bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematological Responses to Megesterol Acetate in Patients with Myelodysplastic Syndrome Involving an Abnormal Chromosome 6.
Authors: Bourg Wilson C. , Launder Theresa M. , Mughal Tariq I. 
Published: October 2019

Abstract
The presence of an abnormal chromosome (chr) 6 often confers a poor prognosis on patients with myelodysplastic syndrome (MDS), particularly therapy related-MDS (t-MDS). We report two patients with MDS and an abnormal chr 6 who achieved significant improvements in their hematological parameters after being subjected to megesterol actetate at 80mg/d; one patient achieved a complete cytogenetic remission, albeit based on a limited study. The first patient, a 73 y female presented with a monocytopenia (thrombocytopenia; 43K/dl), a bone marrow consistent with MDS, blasts 6% and an abnormal chr 6 (sole cytogenetic abnormality) in February 2003. In July 2005 she was asymptomatic with a platelet count of 353K/dl and is due to have cytogenetics shortly. The second patient, a 72 y female presented in December 2004 with trilineage cytopenias, a bone marrow consistent with MDS and a complex karyotype, including an abnormal chr 2, 5, 6, 7 & 16. She had had a history of primary (essential) thrombocythemia of 25 y duration and had received P 32 and intermittent courses of hydroxyurea and was on hydroxyurea at the penultimate presentation and probably had t-MDS. This therapy was promptly discontinued and megesteral acetate commenced at 80mg/d. In July 2005 her hematological parameters had improved significantly (W 3.3K/dl; Hb 11.3g/dl;Platelets 135K/dl); her bone marrow remained hypercellular with reticulin fibrosis and cytogenetic studies revealed a 46XX kayotype in a limited sample. At the time of this report, both patients remain well on megesterol acetate with normal or near normal hematological parameters. MDS is a heterogeneous stem cell disorder and hematological and possible cytogenetic responses are noteworthy. The patient with the sole abnormal chr 6 has remained in hematological remission for over 18 months; the second patient with the complex karyotype is also, remarkably, maintaining near normal hematological parameters. We speculate that megesterol acetate, a relatively inexpensive progestational agent with a defined palce in the management of malignancy-related anorexia may have a role in selected patients with MDS. Updated observations and suggested hypotheses will be presented.
Velcade an Active Agent for Multiple Myeloma Patients. Experience of a Single Center.
Authors: Petrucci Maria Teresa , Martini Vincenza , Gallucci Cristiano , Finolezzi Erica , Levi Anna , Del Bianco Patrizia , Mandelli Franco , Foà Robert 
Published: October 2019

Abstract
Velcade (PS-341, Bortezemib), a proteasome inhibitor, has recently been approved for the treatment of relapsed and refractory multiple myeloma (MM). We hereby report the results obtained using this new drug at our center. Between April 2003 and December 2004 we treated 23 patients with MM. The patient population consists of 13 males and 10 females, with a median age of 53 years (range 32–72); 16 were IgG MM, 6 IgA, 1 light chain. All patients were in stage III of their disease, with a median time of observation (from diagnosis to Velcade therapy) of 59 months (range 11–120), were pretreated with at least two lines of therapies and were refractory or in relapse after the last treatment. Velcade 1.3 mg/m2 was scheduled on days 1, 4, 8 and 11 of a 21-day treatment cycle for 8 cycles according to the tolerability and response. All cycles were delivered in day hospital. A median of 6 cycles (range 3–8) were administered to the overall population. Eleven patients concluded their program, while 12 discontinued the treatment: 1 because she received an allogeneic stem cell transplantation, 7 for adverse events and 4 due to disease progression. In this heavily pretreated population, our primary end point was to obtain a decline in the monoclonal component (MC) of at least 25%. All patients were considered evaluable for response because treated with at least 3 cycles of therapy. Thirteen patients responded to treatment: 1 (4%) obtained a disappearance of the MC, 4 (17%) achieved a reduction of the MC level >75% and 8 (34%) >50%. Six further patients (26%) obtained a decline in the MC <25%. The median number of cycles required to achieve a response was 3 (range 1–8) and the median duration of response was 6 months, with 8 patients presently still responsive. Among the responding patients, 5 relapsed and 4 of them have died due to disease progression. Among the 4 patients (17%) who did not respond to Velcade, 1 died. The majority of adverse events, which resolved with the discontinuation of treatment, were nausea, vomiting, diarrhea, fatigue, thrombocytopenia and peripheral neuropathy. Taking into consideration the very poor prognostic likelihood of our patients, this study adds further evidence con the efficacy of this new drug in MM. Velcade can be considered an effective anti-myeloma drug even though its toxicity must be taken into account in designing new clinical trials.
Identification of RPS14 as the 5q-Syndrome Gene by RNA Interference Screen.
Authors: Ebert Benjamin L. , Pretz Jennifer , Bosco Jocelyn , Chang Cindy Y. , Tamayo Pablo , Galili Naomi , Raza Azra , Root David , Attar Eyal , Ellis Steven R. , Golub Todd R. 
Published: October 2019

Abstract
We report here that haploinsufficiency of the ribosomal protein encoding RPS14 gene causes the characteristic hematologic phenotype that defines the 5q- syndrome. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), was first described in 1974 as a distinct clinical entity associated with deletions of the long arm of chromosome 5. Since that time, the common deleted region has been narrowed in search of the causal gene within the region. However, no biallelic inactivation events have been identified for any of the 41 genes within the critical region, suggesting that a haploinsufficiency mechanism may explain the disease phenotype. We addressed this question through a functional genomic approach, utilizing systematic RNA interference (RNAi) to interrogate the function of each gene in the common deleted region. We introduced 3–5 unique, lentivirally expressed short hairpin RNAs (shRNAs) targeting each of the 41 genes in the region into normal CD34+ human bone marrow hematopoietic progenitor cells and assayed the effects of each shRNA on hematopoietic differentiation. We found that knock-down of a single gene, RPS14, recapitulated the phenotype of the 5q- syndrome: namely, a block in erythroid differentiation (leading to erythroid cell apoptosis) with relative preservation of megakaryocyte differentiation as measured by FACS analysis. Importantly, forced expression of an RPS14 cDNA in primary bone marrow cells from patients with the 5q- syndrome rescued the phenotype, yet had no effect on cells from MDS patients without 5q deletions. In addition, we found that RPS14 haploinsufficiency caused a block in the processing of pre-ribosomal RNA and in the formation of the 40S ribosomal subunit. This ribosomal processing defect is highly analogous to the functional defect seen in Diamond Blackfan Anemia (also characterized by an erythroid differentiation defect and predisposition to AML), thereby establishing an unexpected link between the molecular pathophysiology of acquired 5q- syndrome and congenital bone marrow failure syndromes. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function, highlighting the importance of translational control in hematologic malignancy. The results further suggest that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.
PHA-739358, an Aurora Kinase Inhibitor, Induces Clinical Responses in Chronic Myeloid Leukemia Harboring T315I Mutations of BCR-ABL.
Authors: Paquette Ronald L. , Shah Neil P. , Sawyers Charles L. , Martinelli Giovanni , John Nicoll , Chalukya Meenal , Rocchetti Maurizio , Fiocchi Carina , Comis Sylvia , Capolongo Laura , Laffranchi Bernard 
Published: October 2019

Abstract
Background. The T315I BCR-ABL mutation confers high level resistance to clinically available ABL kinase inhibitors (i.e., imatinib, nilotinib, dasatinib, bosutinib, INNO-406). PHA-739358 is an aurora kinase inhibitor that selectively inhibits the ATP site of Aurora-A, Aurora-B and Aurora-C kinases, and binds with high affinity to both wild type Abl and Abl/T315I in vitro. A multicenter phase II study of PHA-739358 is being conducted in patients with chronic myeloid leukemia (CML) relapsing on imatinib or other c-ABL therapy.
Methods. Seven consenting CML patients (1 in chronic phase, 1 in accelerated phase, 5 in blast phase) were initially entered in this trial and received PHA-739358 dosed at 250 or 330 mg/m2/day administered by a once-weekly 6-hour infusion for 3 consecutive weeks, every 4 weeks. Six out of seven patients had the BCR-ABL T315I mutation. Pharmacokinetic and pharmacodynamic (PD) samples were collected and analyzed during cycle 1. The PD analyses evaluated BCR-ABL inhibition (phospho-CRKL) and Aurora kinase inhibition (phospho-histone H3).
Results. Two patients with T315I mutated BCR-ABL achieved a complete hematologic response (CHR) to PHA-739358. One of these patients treated in accelerated phase achieved a complete cytogenetic response (CCyR) and a complete molecular response after 3 months on the 330 mg/m2 dose level. The CCyR is ongoing after 6 months of treatment. The second patient who achieved a CHR initiated therapy in chronic phase. A minor cytogenetic response was achieved after 3 cycles of therapy at the 330 mg/m2, and a minimal cytogenetic response persists after nine months of treatment. Uncomplicated grade 4 neutropenia and an infusion-related reaction requiring acetaminophen, benadryl and hydrocortisone premedication was observed in one patient. No other grade 3/4 non-hematologic toxicity was observed. Patients with blast crisis did not have CHRs at the dose and schedule employed, although suppression of peripheral blood blasts was evident. PHA-739358 pharmacokinetics were in good agreement with those observed in other phase I - II studies. Average exposure, AUC0-t(168h), observed at 330 mg/m2/day was about 45 uM/h with Cmax values around 4 – 6 uM/h. Pharmacodynamic analyses demonstrated treatment-associated decreases of CRKL phosphorylation in 6 out of 7 patients, including both responders. Modulation of histone H3 phosphorylation was observed in 3 of 5 evaluable patients.
Conclusions. Objective clinical responses to PHA-739358 have been observed in two CML patients with T315I mutations of BCR-ABL, with an acceptable tolerability and safety profile. Additional doses and schedules of PHA-739358 are being investigated in patients with advanced phase CML.
The Predictive Value of Gene Expression Profiles for Acute Graft-Versus-Host Disease after Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning for Hematological Malignancy.
Authors: Masmas Tania N. , Friis-Hansen Lennart , Johansen Jens Vilstrup , Petersen Soren Lykke , Kornblit Brian T. , Winther Ole , Nielsen Finn Cilius , Vindelov Lars 
Published: October 2019

Abstract
Purpose: To test the hypothesis that global gene expression profiles of peripheral blood mononuclear cells (PBMNC) day +14 after hematopoietic cell transplantation with nonmyeloablative conditioning could predict the later occurrence of acute graft-versus-host disease (GVHD) grade II–IV.
Material: Between March 2000 and Marts 2006, 100 patients with hematological malignancies received peripheral blood stem cells from an human leukocyte antigen identical sibling/mother donor or from a matched unrelated donor following nonmyeloablative conditioning with low dose fludarabine and 2 Gy of total body irradiation. Post-transplant immunosuppression consisted of cyclosporine and mycophenolate mofetil. Only patients with sustained engraftment, who did not experience late-onset acute GVHD after day +100 were included; eight patients were excluded due to graft rejection, three patients due to suboptimal RNA or lacking PBMNC samples, and further 15 patients due to late-onset acute GVHD. Seventy-four patients were then eligible for microarray analysis.
Methods: RNA was precipitated from frozen PBMNC from day +14 post-transplant and gene profiling analyses were performed using Human Genome U133 Plus 2.0 GeneChip Array. The array data were normalized, RMA modelled and asinh transformed in R. The differentially regulated gene expression between the group of patients developing acute GVHD before day +40, +56 and +84 post-transplant compared to the patients never experiencing acute GVHD was identified and formed the basis for the subsequent principal component analysis (PCA) and classifying models. No patients experienced acute GVHD between day +85 and +100 post-transplant.
Results: The patients experiencing acute GVHD by different time points were separated from the patients never experiencing acute GVHD by the PCA plot. Furthermore the classifying models could separate the groups correctly in up to 93% of cases in the best of the classifying model. In addition, differentially regulated genes between the two groups were identified.
Conclusion: These data suggest that the pattern of gene expression profiles early post-transplant is able to predict patients with a high risk of later occurrence of acute GVHD from those never experiencing acute GVHD. This knowledge could be exploited to increase the immunosupression and thus prevent acute GVHD in patients at risk. Furthermore, candidate genes of interest for the pathogenesis of acute GVHD have been identified.
Impact of FLT3 Internal Tandem Duplication (FLT3/ITD) on the Outcome of HLA-Identical Sibling Hematopoietic Transplantation for Adult Acute Myeloid Leukemia (AML) in First Remission: Substantial Probability of Leukemia-Free Survival Despite Increased Relapse Risk. A Retrospective Analysis of the EBMT-ALWP.
Authors: Brunet Salut , Labopin Myriam , Cornelissen Jan J. , Socié Gérard , Iori Ana Paola , Verdonck Leo F. , Ruutu Tapani , Gratwohl Alois , Harousseau Jean-Luc , Sierra Jorge , Rocha Vanderson 
Published: October 2019

Abstract
The prognosis of patients with AML and FLT3 internal tandem duplication (FLT3/ITD) is poor. It is unclear whether this mutation has impact on the outcome of allogeneic stem cell transplantation (Allo-SCT) for AML. Different cooperative groups have obtained controversial results. For this reason, registry data including large numbers of patients are of interest. We analysed the predictive value of FLT3/ITD on relapse incidence (RI), non-relapse mortality (NRM) and leukemia-free survival (LFS) in patients with AML in 1st CR who underwent a myeloablative allo-SCT from HLA-identical siblings and were reported to the EBMT. The series included 682 patients, 610 negative ITD/FLT3 and 72 FLT3/ITD positive reported between 1998 and 2007 with a median follow up time of 24 and 11 months, respectively. No significant differences were observed between the two groups regarding gender, median age (38 vs 40 yrs), FAB classification, cytogenetic distribution, number of induction courses to achieve CR, interval diagnosis to transplant (134 vs 133 days), source of stem cells (PB or BM) and CMV serostatus. In contrast, patients with FLT3/ITD had higher leukocyte counts at diagnosis (14 vs 65 × 109/L, p<0.0001), were transplanted with T-cell replete progenitors (78% vs 97%, p<0.0001) and more frequently a female donor to male recipient (yes: 31% vs 20%, p=0.04). Univariate (Table1) and multivariate analyses demonstrated the adverse impact of FLT3/ITD for LFS (HR 0.56, p=0.009) and relapse incidence (HR=2.9, p<0.001) but not for NRM (p=0.83). It is remarkable, however, 53% of FLT3/ITD positive patients transplanted for AML in first CR remain alive and disease-free at 2 years. Other independent prognostic factors for LFS and relapse were: T-cell depleted graft, poor cytogenetics and more than one induction course to achieve first CR. For NRM the only prognostic factor was age ≥ 45 years (HR=1.9, p=0.004). In summary, this analysis shows an adverse impact of FLT3/ITD on transplantation outcome. Despite this finding, half of FLT3/ITD positive AML patients in first CR remain disease-free at 2 years, a proportion that seems higher than with other treatment options.
Table 1. Two years outcomes of HSCT in adults patients with AML in CR1 according to the presence of FLT3/ITD. LFS Relapse NRM FLT3/ITD+ (n=70) 53±7% 36±7% 17±7% FLT3/ITD-(n=610) 64±2% 20±2% 19±2% P (log rank test) P=0.06 P<0.0001 P=0.49
Allogeneic Stem Cell Transplantation Can Be an Effective Post-Remission Strategy for Acute Myeloid Leukemia Patients Aged Less Than 60 Years with Core Binding Factor: A Nation-Wide Retrospective Study in Korea.
Authors: Shin Ho-Jin , Chung Joo Seop , Kim Hyioung-Joon , Sohn Sang Kyun , Min Yoo Hong , Won Jong-Ho , Kim Inho , Lee Je-Hwan , Lee Jae Hoon , Jung Chul Won , Ahn Jin Seok , Lee Kyoo-Hyung , Joo Young Don 
Published: October 2019

Abstract
High-dose cytarabine (HDAC)-based postremission therapy has been generally considered to be more beneficial than allogeneic stem cell transplantation (alloSCT) for AML patients with core binding factor (CBF). However, advancements in methods and supportive care in SCT over decades have led to gradual improvement in the treatment-related mortality rate after alloSCT. Therefore, it could be considered that alloSCT after the first CR in AML with CBF patients may show better results than HDAC chemotherapy alone compared with past. We conducted a retrospective study in 169 patients with CBF AML aged less than 60 years collected in 18 institutions in Korea between 1994 and 2006, with comparing alloSCT (n= 60), autoSCT (n= 31) and HDAC chemotherapy (n= 78) as postremission therapy during first remission. With a median follow-up of 46 months, the probability of disease-free survival (DFS) and overall survival (OS) rates at 5 years were 67.8% and 66.6%, retrospectively. AlloSCT (83.1% ± 5.2%) shows a significantly improved 5-year probability of DFS over autoSCT (59.9% ± 9.6%) or HDAC (60.8% ± 6.2%; p=0.048). There was no differences in 5-year probability of OS from complete remission (CR) between 3 treatment arms. In comparison of DFS and OS according to period of enrollment of patients, 4-year probability of DFS or OS of the three groups prior to 2003 was not different, nonetheless, after 2003, 4-year probability of DFS was better in the group underwent alloSCT in comparison with the group without performing it (86.8% vs 70.0%; p=0.035), and in the group underwent SCT (alloSCT plus autoSCT) in comparison with the group without performing it (89.0% vs 67.3%; p=0.047). 4-year probability of OS has a tendency to be improved slightly in the group underwent SCT than the group without performing it (89.0% vs 67.3%; p=0.08). In comparison with prior to 2003, cumulative treatment-related mortality and relapse risk of alloSCT after 2003 was decreased to 13.5% vs 6.7% and 26.2% vs 6.9%, respectively, and depending on the result, 4-year probability of DFS and OS of the alloSCT showed the improvement from 73.9% and 63.3% prior to 2003 to 93.1% and 90.0% after 2003, respectively. This study has the limitation of retrospective study, nonetheless, it could suggest the possibility that alloSCT as a postremission therapy in AML with CBF patients after the first CR may be appropriate if a HLA matched sibling donor were available.
Description of a Large Duplication in F8 Gene Responsible for Severe Hemophilia A.
Authors: Vinciguerra Christine , Goudemand Jenny , Zawadzki Christophe , Pellecchia Dorothee , Negrier Claude 
Published: October 2019

Abstract
Hemophilia A is a common inherited bleeding disorder, caused by factor VIII (FVIII) deficiency as a result of mutations in the factor VIII gene (F8 gene). Intron 1 and 22 inversions, small insertions/deletions and point mutations are the most common genetic defects responsible for severe hemophilia A. However, a F8 gene mutation is not found in 2–5% of patients with severe hemophilia A (FVIII:C<1IU/dL). Large rearrangements are frequent in other genetic disorders and only one case of exon 13 duplication was described in a patient with mild hemophilia (Casula et al, Blood 1990). We described here a large duplication in F8 gene in a CRM− patient with severe hemophilia A: (FVIII:C < 1 UI/dL, FVIII:Ag < 1%) who developed a high-titer inhibitor (peak 10 BU). A previous investigation did not find intron 1 and 22 inversion or exons /splice sites sequencing abnormalities. The promoter region was also sequenced, but no genetic mutation was then characterized. The duplication was detected by MP/LC (Multiplex PCR/Liquid chromatography) which is a quantitative method able to detect large rearrangements. Initially described by Dehainault et al (Nucl Acids Res 2004) in retinoblastoma patients, this method showed that a duplication affected a large part of F8 gene, e.g. the 3′ part of intron 10, exons 11 to 14 and a part of intron 14. To our knowledge, this is the first duplication responsible for severe hemophila A described so far. This finding suggests that the detection of large rearrangements with quantitative method as MP/LC, QMPSF or MLPA would be useful in hemophilic patients where the screening for inversions or genetic events in the coding regions are unsuccessful. This kind of large gene modifications may indeed account for at least some of the 2–5% cases where the coding sequence does not appeared to be altered. In this case, the truncation of the primary polypeptide sequence did not result in any secretion of the FVIII protein, that may have increased the risk of inhibitor development.
Decreased Bone Mineral Density among Patients with Hemophilia.
Authors: Gerstner Gregory , Damiano Mary Lou , Tom Angela , Worman Christina , Schultz Wendy , Recht Michael , Stopeck Alison T. 
Published: October 2019

Abstract
Background: Osteoporosis among adult males is a major and under-recognized problem in the United States. Patients with hemophilia have several predisposing risks for developing decreased bone mineral density (BMD) and osteoporosis, and may represent an important group to target for screening and treatment for fracture prevention.
Patients and Methods: Patients over the age of 18 with moderate or severe hemophilia A or B (as defined by factor activity < 5%) and no history of prophylactic factor use prior to age 10 were eligible. Bone mineral densities were obtained using DEXA scans (DXA) along with measurements of joint mobility and physical activity and laboratory parameters.
Results: Twenty-eight patients have been consented with accrual ongoing. 21 have undergone DXA scans. Median age of 39 (range 18–61), 86% HCV positive, 26% HIV positive. Median T-score for all sites (lumbar, femoral neck, hip, and other) was −1.7 (−5.8–0.6), with the most effected area being the femoral neck, T-score −1.7 (−5.8–0.8). Based on WHO criteria, 76% of patients had decreased BMD, 33% (n=7) with osteoporosis, and 43% (n=9) with osteopenia. Trends associated with decreased BMD included decreased serum 25-hydroxy-vitamin D levels, increased alkaline phosphatase, and decreased weight. All patients with osteoporosis were HCV positive, and all HIV positive patients had decreased BMD. Median activity scores were lower among osteoporotic patients vs normal BMD. Joint range-of-motion in the lower extremities was limited to 59.5% of predicted values in patients with osteoporosis, 84% in osteopenia, and 93% in patients with normal BMD.
Summary: Patients with hemophilia are at markedly increased risk for developing osteoporosis and osteopenia. Potential predictors of risk for decreased BMD are concurrent HCV and HIV infection, low vitamin D levels, elevated alkaline phosphatase, lower weight, decreased range of motion and lower activity scores. More aggressive screening for decreased BMD among moderate and severe hemophilia patients with initiation of therapy is appropriate.
Median Values Worst T-Score Activity Score (1–5) Joint ROM (% Pred) Weight (kg) 25-Hydroxy-D (ng/mL) Alk Phos (IU/L) Normal BMD 0.1 5 94.0 91.6 28.0 59 Osteopenia −1.6 4 85.0 80.7 23.0 86 Osteoporosis −3.0 3 68.5 73.0 21.8 99