bluuebunny/crossref_metadata_2025_split huggingface dataset:
IRL-1620 Increases the Efficacy of Radiation Treatment in Mice Bearing Lymphoma Cell Induced Tumors.
Authors: Lenaz Luigi , Gulati Anil , Sunila E. 
Published: April 2020

Abstract
PURPOSE. IRL-1620, a selective ETB receptor agonist, has been reported to selectively enhance tumor blood flow and potentiate the efficacy of chemotherapeutics in various tumor models. Improved tumor perfusion is associated with a net increase in tumor oxygenation, which may be exploited to increase the effectiveness of radiotherapy. Since tumor oxygenation increases the radiation-induced cellular damage, IRL-1620 may be helpful to increase radiation sensitivity of tumor. The present study was conducted to determine whether administration of IRL-1620 prior to radiation enhances the efficacy of radiotherapy.
STUDY DESIGN. Male Swiss albino mice (6–8 weeks old; 25–30 g) were used for the study. Tumor was induced by the subcutaneous inoculation of Dalton’s Lymphoma cells (1 million) on the right hind limb. Tumor volume was measured using a digital caliper. Animals with a tumor volume of about 1cc were selected for the study and were divided into six groups (10 mice per group). Group I: No treatment; Group II: IRL-1620 (9 nmol/kg, 5 doses on alternate days); Group III: Radiation (5 × 4 Gy using Cobalt-60 Teletherapy unit (Theratron 780, Canada) on alternate days administered at 1 Gy/min); Group VI: IRL-1620 (1 nmol/kg) + radiation, 5 doses on alternate days; Group V: IRL-1620 (3 nmol/kg) + radiation, 5 doses on alternate days; Group VI: IRL-1620 (9 nmol/kg) + radiation, 5 doses on alternate days. Mice were shielded with lead except for a 3-cm-diameter circular field where the tumor was centered. IRL-1620 was administered via tail vein 15 minutes prior to radiation administration. Tumor diameter was measured twice a week for a total of 70 days.
RESULTS. Tumor bearing mice without any treatment showed a progressive increase in tumor volume and all the animals died by 53 days after tumor induction. Radiation alone did not significantly reduce tumor volume when compared to controls (possible due to hypoxic condition). There was no significant increase in the survival. All the animals (10 out of 10) died by 56 days after tumor induction. Animals treated with radiation 15 min after administration of 9 nmol/kg IRL-1620 reduced the tumor volume significantly and there was significant increase in life span. It was found that only 4 out 10 animals died by 70 days after tumor induction. Animals treated with radiation 15 min after administration of 3 nmol/kg IRL-1620 delayed the development of tumors. It was found that 7 out 10 animals died by 70 days after tumor induction. Animals treated with radiation 15 min after administration of 1 nmol/kg IRL-1620 along with radiation delayed tumor development. It was found that 9 out 10 animals died by 70 days after tumor induction.
CONCLUSION. It is concluded that IRL-1620 significantly enhanced the efficacy of radiation treatment in Dalton’s Lymphoma cells induced tumor model by reducing tumor volumes and increasing the survival.
Long-Term Dosing of AMG 531 in Thrombocytopenic Patients with Immune Thrombocytopenic Purpura: 48-Week Update.
Authors: Kuter David , Bussel James , George James , Aledort Louis , Lichtin Alan , Lyons Roger , Nieva Jorge , Wasser Jeffrey , Bourgeois Emanuelle , Kappers-Klunne Mies , Lefrere Francois , Schipperus Martin , Kelly Reggie , Christal Jenny , Guo Matthew , Nichol Janet 
Published: April 2020

Abstract
AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was &gt;50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count &gt;450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a &gt;25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.
Telomere-Based Pre-Clinical Therapy of Human Lymphoid Malignancy in a SCID Xenograft Model.
Authors: Longe Harold O. , Sinha Anupama , Faller Douglas V. , Denis Gerald V. 
Published: April 2020

Abstract
We continue to develop and extend our novel adjuvant therapy approach to lymphoid malignancy. We supplement CHOP with DNA oligonucleotides that mimic the chromosomal telomere, which we call a “T oligo.” These agents are homologous to the 3′ overhang nucleotide sequence of telomeres and have previously been shown to have anti-tumor activity in animal models of malignant melanoma and breast cancer. They are currently being evaluated in melanoma and breast cancer patients. If introduced into human or murine normal, proliferating primary B cells or T cells, T oligo causes transient cell cycle arrest, while exerting no toxicity, but if introduced into human or murine malignant B cells or T cells, the arrest is followed by p53 phosphorylation, p21 message induction and ultimately p53-dependent apoptosis. Other p53-related effector molecules, such as p73, are also likely to be involved. The mechanism immediately suggests a novel method of chemotherapy for leukemia and lymphoma as an adjuvant with CHOP. Furthermore, we have previously shown with in vitro assay and in vivo mouse models of diffuse large B cell lymphoma (DLCL) that T oligo produces a more-than-additive toxicity towards lymphoma cells when combined with vincristine. T oligo alone or in combination with sub-therapeutic doses of CHOP, the standard of care for DLCL, dramatically reduced lymphoma burden in spleen, lung, bone marrow and peritoneum. In combination, which we refer to as T-CHOP, there was a greater reduction in tumor burden than with either therapy alone. We now show in SCID mouse xenograft models of human T cell malignancies, using a Jurkat T cell leukemic line or a MOLT-4 T cell leukemic line that T oligo also works alone to reduce tumor burden dramatically and increase survival. Interestingly, because T oligo-driven apoptosis occurs in p53-null, human lymphoid tumors, even chemotherapy-resistant lymphoid tumors are nevertheless sensitive to T oligo treatment, which may have profound benefit for relapsed leukemia or lymphoma patients.
The European Leukemia Net CML Registry - Objectives, Achievements and First Results.
Authors: Hasford Joerg , Rosti Gianantonio , Baccarani Michele , Hehlmann Rudiger , Guilhot Joelle , Rousselot Phillippe , Cervantes Francisco , Hellmann Andrzej , Steegmann Juan L. , Colita Adriana , Markl Gertraud , Pfirrmann Markus , Simonsson Bengt 
Published: April 2020

Abstract
In 2004/2005, the European Chronic Myeloid Leukemia (CML) Registry was established within the European Leukemia Net (ELN) which is funded by the EU. The purpose is to collect prospectively baseline, follow-up and outcome data of CML patients treated with imatinib or with more recent tyrosine kinase inhibitors in a standardized format. Among the objectives are the development and validation of prognostic scores, the analysis of various prespecified subgroups, e.g. of patients with imatinib failure or of patients who discontinued imatinib after complete cytogenetic remission and to support the design and analysis of future clinical trials. At present individual patient data of about 1460 bcr/abl positive CML patients from France, Germany, Italy, Poland, Romania and Spain are in the data bank. Patients were treated either with 400 or 800 mg imatinib/day as mono or combination treatment. About 40% of the patients are female. Using the New CML Score the proportion of low risk patients varies between 35% – 89% (high risk: 0% – 13%) among the participating countries. First analyses of outcome data, here the proportion of cytogenetic remissions at month 12, indicate that the results of the IRIS trial can be reproduced. With more countries participating and longer observation times the European CML Registry promises to provide highly interesting data.
Downregulation of Receptor Activator of Nuclear Factor kB Ligand (RANKL) in Chronic Myeloid Leukemia Patients Receiving Imatinib Mesylate Is Dose-Dependent.
Authors: Albano Francesco , Zagaria Antonella , Anelli Luisa , Guastadisegni Maria , Pannunzio Alessandra , Spinosa Giuseppina , Rocchi Mariano , Liso Vincenzo , Specchia Giorgina 
Published: April 2020

Abstract
The receptor activator of the nuclear factor kB ligand (RANKL) is a key molecule in the pathogenesis of malignant osteolytic lesions in multiple myeloma or bone metastases in prostate and breast cancer. Inhibition of RANKL is therefore a promising new therapy for controlling bone loss and pain in bone tumors and associated osteolysis. Changes in bone and mineral metabolism developing in a proportion of patients taking imatinib for either chronic myeloid leukemia (CML) or gastrointestinal stromal tumors have previously been described. The aim of our study was to verify in CML patients the effect of imatinib on RANKL bone marrow molecular expression.
The study included 13 CML patients (7 males, 6 females, median age 37 yrs). Six were treated with imatinib at standard dosage (400 mg) and the remaining 7 at higher doses (&gt; 400 mg). The median duration of imatinib therapy was 28 months (range 13 – 44 months).
The RANKL gene expression level was determined by Real-Time PCR using 1X Platinum SYBR Green qPCR SuperMix-UDG. Variations in RANKL gene expression level were estimated by comparing the values of 2−Δ Δ Ct obtained in CML patients at diagnosis and during imatinib treatment. For each of the tested cases the sample at diagnosis was utilized as calibrator and 28S rRNA was used as reference gene.
Eight (62%) patients showed a downregulation of RANKL gene expression, the fold decrease ranging from 0.01 to 0.47 as compared to the value at diagnosis; among these 8 patients, 6 (75%) were treated with imatinib at standard dosage. Instead, 5 (38%) patients showed an upregulation of RANKL, the gene expression fold increase ranging from 1.43 to 4.94 as compared to the gene level observed at CML onset; all these 5 patients were treated with high doses of imatinib. There was no association between RANKL expression and the duration of imatinib treatment.
These findings suggest that imatinib mesylate could control RANKL expression. At standard dosage, imatinib can downregulate RANKL production. The RANKL upregulation observed in CML patients treated with high doses of imatinib could be explained by the possible activation of the immune system cells, such as T and B cells, induced by the tyrosine kinases inhibitor. Further studies are needed to verify the minimal effective dose of imatinib on RANKL expression, with the aim of administering it as an antiosteolytic agent in such diseases as osteoporosis, metastatic bone disease, and multiple myeloma.
Impact of Age in the Outcome of Patients with Chronic Myeloid Leukemia in Late Chronic Phase: Clinical and Molecular Results of a Phase II Study of the GIMEMA CML Working Party.
Authors: Martinelli Giovanni , Palandri Francesca , Iacobucci Ilaria , Bassi Simona , Castagnetti Fausto , Amabile Marilina , Cilloni Daniela , Poerio Angela , Soverini Simona , Rege-Cambrin Giovanna , Iuliano Franco , Alimena Giuliana , Latagliata Roberto , Testoni Nicoletta , Pane Fabrizio , Saglio Giuseppe , Rosti Gianantonio , Baccarani Michele 
Published: April 2020

Abstract
To assess the effect of age on response and compliance we performed a sub-analysis within a phase II trial of the GIMEMA CMLWorking Party (CML/002/STI571). Since the WHO cut-off age to define an older patient is 65 years, we identified: 226/284 (80%) younger patients (below 65 years) and 58/284 (20%) older patients (above 65 years) before starting imatinib. Responses (hematologic and cytogenetic) were lower in older age group but progression free survival and overall survival probabilities (median observation time 3 years) were the same. Moreover, among complete cytogenetic responders, no differences were found in the level of molecular response between the 2 age groups. As probably expected, older patients experienced more adverse events (AEs), both hematologic and non-hematologic: this worsen compliance, however, did not prevent a long term outcome similar to younger ones. CML
Dasatinib (SPRYCEL®, BMS-354825) Phase-I/II Study of Patients with Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Imatinib: Results of the CA180031 Study in Japan (Phase I Portion).
Authors: Sakamaki Hisashi , Fujisawa Shin , Tobinai Kensei , Taniwaki Masafumi , Miyawaki Shuichi , Jinnai Itsuro , Utsunomiya Atae , Tanimoto Mistune , Morishima Yasuo , Okada Masaya , Miyazaki Yasushi , Uoshima Nobuhiko , Seriu Taku , Ohno Ryuzo 
Published: April 2020

Abstract
Dasatinib (SPRYCEL®, formerly BMS-354825) is a potent, orally active, multi-targeted kinase inhibitor active against BCR-ABL and SRC family kinases. Studies outside Japan have demonstrated that dasatinib is highly effective in overcoming resistance and intolerance to imatinib (im), inducing durable cytogenetic and hematologic responses in this CML patient population. In establishing the dose for non-Japanese patients, the maximum tolerated dose failed to be reached and the 70-mg-twice-daily (BID) dose was determined to provide the optimal benefit-risk profile. Based on clinical experience to date, dasatinib has the potential to have a major impact on the current treatment paradigm for patients with CML resistant or intolerant to prior therapy, including im. To assess the safety and efficacy of dasatinib in Japanese patients, a phase-I/II study was conducted in patients with all phases of im-resistant or -intolerant CML. In the phase-I portion of this study, dasatinib was administered at one of three escalating dose levels for a period of 4 weeks: 50 mg, 70 mg, or 90 mg BID. As of July 2006, 15 eligible patients have been enrolled and treated. Six evaluable patients (4F, 2M; median age 43 y [range 27–56]; 4 im-resistant, 2 im-intolerant) were treated at the 50 mg BID dose level and one dose-limiting toxicity (DLT) was observed (grade 4 thrombocytopenia). Two patients experienced transient grade 3 ALT elevations but as treatment was uninterrupted, these were not considered DLTs. A further 6 evaluable patients (6M; median age 42 y [range 27–55]; 3 im-resistant, 3 im-intolerant) were treated at the 70 mg BID dose level and one DLT was observed (grade 4 thrombocytopenia). Three patients have recently been enrolled at the 90 mg BID dose level. As the safety of the 70 mg BID dose was established in the phase-I portion of the study, the use of this dose is being expanded into the phase-II element, which plans to evaluate cytogenetic response in chronic phase CML patients at 24 weeks, and hematologic response rate in accelerated- or blast-phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients at 12 weeks. Accrual to the phase-II portion of this study is ongoing. Updated data including baseline mutational analyses will be presented at the meeting.
Synergism between Anti-Leukemia Therapeutics and Isoprenoid Pathway Inhibitors in K562 Leukemia Cells.
Authors: Askeland Eric J. , Wiemer Andrew J. , Hohl Raymond J. 
Published: April 2020

Abstract
Chronic myeloid leukemia (CML) is a consequence of the BCR-ABL oncogene which mediates a phosphorylation cascade of downstream effectors including those of the Ras family. Drugs that target the isoprenoid pathway, such as the farnesyl transferase (FT) inhibitors have shown promise as novel anti-cancer therapies for some hematologic malignancies. Leukemias are treated with specific inhibitors, like imatinib mesylate in the case of CML, and less-specific chemotherapeutic drugs such as the pyrimidine analog cytarabine (ara-C). We systematically evaluated combinations of these and other agents with isoprenoid pathway inhibitors for synergistic anti-leukemia effects. Toxicity was measured in the BCR-ABL-expressing K562 cells using an MTT assay, and drug synergy was assessed using a modified isobologram method. Cell cycle distribution, Annexin-V apoptosis detection, and Western blot analyses were performed on cells treated with synergistic drug combinations. Imatinib mesylate exhibited significant synergy with the squalene synthase inhibitor zaragozic acid, but not with inhibitors for HMG coenzyme A reductase (lovastatin), FPP synthase (zoledronic acid), GGPP synthase (digeranyl bisphosphonate), and FT (alpha-hydroxyfarnesyl phosphonate). Western blot analysis revealed a moderate decrease in Ras protein levels upon treatment with zaragozic acid. This zaragozic acid-mediated decrease in Ras protein may explain the synergy seen between the drugs since imatinib mesylate also affects Ras by decreasing its phosphorylation through inhibition of the BCR-ABL protein. Apoptosis detection and cell cycle distribution did not yield insight into the mechanism underlying this synergy. Ara-C displayed synergy with digeranyl bisphosphonate in the MTT assay. Subsequent cell cycle analysis showed a concentration-dependent G0–G1 arrest by digeranyl bisphosphonate which was enhanced by ara-C. Annexin-V/propidium iodide staining revealed increased cellular apoptosis in response to either digeranyl bisphosphonate or ara-C with synergistic apoptosis to combination treatments. Western blot analysis for anti-apoptotic proteins showed a decrease in Mcl-1 and Bcl-XL protein levels in the presence of digeranyl bisphosphonate. Ara-C has been shown to alter pro-apoptotic and anti-apoptotic proteins in a manner that induces apoptosis. These modifications in pro- and anti-apoptotic proteins and alterations in cell cycling may constitute a mechanism for the synergy seen between digeranyl bisphosphonate and ara-C. Discovery of these synergistic combinations is important because translation of these cell culture results to in vivo testing and human clinical trials may enhance treatment efficacy and diversify available treatment options. Future work will focus on further determining the mechanisms for these synergistic interactions, finding new synergistic combinations, and applying these regimens to in vivo models and clinical trials.
Clonal Chromosomal Abnormalities in Philadelphia Negative Cells during Dasatinib Treatment in Five Patients with Chronic Myeloid Leukemia.
Authors: Dubruille Viviane , Talmant Pascaline , Loiseau Herve Avet , Moreau Philippe , Harousseau Jean-Luc 
Published: April 2020

Abstract
The emergence of clonal chromosomal abnormalities in Philadelphia negative cells was reported during Imatinib treatment in several patients with chronic myeloid leukemia (CML) in different phases (chronic phase, accelerated phase and blastic crisis). Recently, new tyrosine kinase inhibitors were used in treatment of Imatinib-resistant or Imatinib-intolerant chronic myeloid leukemia. We describe 5 patients with chromosomal abnormalities in Philadelphia negative cells during treatment with Dasatinib. At the beginning of treatment, 4 patients were in chronic phase, 1 patient was in accelerated phase. All patients were in cytogenetic relapse. Additional cytogenetic abnormalities were described in Philadelphia positive cells only in one case (accelerated phase). Clonal cytogenetic abnormalities (4 trisomy 8, 1 monosomy 7) appeared in Philadelphia negative cells during Dasatinib treatment (after 6 months in 1 patient, 9 months in 4 patients).At this time, 4 patients (Imatinib- resistant) received Dasatinib at the dose of 40 mg twice daily (dose reduction due to hematological toxicity); 1 patient (Imatinib cutaneous intolerance in chronic phase) received 140 mg daily. Two patients were in complete cytogenetic response, 2 patients were in partial cytogenetic response (10% and 8.5% Philadelphia positive cells) and obtained a complete cytogenetic response 3 months later, and 1 patient was in minor cytogenetic response. For 2 patients, the presence of trisomy 8 was transient, for 3 patients chromosomal abnormalities were persistent; none showed myelodysplastic changes. At present, all patients are still treated by Dasatinib with the same dosage. Cytogenetic abnormalities occur in Philadelphia negative cells in a fraction of patients with CML treated with Dasatinib. Philadelphia negative abnormal clone can persist despite complete cytogenetic response achievement. Their incidence, etiology and prognosis remain to be clarified and with a short follow-up, no clear clinical consequences can be identified.