma patients.
Alternate Week Administration of the Farnesyltransferase Inhibitor Tipifarnib (ZARNESTRA®, R115777) in Patients with Myelodysplastic Syndrome: Results of a Phase 1 Study.
Authors: Kurzrock Razelle , Verstovsek Srdan , Wright John J. , Pilat Susan R. , Cortes Jorge E. , Estey Elihu H. , Giles Francis J. , Beran Miloslav , Kantarjian Hagop M. 
Published: April 2020

Abstract
Tipifarnib (ZARNESTRA®, R115777), an oral selective inhibitor of farnesyltransferase (FTase), demonstrates potent antiangiogenic, antiproliferative, and apoptotic effects. This phase 1 study assessed the tolerability and response rate in patients with myelodysplastic syndrome (MDS) receiving tipifarnib on an alternate week (1 week on/1 week off) schedule. Starting dose of tipifarnib was 100 mg BID, for a total initial treatment period of 8 weeks, with a standard 3+3 design. Dose escalation was 100 mg PO BID until grade 2 nonhematologic toxicity was observed, then 100 mg total dose per day escalation until the maximum tolerated dose (MTD) was reached. Sixty-three patients were treated (median age 68 years; range, 35–84 years) with RA (n = 15), RARS (n = 6), RAEB (n = 26), RAEB-t (n = 8), and CMMoL (n = 8). Five patients (8%) had IPSS score low, 27 (43%) INT-1, 23 (36%) INT-2, and 8 (13%) high. Three patients had an N-Ras mutation and one had a K-Ras mutation. A total of 63 patients were evaluable for toxicity and 61 were evaluable for response (1 noncompliant, 1 ineligible). This alternate week regimen of tipifarnib was well tolerated; the most common toxicity was myelosuppression (all grades, 60% of patients). No side effects were reported by 20% of patients. Nonhematologic toxicities (all grades) included fatigue (20%), skin rash (9%), diarrhea (16%), increase in SGPT (14%), increase in bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), insomnia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib 1,300 mg/day to 1,500 mg/day. The MTD of tipifarnib in this patient population was 1,200 mg/day. Fifteen of 61 (25%) evaluable patients responded (3 CRs and 12 hematologic improvements). Major platelet responses were most common; they were observed in 11 of 15 responders. There was no obvious dose-response relationship and three of the fifteen patients (20%) at the lowest dose level (100 mg bid) responded including one CR. Only one patient among the responders (hematologic improvement) had a Ras (N-Ras) mutation. Median time to response was eight weeks (range, 4–32 weeks). In conclusion, an alternate week regimen of tipifarnib was well tolerated and a response rate of 25% was achieved in this phase 1 study in MDS patients. Responses were seen at all dose levels, and major platelet responses were most common. This schedule is therefore conducive to combination regimens as well as to maintenance therapy.
Analysis of Survival, AML Transformation, and Transfusion Independence in Patients with High-Risk Myelodysplastic Syndromes (MDS) Receiving Azacitidine Determined Using a Prognostic Model.
Authors: Silverman Lewis R. , McKenzie David R. , Peterson Bercedis L. , Demakos Erin P. , Holland James F. , Larson Richard R. ,   The Cancer Leukemia Group B (CALGB).
Published: April 2020

Abstract
The International Prognostic Scoring System (IPSS) requires cytogenetic data to evaluate risk in MDS. Cytogenetic data were not available for all patients from the CALGB trial 9221 (Silverman et al, JCO2002; 20:2429). Therefore, we developed an alternative prognostic model that identified a homogeneous subgroup of high-risk MDS patients based on the following risk factors: percent marrow blasts, number of cytopenias, age, gender, FAB classification, and time since diagnosis (IPSS used data at time of diagnosis; CALGB 9221 used data at time of randomization). The model was validated using 2,318 patients from the MDS Registry, Düsseldorf. Using these baseline prognostic factors, we predicted survival for each of the 191 CALGB patients, identified a high-risk subgroup with a survival prognosis of ≤ 1.2 years (the IPSS INT-2 survival median), and compared azacitidine to supportive care. Patients were analyzed as randomized (azacitidine or supportive care) according to the intention-to-treat (ITT) principle. The two groups had similar demographic and disease characteristics. All 70 high-risk patients were followed until death. There was a statistically significant difference in overall survival curves between the azacitidine and supportive care groups (p=0.03). The one-year survival rate was 63% (95% CI: 47 to 78%) in the azacitidine group and 37% (95% CI: 19 to 54%) in the supportive care group (p=0.03; 26% difference with a 95% CI of 3 to 49%). The two-year survival rate was 35% (95% CI: 20 to 50%) in the azacitidine group and 13% (95% CI: 1 to 25%) in the supportive care group (p=0.03; 22% difference with a 95% CI of 3 to 41%). Similarly, statistically significant differences in time to AML transformation, and death or AML transformation, were observed. Transfusion independence was defined as free from transfusions for at least 2 months. Among patients who were RBC transfusion dependent at baseline, a significantly greater number of patients from the azacitidine group (11/25, 44%) compared with patients from the supportive care group (1/14, 7%) achieved transfusion independence (p=0.03; 37% difference with a 95% CI of 7 to 59%). Additionally, patients in the azacitidine group with baseline transfusion independence experienced significantly prolonged duration of RBC (p&lt;0.0001) and platelet (p=0.0002) transfusion independence compared with those in the supportive care group. Use of this prognostic model has identified a subgroup of high-risk MDS patients who significantly benefited from treatment with azacitidine.
Time of Even Analysisa
Azacitidine Prolongs Survival and Time to AML Transformation in High-Risk Myelodysplastic Syndrome (MDS) Patients ≥ 65 Years of Age.
Authors: Silverman Lewis R. , McKenzie David R. , Peterson Bercedis L. , Demakos Erin P. , Malone Neil T. , Holland James F. , Larson Richard A. ,   The Cancer Leukemia Group B (CALGB).
Published: April 2020

Abstract
The prognosis for patients with refractory anemia with excess blasts (RAEB) or RAEB in transformation (RAEB-T) ≥ 65 years of age has been poor. These high-risk patients are often not eligible for intensive induction/transplantation regimens or combination chemotherapies, leaving few treatment options besides supportive or palliative care. In the publication of the CALGB trial by Silverman et al (JCO2002;20:2429), no age- and/or risk- related subgroup analyses for azacitidine (Vidaza®) were presented. To assess the treatment effect of azacitidine versus supportive care on survival and time to AML transformation in a homogeneous sample of high-risk patients with MDS, we performed a subgroup analysis on the 191 patients included in the CALGB trial. All patients with a baseline diagnosis of RAEB or RAEB-T who were ≥ 65 years of age were included in the comparative analysis, using intent-to-treat (ITT) principles based on randomization to azacitidine or supportive care. Efficacy was analyzed using three survival endpoints: overall survival, time to death or AML transformation, and time to AML transformation. In all, 31 azacitidine patients and 37 supportive care patients met the criteria for this high-risk subgroup analysis. No significant differences in demographics or disease characteristics between the two groups were observed. For all three survival analyses, a statistically significant difference was observed for patients in the azacitidine group compared with those in the supportive care group. (Table) Median time to transformation to AML, in particular, was prolonged for 24 months in azacitidine patients compared with patients in the supportive care group. A sensitivity analysis of the overall survival results was conducted by performing 10 additional subgroup analyses based on ages ≥ 60 through ≥ 70 years in increments of one year with all overall survival results remaining significant (p &lt; 0.05, except for 2 subgroup analyses based on ages ≥ 60 and ≥ 66 where both p-values were 0.051). The sensitivity results demonstrated robust patient benefit in the subgroup ≥ 65 years of age. The most common adverse event observed with azacitidine was myelosuppression, which decreased in frequency as therapy continued. Azacitidine provided clear treatment effect and patient benefit to this difficult-to-treat, high-risk group of RAEB and RAEB-T patients ≥ 65 years of age by significantly prolonging overall survival and time to AML transformation.
Time of Even Analysis
Rates of Infection and Bleeding Are Not Increased in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine Compared with Supportive Care.
Authors: Silverman Lewis R. , McKenzie David R. , Peterson Bercedis L. , Odchimar-Reissig Rosalie , Hinkle Randy , Backstrom Jay T. , Larson Richard A. ,   The Cancer Leukemia Group B (CALGB).
Published: April 2020

Abstract
MDS are heterogeneous hematopoietic disorders characterized by dyspoiesis and cytopenias. Most patients with high-risk MDS die within 1 year from infection or hemorrhage usually attributable to bone marrow failure or progression to AML. In a phase 3, open-label, multicenter, randomized study comparing azacitidine (Vidaza®) plus supportive care (N=99) versus supportive care alone (N=91) in patients with MDS (JCO2002;20:2429), treatment with azacitidine was associated with worsening of pre-existing cytopenias in up to 78% (115/147) of patients with pre-existing cytopenias. The median time to first occurrence of any worsening cytopenia was 8 days (interquartile range: 6 to 15 days). All patients were treated with the same initial dose of azacitidine (75 mg/m2/day); no dose adjustments were made for pre-existing cytopenias despite the severity. We examined rates of infection and bleeding associated with azacitidine therapy in comparison with the rates seen with the underlying disease (supportive care). Our results are based on re-collected data from patients described in the published report; our analyses were conducted separately and independently. Total exposure for azacitidine was the cumulative time from the first dose to the end of study (30 days after last dose), and for supportive care was the cumulative time from randomization to withdrawal from study or day prior to crossover. The azacitidine group included all patients exposed to azacitidine (N=150), which included patients randomized to azacitidine (N=99) and patients after crossing over from supportive care (N=51). Similar to the rate of infections previously reported in patients with MDS (AJM1991; 90:338), infections occurred in patients in the supportive care group at nearly one per patient-year. However, infections occurred at an overall lower rate (patient-years) in the azacitidine group (0.64) compared with the supportive care group (0.95). (Table). Similarly, the overall rate (patient-years) of bleeding events was comparable between azacitidine (0.56) and supportive care (0.60). In particular, bleeding events in the gastrointestinal system occurred at a similar rate between the azacitidine group (0.26) and the supportive care group (0.25). This was also true for bleeding events in the central nervous system (azacitidine: 0.01, supportive care: 0.02). The rates of infection and bleeding were 3 to 4 times higher during cycles 1 and 2 in both treatment groups, reflecting the severity of the underlying disease at study entry. In summary, despite the potential to exacerbate pre-existing cytopenias early in therapy, treatment with azacitidine did not increase the rate of infection and bleeding above the rate due to the underlying disease.
Infection Rates (Patient-Years of Exposure) in Protocol 9221
Response Rates Using International Working Group (IWG) Criteria in Patients with Myelodysplastic Syndromes (MDS) Treated with Azacitidine.
Authors: Silverman Lewis R. , McKenzie David R. , Peterson Bercedis L. , De Castro Carlos M. , Ellerton John , Knapp Kathryn N. , Beach C.L. , Larson Richard A. ,   The Cancer Leukemia Group B (CALGB).
Published: April 2020

Abstract
The CALGB conducted a series of clinical trials with azacitidine (Vidaza®) administered subcutaneously or intravenously in patients with MDS using the FAB classification (JCO2002;20:2429). Since the publication of these CALGB studies (8421, 8921, 9221), new response criteria for evaluating new treatments for MDS have been published by the IWG (Blood2000;96:3671). Two general differences between the CALGB and IWG response criteria are the required duration of improvement (CALGB: ≥4 weeks; IWG: ≥8 weeks) and peripheral blood values (CALGB: different criteria for hemoglobin targets for males and females; IWG: same criteria for males and females). The results reported here are based on re-collected data from patients described in the published report. After applying the IWG response criteria, the overall response rate (CR+PR+HI) in the azacitidine groups were similar across studies 8421, 8921, and 9221: 44% (21/48), 40% (28/70), and 48% (47/99), respectively.
Best Response using IWG Response Criteria for MDS in Studies 8421, 8921, and 9221
Median duration of any response (CR, PR or HI) in the 114 azacitidine-treated responders was 366 days (range: 56 to 4641+ days). The median duration of CR in the 32 azacitidine-treated responders was 379 days (range: 92 to 4412+ days). The median number of cycles from first treatment with azacitidine to any response (CR, PR or HI) was 3 cycles (range: 1 to 17 cycles). Although 75% of the responders achieved a response by cycle 4, the other 25% achieved a response as late as cycle 17. The majority (90%) of responders achieved a response by cycle 6. Best response was observed, on average, 2 cycles after the initial response. In summary, reanalysis of the response rates using IWG criteria demonstrate consistent results across three sequential studies and further validate the superiority of azacitidine over supportive care alone.
Vitamin K2 (VK2) Monotherapy and VK2 Plus D3 Combination Therapy in Low-Risk Myelodysplastic Syndrome: A Prospective Japanese Study.
Authors: Miyazawa Keisuke , Ohyashiki Kazuma , Akiyama Nobu , Kanda Yoshinobu , Tohyama Kaoru , Omine Mistuhiro , Mitani Kinuko 
Published: April 2020

Abstract
Vitamin K2 (VK2) analogs, including menaquinone-4 (MK4) but not vitamin K1, effectively induce apoptosis in acute myeloid leukemia cells (AML). Apoptosis induction by VK2 is specific toward leukemia cells, and almost no effect is observed in normal hematopoietic progenitor cells (Miyazawa K, Leukemia 1999, 2000, 2001). Combined treatment with VK2 plus 1α, 25-dihydroxy-vitamin D3 (D3) dramatically enhanced differentiation of leukemia cells as compared to the cells treated with D3 alone. Concomitant with the induction of differentiation and final maturation by VK2 plus D3, the cells became resistant to various apoptotic stimuli (Funato K, Leukemia, 2002). VK2 has been shown to improve the supportive hematopoietic functions of bone marrow stromal cells (Miyazawa K, Stem Cell Dev. 2004). Since VK2 (MK4, GlakayR) has been used to treat patients with osteoporosis in Japan, its non-toxicity and safety for long-term daily administration have already been well established. Case reports demonstrating the clinical benefits of using VK2 with or without D3 for treating patients with myelodysplastic syndrome (MDS) and AML have been accumulating, i.e. improving cytopenias in refractory anemia (RA) and reduction of blast cells in AML. We performed a multicenter prospective trial to determine the therapeutic benefit of VK2 with or without D3 in MDS. Patients with RA/RCMD with low/ int-1 by IPSS received VK2 (Glakay, 45 mg/day, po) for 16 weeks. The therapeutic response was assessed according to the International Working Group Criteria. Patients who did not respond to VK2 were sequentially re-registered and received a combination of VK2 plus D3 (alfacalcidol, AlfarolR, 0.75 microgram/day, po) for 16 weeks. Patients showing response to VK2 alone or VK2 plus D3 after 16 weeks continued to receive therapy for a total of 12 months. Forty-three patients have been enrolled and 29 patients were evaluable for their response to VK2. Five patients (17.2 %) showed improvement of cytopenia (major HI-E (1), minor HI-E (2), major HI-P (3), and minor HI-P (1)). Twenty out of 24 patients who showed no response to VK2 alone subsequently received VK2 plus D3. Eleven patients were eligible for evaluation and 4 patients (36.4%) showed improvement of cytopenia in response to VK2 plus D3 (major HI-E (3), minor HI-E (1) and major HI-P (1)). Four out of 7 patients (57 %) with anemia showed hematologic response. No adverse events were observed, except for one case of skin rash (Grade I) during VK2 plus D3 therapy. These data suggest that the therapeutic response rate is improved by combined treatment with VK2 plus D3 as compared with that by VK2 monothrapy. Safety and low price also support the therapeutic benefit of VK2 with D3 for improving cytopenia in RA.