bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome after Second Autologous Stem Cell Transplantation as Salvage Therapy in Patients with Relapsed Multiple Myeloma.
Authors: Mikhael Joseph R. , Samiee Sara , Stewart A. Keith , Chen Christine , Trudel Suzanne , Franke Norman , Winter Andrew , Chang Hong , Reece Donna E. 
Published: October 2019

Abstract
Background: Single autologous stem cell transplant (ASCT) is considered the standard of care for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. The role of a second ASCT as salvage therapy is unclear.
Method: Retrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital.
Results: Between March 1992 and August 2004, 28 MM pts received a second ASCT for relapsed MM at our institution. Median age was 57 years (range 39–69) at second transplant. 17 pts were male.
Immunoglobulin subtype included IgG (16), IgA (8), light chain (1), nonsecretory (2) and IgM(1). Median initial albumin was 42g/l (27–48). In 15 patients in whom cytogenetic studies were available, 2 were positive for the 13q deletion.
Transplant conditioning regimen for first transplant was melphalan (MEL) + TBI +/− etoposide (E) in 6, MEL alone in 15 and other regimens in 7 pts. 2nd ASCT conditioning consisted of MEL + TBI +/− E in 2, MEL alone in 25 and BU+CY in 1. Median CD34 counts were 10.96x106/L and 4.85x106/L for 1st and 2nd ASCT respectively.
The median time from diagnosis to first transplant was 9 months (2–74). The median time to relapse after the first transplant was 29 months (6–85), with a median interval between transplants of 39 months (6–99). The median time to progression after the second transplant was 13 months (5–56).
No transplant-related deaths occurred.
At median follow-up after 2nd ASCT of 15 months (1–60), 20 (71%) pts are alive. Twelve pts (43% of all pts) are free of disease progression. The 5-year actuarial progression-free survival (PFS) and overall survival (OS) was 47% and 32%, respectively. Long term progression-free status based on the progression-free interval after 1st transplant is summarized in the following table:
Interval Total number of pts Number of progression-free pts ≤ 12 months 1 0 (0%) 12–24 months 9 3 (33%) ≤ 24 months 18 9 (50%)
Conclusions:
2nd ASCT is a feasible and safe salvage therapy in relapsed MM patients; 2nd ASCT is effective in providing prolonged remission over one year; 2nd ASCT is most effective in patients whose time to progression after 1st ASCT exceeds 24 months.
Sufficient Mobilization of Peripheral Blood Stem Cells by Single Dose Application of Pegylated G-CSF in Patients with Multiple Myeloma, Interim Analysis of a Phase II Study.
Authors: Fruehauf Stefan , Timon Seeger , Buss Eike C. , Topaly Julian , Ho Anthony D. , Goldschmidt Hartmut 
Published: October 2019

Abstract
Autologous peripheral blood stem cell (PBSC) transplantation leads to significant prolongation of survival in patients with multiple myeloma. For PBSC mobilization a combination of myelosuppressive chemotherapy and granulocyte colony stimulating factor (G-CSF) are administered. The optimal application of G-CSF is twice daily. New G-CSF formulations with prolonged half-life carry the promise of reduced patient strain, increased compliance and via continuously high G-CSF serum levels possibly improved PBSC mobilization. We initiated a study with pegfilgrastim-supported mobilization chemotherapy in stage II and III myeloma patients. Patients received up-front treatment with three cycles of vincristin, doxorubicin, dexamethason (VAD) or thalidomide, doxorubicin, dexamethason (TAD).
The mobilization regime consisted of four days chemotherapy with cyclophosphamide 1g/m2 day1, doxorubicin 15mg/m2 day 1-4, dexamethason 40 mg d 1-4 p.o. (CAD) and a single administration of 12 mg pegfilgrastim subcutaneously on day five. To date 17 patients (median age 56, 10 female, 7 male) have received pegfilgrastim and maximum CD34+ cell counts were observed 10-18 days (mean 13 days) after treatment with a range between 24 and 827 (mean: 161) CD34+ cells per μl. 15 patients underwent leukapheresis. In total, 6.6 * 10e6 to 40.5 * 10e6 (mean 15.3 *10e6) CD34+ cells per kilogram body weight were collected. 9 patients achieved the target number of 7.5 * 10e6 CD34+ cells per kilogram body weight during a single apheresis, while 4 patients needed two and 2 patients needed three apheresies on consecutive days. Two patients required additional administration of filgrastim. Two patients received 6 mg pegfilgrastim off study. Both achieved sufficient numbers of CD34+ cells (12.7 and 20.8 * 10e6 CD34+ per kg BW). There were only minimal adverse effects. Four patients reported of bone pain or nausea. Mobilization failures did not occur in this patient population.
On the basis of these first results we conclude that a single dose application of 12 mg pegfilgrastim after CAD treatment leads to sufficient mobilization of CD34+ cells in stage II and III myeloma patients comparable to historical data with filgrastim-supported mobilization chemotherapy.
B Cell Receptor (BCR) Ligation Enhances Cell Survival in Progressive Chronic Lymphocytic Leukemia (CLL).
Authors: Deglesne Pierre-Antoine , Chevallier Natalie , Letestu Remi , Salanoubat Celia , Sanhes Laurence , Nataf Joelle , Varin-Blank Nadine , Ajchenbaum-Cymbalista Florence 
Published: October 2019

Abstract
Recent gene profiling studies demonstrated that signalisation through the BCR plays a central role during CLL disease progression. However, incidence of BCR engagement on cell survival remains unclear as both increased and decreased apoptosis have been reported after BCR ligation by anti-mu antibodies. We investigated the effect of anti-mu exposure on fresh cells from 32 untreated CLL cases. Cell viability was assessed both by MTT assay and Annexin V/ IP labelling. Culture conditions were set after time and dose experiments. A 25% increase of viability, obtained by MTT assay after 72h of culture, was considered as significant. When a coated rabbit anti-human IgH mu specific antibody was used, it significantly prevented apoptosis in 20/32 cases (named responders) and never increased it. On the same CLL cases, soluble goat F(ab’)2 anti-human IgH mu specific antibody increased apoptosis in all but one case. However, coating of this latter antibody to the culture plate cancelled the pro-apoptotic effect and restored cell survival promoting effect in 13/14 cases tested. Unspecific effects were ruled out using control antibodies. Cytometry experiments and confocal microscopy demonstrated that uncoated antibody was rapidly internalized and degraded. In responders cases, enhanced survival was supported by increased expression of early cell cycle protein cyclin D2 and cdk4. There was no subsequent cell cycle progression as shown by IP staining and absence of pRB phosphorylation most likely related to the lack of p27 down regulation. There was a strong correlation between the extent of apoptosis prevention after anti-mu exposure and disease progression. Indeed, the 12 over 32 cases who were found to have no IgVH somatic hypermutations, happened to be all responders. Conversely among the 20 mutated cases, 12/20 were non responders and had a clinically stable disease. As for the 8 responders with somatic mutations, four had detectable levels of ZAP 70 protein and 2 others had a clinically progressive disease. In conclusion, coated anti-mu antibody is likely to mimic in vivo conditions of stimulation, suggesting that BCR ligation could play a major role in the pathophysiology of the progressive disease, giving a survival advantage to these CLL cells
Individualized Once-Daily Dosing of Intravenous Busulfan: A Pharmacokinetic Study in Patients Undergoing Conditioning for Allogeneic Stem Cell Transplantation.
Authors: Kangarloo Shabal B. , Naveed Farrukh , Andersson Borje S. , Quinlan Diana , Russell James A. 
Published: October 2019

Abstract
Background: Busulfan (Bu) given in myeloablative doses is a frequent component of preparative regimens for hematopoietic stem cell transplantation. Variations in the area under the concentration/time curve (AUC) for oral Bu may result in over/under dosing, which may increase the risk of toxicity or reduce efficacy. The availability of an IV formulation of busulfan reduces this by eliminating variability in absorption but inter-patient differences in metabolism remain. A pharmacokinetically guided test dose strategy before the high dose Bu may be used to achieve a specific target AUC.
Purpose: To establish a reliable model to predict a therapeutic dose of IV Bu from a small test dose in order to improve inter-patient variability in AUC.
Methods: Pharmacokinetic (PK) analysis was performed on 35 paired patient samples, comparing a limited sampling test dose to the therapeutic high dose. For the test dose, an AimPlus infusion pump was used to administer 12 mg of IV Bu over a 20-minute infusion on day −6. High dose Bu was given at a dose of 3.2mg/kg daily over 4 hours on days −5 to −2. The test dose PK parameters were compared to the high dose IV Bu PK parameters on day −3. Busulfan concentrations in plasma were determined by UV-HPLC. All concentration-time plasma Bu data were analyzed by non-compartmental analysis using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA).
Results: The mean (CV%) PK parameters for the 12 mg test dose patients were as follows: Cmax, 0.36 ug/mL (30.4%); clearance (CL), 16.3 L/hr (21.4%); volume of distribution Vd, 57.4 L (26.1%); elimination half-life, 2.4 hr (16.1%); and AUC, 199 μM.min (23.6%). The mean (CV%) Cmax, CL, Vd, half-life, and AUC for the once daily high dose were 3.95 ug/mL (22%), 11.7 L/hr (25.4%), 46.3 L (25.3%), 2.8 hr (15.6%), and 5190 μM.min (22.7%) respectively. The range of AUC for the high dose was 2832 to 7354 μM.min. The ratio of the high dose over the test dose required a correction factor “k” of 1.45 to be equivalent to the ratio of the AUC high dose over the AUC test dose.
Conclusion: Dosing based on patient weight results in 2–3 fold variability of AUC. The fact that a correction factor based on the test dose is needed is most likely due to the statistically significantly higher CL of busulfan during the test dose as compared to the high dose CL. This raises questions concerning the proposed linear kinetics of IV busulfan. However using the above correction factor and given a target therapeutic AUC, it is possible to individualize the therapeutic dose for IV busulfan based on this test dose strategy.
Expression of P73 Splice Variants Correlates to Resistance to DNA Damaging Drugs in Childhood T-Lineage Acute Lymphoblastic Leukemia.
Authors: Meier Marrit , Den Boer Monique L. , Meijerink Jules P.P. , Passier Monique , Van Wering Elisabeth R. , Janka-Schaub Gritta E. , Pieters Rob 
Published: October 2019

Abstract
Children with T-lineage Acute Lymphoblastic Leukemia (T-ALL) have a higher relapse-risk and are in-vitro more resistant to therapeutic drugs compared to ALL patients with a precursor-B phenotype. Cellular resistance to anti-cancer agents has previously shown to be associated with failure of P53 family member signaling by abrogation of P53 function due to loss-of-function mutations or dominant-negative inhibition by isoforms of P73 lacking (part of) the N-terminal transactivation domain (P73ΔEX2, P73ΔEX2/3, ΔN-P73 and ΔN’-P73). Since p53 mutations are not commonly found in T-ALL, we investigated the expression levels of p73 splice variants in relation to drug resistance in children with T-ALL. Splice variants were quantitatively measured at the mRNA level in leukemic cells of 55 T-ALL patients and mononuclear cells of 12 non-leukemic controls. TA-p73 (transactivation competent), p73Δex2, p73Δex2/3, ΔN-p73 and ΔN’-p73 were all found to be present at a relatively higher mRNA level in T-ALL patients than controls (P < 0.05 for all), suggesting that expression of the TP73 gene is deregulated in T-ALL. Resistance of T-ALL cells to the DNA damaging drug daunorubicin correlated with mRNA levels of the dominant-negative variants of p73, i.e. ΔN-p73 and ΔN’-p73 (Rs = 0.38, P = 0.03). In contrast, expression of none of the variants, including ΔN-p73 and ΔN’-p73, was related to resistance of T-ALL cells to non-DNA damaging drugs (prednisolone, vincristine and L-asparaginase). In conclusion, high expression of ΔN-p73 and ΔN’-p73 variants possibly contributes to resistance to DNA damaging drugs in childhood T-ALL.
Oncogenic TLS-ERG Fusion Protein Promotes Differentiation of Myeloid Progenitors into Myeloblasts but Blocks Their Terminal Differentiation.
Authors: Zou Junhui , Zielinska-Kwiatkowska Anna , Blackburn Michael L. , Ichikawa Hitoshi , Yang Liu 
Published: October 2019

Abstract
In a subset of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in blast crisis, the TLS (translocation liposarcoma) gene is fused to the ERG (ets-related gene) gene through a recurrent t(16;21) translocation. This chromosomal translocation results in the generation of the TLS-ERG fusion protein. More recently, the same TLS-ERG fusion protein has also been identified in Ewing’s sarcoma in children. To investigate the oncogenic mechanism of TLS-ERG, we stably expressed TLS-ERG or its mutant TLS-ERGΔets in mouse L-G myeloid progenitor cells through retroviral transduction. L-G cells normally proliferate in the presence of IL-3 and undergo terminal differentiation into hypersegmented neutrophils when treated with G-CSF. In contrast, expression of TLS-ERG in L-G cells led to spontaneous differentiation into immature myeloblasts but G-CSF treatment of these cells failed to induce terminal differentiation. L-G myeloblasts harboring TLS-ERG were characterized by high levels of myeloperoxidase (MPO), a phenomenon also observed in immature myeloblasts isolated from human leukemia patients with the t(16;21) translocation. As deletion of the ets DNA-binding domain from TLS-ERG abolished its ability to promote spontaneous myeloblast differentiation or the ability to up-regulate the MPO gene, we further examined how TLS-ERG fusion protein might affect the functions of other regulators such as PU.1, an ets transcription factor known to play a critical role in the differentiation of myeloid progenitors. Though both proteins have similar DNA-binding property, TLS-ERG differs from PU.1 through binding directly to RNA polymerase II as well as through escaping repression by histone modification enzymes. Together, these findings suggest that the TLS-ERG fusion protein can cause blockage of myeloid differentiation by interfering with the gene expression program normally controlled by key regulators.
Single or Tandem Autologous Stem-Cell Transplantation Given According to Prognostic Factors at Relapse for Hodgkin Lymphoma.
Authors: Brice Pauline , Morschhauser Franck , Divine Marine , Ferme Christophe , Salles Gilles 
Published: October 2019

Abstract
Patients with relapsed hodgkin lymphoma (HL)have a different prognostic after high-dose therapy (HDT)according to time to relapse and extend of relapse. From 1995 to 1997, 48 patients with early relapse or refractory HL were included in a pilot study of tandem transplantation to evaluate the feasibility before the protocol. From 1998 to 2002, 200 patients with refractory disease or first relapse of HL were prospectively treated with induction chemotherapy followed by HDT and autologous stem-cell transplantation (ASCT). Patients were stratified in 2 groups according to prognostic factors at relapse: groupe 1 (unfavorable relapse: primary refractory disease or early/disseminated relapse) and group 2 (favorable relapse: patients with either early or disseminated relapse). Induction chemotherapy consisted of ifosfamide/etoposide with doxorubicin (IVA) in 70% of patients or with vinorelbine and mitoguazone (MINE)for the remainings. Group 1, patients received 2 cycles of chemotherapy, PBSC collection and tandem ASCT, with a CBV mitoxantrone (30 mg/m2) and 2 months later cytarabine (6g/m2), melphalan (140mg/m2)with total body irradiation (40%) or busulfan (12 mg/kg) followed by the second ASCT.
Group 2, patients received 3 cycles of chemotherapy, PBSC collection and a BEAM regimen followed by ASCT. Final results, updated, January 2005 are presented with 245 evaluable patients.
Results: after induction chemotherapy overall response rate was at 61% in group 1 and 96% in group 2. In group 1, 70% received the two ASCT, the major reason not to receive the procedure was disease progression after induction chemotherapy (10%) or after the first ASCT (15%), than low stem-cell collection (4%) or toxicity (2%). In group 2, 97% of patients received ASCT and 1 patient received a tandem ASCT for refractory relapse. 5 patients died from toxicity in group1 and none in group2, but 2 secondary leukemia were observed in this group. In intent to treat analysis, at a 3 years median follow-up from the relapse, the EFS was at 45% in group 1 versus 75% in group 2 and the survival at 55% in group 1 versus 80% in group 2. Despite a different consolidation between group 1 and 2, results remained better in group 2. In conclusion, these results confirmed the importance of prognostic factors at relapse of HL.No differences were found in the unfavorable group 1 between refractory patients and early/disseminated relapse. HL patients with adverse prognostic factors (group 1) but responding to second line chemotherapy and eligible for tandem ASCT may benefit from this procedure with an EFS at 70%. The major cause of failure was chemoresistance either at induction or after high-dose therapy.
Killer Cell Immunoglobulin-Like Receptor Genotype and HTLV-1 Associated Disease’s Susceptibilities.
Authors: Obama Kosuke , Furukawa Yoshitaka , Tara Mitsutoshi , Marshall Sara , Levoguer Alison , Saito Mineki , Bangham Charles , Osame Mitsuhiro 
Published: October 2019

Abstract
[Introduction] Natural killer (NK) cells show cytotoxicity against virus-infected cells and some tumor cells. The highly polymorphic killer cell immunoglobulin-like receptors (KIRs) which recognize HLA class 1 molecules play a major role in these cytotoxic activities, and also express on some T-cells. Human T-lymphotrophic virus-1 (HTLV-1) is a caucassive agent for leukemia and some autoimmune diseases. We investigated the correlations between the KIR genotype and susceptibilities to HTLV-1 associated diseases i.e. adult T-cell leukemia (ATL) and HTLV-1 associated myelopathy (HAM).
[Materials and Methods] Fifty six HTLV-1 carriers, fifty one ATL patients and fifty seven HAM patients were recruited in this study. Genotyping of six KIR genes (3DL1, 2DL5, 2DS1, 2DS2, 2DS3 and 3DS1) was performed using PCR amplification with sequence specific primers (Martin et al. J Immunol 2002).
[Results and Conclusion] Frequencies of each KIR and genotype were analysed as described in Table. Genotype means the pattern of positive KIR combinations. Significant differences between carrier vs. HAM in genotype 2 (p=0.01), and ATL vs. HAM in genotype 4 (p=0.01) were observed. Increased frequencies of genotype 3 and 2DS3 allele in HAM compared to carrier were also observed although these tendencies were not statistically significant. These preliminary results suggest that KIR gene polymorphism may play a role in determining susceptibility to HTLV-1 associated diseases.
KIR genetype and HTLV-1 associated diseases Genotype 3DL1 / 2DL5 2DS1 / 2DS2 2DS3 / 3DS1 Carrier (%) * ATL (%) * HAM (%) * * this measns the genotype frequency; Y, positive; N, negative 1 Y / N N / N N / N 51.8 47.1 63.2 2 Y / Y Y / N N / Y 26.8 21.6 8.8 3 Y / Y Y / N Y / Y 1.8 7.8 10.5 4 Y / N N / Y N / N 5.4 11.8 0 5 Y / Y N / Y Y / N 1.8 2.0 7.0 6 N / Y Y / N N / Y 1.8 2.0 3.5 7 Y / Y Y / Y N / Y 1.8 3.9 1.8 Others 8.9 3.9 3.5 Carrier (%) 96.5 / 42.9 39.3 / 16.1 10.7 / 35.7 ATL (%) 96.1 / 41.2 39.2 / 21.6 9.8 / 39.2 HAM (%) 94.7 / 36.8 29.8 / 14.0 22.8 / 28.1
Plasma Brain Natriuretic Peptide, Serum Troponin T and Echocardiographic Evaluation in Children Treated with Doxorubicin*.
Authors: Jackowska Teresa , Wasilewski Robert , Wasik Maria , Golabek Malgorzata , Matysiak Michal 
Published: October 2019

Abstract
Background: Doxorubicin (DOX) is one of the most effective agents in treatment of acute lymphoblastic leukaemia (ALL). However, a potential heart damage caused by DOX in patients who have been cured of ALL may lessen the success of their cure. Plasma brain natriuretic peptide levels and cardiac Troponin T are highly sensitive biochemical markers for myocardial damage.
Objectives of the study: We aimed to measure N-terminal proBNP (8–29) (Nt-proBNP) and serum Troponin T(cTnT) levels in 125 children (98 with ALL after completion of treatment with DOX and 27 healthy children). Median age at diagnosis was 5.5 years.
Methods used: Concentration of plasma N-terminal proBNP was measured in children by enzyme immunoassay (Biomedica). cTnT levels were measured by an electrochemiluminescence immunoassay process (Third generation) on the Elecsys 1010 System (Roche Diagnostic). Echocardiograms were performed by paediatric cardiologists. Using two-dimensional M-mode echocardiography shortening fraction (%SF) and ejection fraction (%EF) were determined as systolic function.
Results: The cumulative DOX doses were 240mg/m2. None of the patients had clinical signs or symptoms of cardiotoxicity. All of the patients had normal systolic function parameters. Mean Nt-proBNP plasma levels were normal − 64 fmol/ml (10.3–597.3 fmol/ml) in all examined children. Mean Nt-proBNP both in ALL patients (63.8 fmol/ml) and in healthy (58.4 fmol/ml) were within the normal range. Out of the 98 patients 45 (46%) had slightly elevated Nt-proBNP levels in comparison with healthy subjects. Nt-proBNP plasma levels were not significantly different in boys (55.8 fmol/mL) in comparison with girls (56.3 fmol/mL. In all patients the serum levels of cTnT were below the detection limit (<0.010 ng/ml).
Conclusion: Our preliminary results suggest that measurement of Nt-proBNP plasma levels is useful in the detection of subclinical left ventricular dysfunction in children with ALL receiving DOX therapy.