bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.
Authors: Cortes Jorge , Talpaz Moshe , O’Brien Susan , Garcia-Manero Guillermo , Ravandi-Kashami Farhad , Giles Francis , Faderl Stefan , Wierda William , Shan Jianqin , Rios Mary Beth , Kantarjian Hagop 
Published: April 2020

Abstract
When treated with imatinib, pts with CML in AP have a hematologic response rate of over 80%, and 25% achieve a major cytogenetic (CG) response. These results are superior to any other therapy available and have established imatinib as the standard of care for AP CML. However, a survival benefit was not defined in these single-arm studies. With longer follow-up of pts in AP treated with imatinib, we investigated whether imatinib therapy led to a survival advantage over other therapies that have been used for this disease. For this analysis, AP was defined as the presence of any of the following: blasts ≥15%, blasts + promyelocytes ≥30%, basophils ≥20%, platelets (plts) &lt;100 x109/L unrelated to therapy, or clonal evolution. Since 1982, 395 pts with AP have been treated at MDACC: 177 (45%) with imatinib and 218 (55%) with other therapies including IFN-α-based therapy (n=102), homoharringtonine (n=36), decitabine (n=47), daunorubicin + ara −C (n=24), or others (n=9). The rate of complete hematologic response was 82% with imatinib and 38% with others (p &lt; 0.0001), and major cytogenetic response was 48% and 13%, respectively (p &lt;0.0001). The median follow-up is 41 months (mo) (range, 3 – 206): 38 mo (3 to 63) for the imatinib group and 82 mo (3 to 206) for the others. A total of 249 pts have died: 67 in the imatinib cohort and 182 in the control group. The median survival was 21 months for the control group, and has not been reached for the imatinib cohort (estimated rate 53% at 3 yrs). Clinical characteristics adversely affecting survival (p&lt;0.05) included time from diagnosis to treatment &gt;36 mo, splenomegaly, Hgb &lt;10 g/dl, plts &lt;100 x109/L, peripheral or marrow blasts ≥5%, marrow basophils &gt;5%, blasts + promyelocytes &gt;5%, clonal evolution, and treatment with imatinib. Pts treated with imatinib were older, but had fewer pts with splenomegaly, high blasts or clonal evolution than the control group. By multivariate analysis, the independent pre-treatment characteristics associated with survival (p&lt;0.05) were splenomegaly, anemia, presence of peripheral blood blasts, and disease duration &gt;1 yr. After adjusting for these differences in a multivariate analysis, treatment with imatinib was the most significant prognostic factor associated with improved survival (p&lt;0.0001). We conclude that treatment with imatinib has changed the natural history of AP CML with an expected median survival in excess of 3 years.
Outcome of Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia. A Comparison of Cyclophosphamide and Total Body Irradiation Versus VP16 and Total Body Irradiation Conditioning Regimens.
Authors: Gassas Adam , Sung Lillian , Saunders Fred , Doyle John 
Published: April 2020

Abstract
Stem cell transplantation (SCT) has become the standard therapy for children with relapsed acute lymphoblastic leukemia (ALL) or certain high-risk features at diagnosis. The authors report their experience with SCT for 108 children with ALL conditioned with 2 different regimens over 14 years period. Children (0–18y) who received fully matched-related (MRD) or fully matched-unrelated (MUD) for a diagnosis of ALL in the Hospital for Sick Children, Toronto between 1990–1998 were conditioned with a single dose of VP16 (60mg/kg infused over 4 hours) and fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (VP/TBI). Between 1998–2003, children with ALL were conditioned with cyclophosphamide 50mg/kg infused over 1 hour daily for 4 days followed by fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (CY/TBI). All children received cyclosporine A and a short course of methotrexate for graft versus host disease (GVHD) prophylaxis.
Results: Sixty-two children with ALL were conditioned with VP16/TBI, 36 MRD transplantation and 26 MUD transplantation. Median age at SCT was 9.4y (range 0.8–19.4). Remissions status at SCT were; complete remission (CR) 1 (n=17), CR 2 (n=32), and CR 3 (n=12) and one patient received SCT in relapse. Forty-six patients were conditioned with CY/TBI, 23 MRD transplantation and 23 MUD transplantation. Median age at SCT was 9.2y (range 1–17.5) Remissions status at SCT time were; CR 1 (n=11), CR 2 (n=29), and CR 3 (n=6). Neutrophils engraftment (defined as absolute neutrophil count (ANC) of &gt; 0.5 x 109/l for 2 consecutive days) occurred at 19d (range 10–28d) and 17d (range 10–28d) for the VP16/TBI and the CY/TBI groups, respectively. Two patients failed to engraft in the VP16/TBI group, one required re- conditioning with cyclophosphamide and ATG and a second dose of stem cells from the same donor, the other patient sustained a fatal intracranial hemorrhage. There was no significant difference in three years event free survival (EFS) and overall survival (OS) between the groups with EFS and OS of 47 ± 7%, 55 ± 7% for the VP16/TBI and 51 ± 8%, 53 ± 8% for the CY/TBI group. There was no significant difference in the incidence of acute or chronic graft versus host disease (GVHD), transplant related mortality (TRM) between the 2 groups.
Conclusion: Both VP16/TBI and CY/TB regimen are equally effective preparative regimens for SCT in pediatric ALL.
Imatinib’s Potential Effects on Fertility, Immunity and Pulmonary Function: A Prospective Study in Patients with Previously Untreated CML.
Authors: Seymour John Francis , Grigg Andrew , Reynolds John , Matthews Jane , Schwarer Anthony P. , Herrmann Richard , Taylor Kerry McDonald , Hertzberg Mark S. , Mills Anthony , Guzzo-Pernell Nancy , Copeman Michael , Lynch Kevin , Hughes Timothy 
Published: April 2020

Abstract
Imatinib therapy was rapidly introduced for CML because of its efficacy and tolerability, so ongoing scrutiny is warranted to elucidate any effects not seen in registration trials. Imatinib strongly inhibits several tyrosine kinases (abl, arg, kit, and pdgfr’s) with functions in normal tissues. Mice lacking these genes have impaired male fertility (abl or kit knockouts), B- and T- cell lymphopenia (abl), emphysema (pdgf) and glomerular dysfunction (pdgf). Hence, we prospectively analysed chronic-phase CML patients on higher-dose imatinib (Hughes TP et al. Abstract #95 ASH 2003) for fertility, immunoglobulin levels, lymphocyte sub-sets and pulmonary function over 1 year. 39/103 patients participated in the safety sub-study, with median age 50 (range 28–75), on median daily imatinib doses of 558–575mg.
In 20 males tested, median serum testosterone (in nmol/L) changed little, from 12.8 at baseline to 14.7 at 6 months, to 11.4 at 1 year (Wilcoxon p=0.05). Serum LH, FSH and oestradiol were unchanged. Only 2 patients had repeat sperm counts: one recovered from azoospermia to have low counts; the other had normal counts at baseline and 6 months. In 20 females, there were no changes in median serum progesterone, oestradiol or LH. FSH (in U/L) fell from 25 to 5 at 6 months, but rose to 21 at 1 year (p=0.03). Median serum IgG levels (in g/L; n=34) fell from 10.5 to 9.8 at 6 months, to 8.6 at 1 year (p&lt;0.0001). Serum IgM (in g/L) also fell from 1.4 to 0.8 at 6 months, to 0.9 at 1 year (p=0.0003). Serum IgA declined from 1.6 to 1.5g/L (p=0.002). There were no consistent changes in median B−, NK− or CD8+ T-cell counts (n=26). T-cell counts declined, with falls in CD4+ cells (x10^9/L) from 1.0 to 0.7 at 6 months, to 0.6 at 1 year (p=0.003). 3 of 39 patients had Grade 3–4 infections; in all 3, lower IgM’s were noted (with one below normal) at 6 months; in one case IgG and IgA also fell below normal. Pulmonary function tests (n=32) showed no consistent changes. Median FEV1 (in L) fell from 3.64 to 3.22 at 6 months (p=0.03), but rose to 3.52 at 1 year. Vital Capacity (in L) also fell from 4.89 to 4.12 at 6 months (p=0.02), but rose to 4.60 at 1 year. DLCO improved marginally. PEFR (in L/sec) trended down from 8.79 to 7.37 at 6 months, to 7.68 at 1 year. There was no evidence of glomerular dysfunction, measured by 24-hour urinary protein. In summary, in patients with chronic-phase CML treated with imatinib at a median dose of ~600mg/day for 1 year, changes in hormonal, immune and pulmonary parameters were recorded. Declines in serum IgG and IgM were highly significant, but were not associated with lower B-cell numbers. These data reveal novel and potentially clinically relevant effects in CML patients on imatinib.
Treosulfan/Fludarabine - a Low Toxicity but Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.
Authors: Holowiecki Jerzy , Giebel Sebastian , Wojnar Jerzy , Krawczyk-Kulis Malgorzata , Wylezol Iwona , Kruzel Tomasz , Markiewicz Miroslaw 
Published: April 2020

Abstract
Although allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only treatment of proved long-term efficacy in chronic myeloid leukemia (CML), high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome.
In a series of 13 CML patients (age 35, range 16–52 years) we introduced a novel myeloablative conditioning regimen consisting of Treosulfan (alkylyting agent, soluble Busulfan-derivative) 14 g/m2/d. on days −6, −5, −4, Fludarabine 30 mg/m2/d on days −5, −4, −3, −2, −1, and, in case of unrelated donor transplants (URD-HSCT), anti-thymocyte globulin (Thymoglobulin) at a total dose of 6 mg/kg. Twelve patients were in the 1st chronic phase, one - in 2nd chronic phase. Median disease prior to alloHSCT equaled 10 (6–90) months. 8 patients were given transplant from an unrelated donor, 5 - from HLA identical sibling. GVHD prophylaxis consisted of cyclosporin A and short-course Methotrexate.
All patients engrafted after a period of absolute agranulocytosis. Median time to neutrophil recovery &gt;0.5 G/L was 24 (13–42) days, and to PLT &gt;50 G/L - 21 (13–38) days. 1/13 patient experienced grade 3 mucositis; no severe neutropenic infection nor hepatic toxicity was observed. None of the patients developed grade III–IV acute GVHD, 1/13 patient experienced grade II acute GVHD. One patient died of EBV-related lymphoproliferative disease; the cumulative incidence of transplant-related mortality at 1 year equaled 8% (1/13).
11/13 patients achieved complete molecular remission and complete donor chimerism within 100 days after alloHSCT. The remaining two patients required immunosuppression taper and additional interferone treatment. The probability of current disease-free survival at one year equaled 92%. We conclude that Treosulfan/Fludarabine +/− ATG myeloablative conditioning is characterized by reduced toxicity and low incidence of acute GVHD. This together with high anti-leukemic efficacy makes the regimen feasible in CML patients.
Experience with Epidural Anesthesia in Pregnant Women with Von Willebrand Disease.
Authors: Varughese Jay , Cohen Alice J. 
Published: April 2020

Abstract
Von Willebrand Disease (vWD) is an autosomal dominant inherited bleeding disorder that is characterized by epistaxis, mucosal and postoperative bleeding, menorrhagia and postpartum hemorrhage. In particular, there is a paucity of safety data for, and thus a reluctance to use, epidural anesthesia (EA) for delivery. We thus conducted a review of all women followed with vWD in a referral hemophilia clinic who had ≥ 1 pregnancy. Thirty-three subjects were screened; 31/33 (94%) had type 1 and 2/33 (6%) had type 2A vWD. There were 59 term pregnancies (range 1–3 per patient), and 5 fetal losses (in 4 patients). Of the term pregnancies, 16/59 (27%) were delivered by Caesarian Section (C-Section), complicated by postpartum hemorrhage in 3 (19%); 43/59 (73%) were delivered by normal spontaneous vaginal delivery (NSVD), complicated by hemorrhage in 21 (49%) (p=0.05). EA was administered during 14 (13 with type 1 vWD) of 59 (24%) of the deliveries, all without DDAVP, plama-derived factor VIII-von Willebrand factor containing concentrates or blood products, and in no patient were bleeding complications encountered at the site of EA nor were there any neurologic complications. Conclusion: Postpartum hemorrhage was a common complication in patients with vWD, more after NSVD than C-Section. In a selected subset, EA was safely administered without bleeding complications, possibly due to pregnancy induced increase in factor VIII:C and von Willebrand factor activity counteracting the tendency to bleed. Larger series and prospective studies should be performed to confirm the safety of EA and the relationship to coagulation factor levels in pregnant women with vWD.
Efficacy and Safety of the Gardos Channel Inhibitor, ICA-17043, in Patients with Sickle Cell Anemia.
Authors: Ataga Kenneth I. , DeCastro Laura M. , Swerdlow Paul , Saunthararajah Yogen , Smith Wally ,   The ICA-17043 Study Investigators6
Published: April 2020

Abstract
The rate and extent of hemoglobin S (HbS) polymer formation in the circulating sickle erythrocyte (RBC) is strongly influenced by the intracellular concentration of HbS. ICA-17043 (bis(4-fluorophenyl)phenyl acetamide) is a novel Gardos channel inhibitor that specifically blocks Ca++-dependent K+ efflux from the human RBC. By limiting the loss of K+, Cl−, and water, this drug preserves the hydration status of the RBC, prevents increases in HbS concentration and thereby inhibits HbS-polymerization. We hypothesized that ICA-17043 could decrease both the hemolytic rate and vaso-occlusive complications of sickle cell anemia (SCA). In a recently completed multicenter, parallel-group, randomized, double-blind, dose-range-finding study, we examined the efficacy and safety of ICA-17043 in patients with SCA. In this 12-week study, 90 patients were randomized into 3 arms: placebo; low dose ICA-17043 (6 mg); and high dose ICA-17043 (10 mg). The primary outcome variable was the change in hemoglobin (Hb) from baseline to the end of the study. A total of 90 subjects were enrolled in this study, 80 of whom completed the 12-week treatment period. Using an intent-to-treat analysis, we found a significant increase from baseline of the total Hb when the subjects in the high dose arm (0.68 ± 0.11 g/dL, S.E.) were compared to those in the placebo arm (0.01 ± 0.12 g/dL), p &lt; 0.001. Although an increase in Hb was also seen in the subjects in the low dose arm (0.28 ± 0.15 g/dL), this smaller change failed to reach statistical significance.
Figure Figure
In addition to the increase in Hb (as well as similar increases in hematocrit and RBC count), statistically significant decreases were noted after 12 weeks on 10 mg of ICA-17043 vs. placebo in the following variables: a) dense RBC (% with Hb &gt;41 g/dL) [−2.41 vs. −0.08, p &lt; 0.001]; b) reticulocyte count (%) [−4.12 vs. −0.46, p &lt;0.001]; c) LDH (u/L) [−121 vs. −15, p = 0.002]; and d) indirect bilirubin (mg/dL) [−1.18 vs. 0.12, p &lt; 0.001]. ICA-17043 was well tolerated by the subjects. The most common adverse experiences were diarrhea and nausea, both of which occurred more frequently in the subjects receiving active treatment than in those on placebo. No patients died during the study, and only 3 of the 10 patients who dropped out of the study did so because of adverse events. In summary, we found that 12 weeks of treatment with ICA-17043 at a dose of 10 mg/d produced a significant increase in Hb and significant decreases in the various markers of RBC destruction. Furthermore, we found this drug to be safe and well tolerated. Therefore, based on the beneficial, dose-dependent RBC effects, a Phase III study has now been designed that will examine the clinical effect of ICA-17043 on the frequency of vaso-occlusive events in patients with sickle cell disease.
Pharmacokinetics of C1 Esterase Inhibitor, Human (Pasteurized) in Subjects with Hereditary Angioedema.
Authors: Kreuz Wolfhart , Martinez-Saguer Inmarculada , Stoll Hildegard , Knaub Sigurd , Klingebiel Thomas 
Published: April 2020

Abstract
Hereditary and acquired deficiencies in C1 inhibitor (C1-INH) function can result in potentially life-threatening attacks of hereditary angioedema (HAE). A highly purified and pasteurized C1-INH concentrate has been used effectively as prophylaxis against and treatment for angioedema attacks in patients with hereditary C1-INH deficiencies, but relatively little is known about its pharmacokinetic properties.
Objective: To evaluate the pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert®P) in two groups of patients with hereditary angioedema (HAE) receiving this preparation either as individual replacement therapy (IRT, regular, immediate treatment of first HAE symptoms in patients with frequent and severe attacks) or as on-demand treatment.
Methods: Forty subjects (15 under IRT, 25 under on-demand treatment) with HAE received intravenous injections of C1-INH (542–1,617 U) in an attack-free interval in a prospective, open, uncontrolled, single-center study. Blood was sampled for determination of C1-INH with a commercially available functional chromogenic assay for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a single-compartment model and IVR was determined using standard methods.
Results: The mean (± SD) time to maximum plasma concentration (Tmax) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the area under the time versus plasma concentration curve (AUC) was 20.5 ± 19.1 hour•U/mL, the elimination half-life (t½) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours, total body clearance (Cl) was 1.1 ± 0.6 mL/kg/hour, and volume of distribution at steady state (Vss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 20.0 ± 14.5 hour•U/mL, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, 1.2 ± 1.0 mL/kg•hour, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. Children tended to have slightly lower half-life and a slightly higher Vss compared to adults.
Conclusions: C1-INH concentrate has a short Tmax and a long, t½ and MRT consistent with the rapid onset of clinical efficacy for this preparation in subjects suffering angioedema attacks and the ability to effectively carry out IRT with injections administered every 2–5 days. This analysis provides to our knowledge the most comprehensive pharmacokinetic evaluation in subjects with HAE.
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) with Transfusion Requirement. Effect of Danazol in 18 Patients with Long Follow-Up.
Authors: Fernandez Jose , Riveros Dardo , Garay Guy , Campestri Reinaldo , Garate Gonzalo , Grand Beatriz , Dupont Juan , Cacchione Roberto 
Published: April 2020

Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a relatively uncommon, autosomal dominant disorder characterized by telangiectases that develop in the skin, mucous membranes, and visceral organs. Mucous localization may seldom bleed profusely, especially epistaxis and upper gastrointestinal (GI) tract. Effective drug treatment is not well established, and multiple blood transfusions and endoscopic or surgical procedures may be the ultimate solution to the frequently bleeding HHT patient. Danazol (DZ) is a mild androgen that has been used in small series of HHT pts with ambiguous results. Its toxicity profile in long standing administration is now well known. Eighteen patients with HHT with transfusion requirements (TR) were treated with DZ at 400–600 mg/daily for the initial three months and 200–400 mg/daily thereafter as a maintenance treatment. At the time of initiation of DZ therapy, median age was 54 yr-old (32–73), nine were female and 9 male, and the median previous TR was 16 RBC units/yr. (2–46). All patients had epistaxis and oral cavity bleeding, with 2 additional upper gastrointestinal tract active bleeding that were detected in ten patients in which an upper GI endoscopy was performed. One patient had a cerebral angioma, surgically treated. None had pulmonary fistula. All patients had some kind of iron treatment. DZ was the first drug treatment intended to reduce the HHT bleeding in 10/18 pts. Median follow-up was 7 years (1.2–14) and two pts were lost to follow-up at 4 and 11 years respectively. At three months of DZ therapy, 12/18 pts (66.6%) showed a remarkable reduction of bleeding, and in 6 patients that showed no response, DZ treatment was stopped. In 7 pts (39%) TR dropped to none and in 5 pts median RT dropped from 22 RBC units/yr. to 10 units/yr. Two of responders had a relapse with upper GI tract bleeding and 1 pts with epistaxis within the first 2 years of DZ treatment. Attempts to reduce the maintenance dose below 200 mg/daily were related to new bleeding or worsening of the active sites. None of the long standing DZ therapy had any significant toxicity. DZ treatment have shown efficacy and safety in this cohort of HHT patients. Mecanism of action may involve the increase of synthesis or expression of ALK-1 dependent proteins and less likely of endoglin. We propose DZ as a first line treatment for the transfusion dependent HHT patients.
Hereditary Protein S Type III Deficiency Is Not a Risk Factor for Venous and Arterial Thrombosis, in Contrast to Protein S Deficiency Type I. Results from a Family Cohort Study To Assess the Clinical Impact of a Laboratory Based Classification.
Authors: Brouwer Jan-Leendert P. , Veeger Nic J.G.M. , van der Schaaf Wim , Kluin-Nelemans Hanneke C. , van der Meer Jan 
Published: April 2020

Abstract
A family cohort study was performed to assess the absolute risk of thromboembolism associated with inherited protein S (PS) deficiency type I and type III. Probands were consecutive patients with thromboembolism and either type I or type III deficiency. Of living first degree relatives (age&gt;15 years), 156 (90%) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) were analyzed. Annual incidences of venous thromboembolism were 1.47 and 0.17 in deficient and non-deficient relatives in cohort 1 (RR 8.9; 95% CI 2.6–30.0), and 0.27 versus 0.24 in cohort 2 (RR 0.9; 95% CI 0.4–2.2). The cut off level of free PS to identify subjects at risk was 30%. Lower levels were found in 40% and 1% of relatives in cohort 1 and 2, respectively. We demonstrated that the cut-off level of free PS is considerably lower than the lower limit of its normal range in healthy volunteers, that is commonly used (in our study 30% in stead of 65%). If we had used only a total PS assay, 8 (2%) relatives at risk would have been missed, but 67% (346/517) of relatives would not be tested. Only testing for free PS deficiency (free PS levels &lt;65%) would have increased the number of tested relatives, but 179 (35%) relatives would be wrongly classified as at risk. Neither type I nor type III deficiency were associated with arterial thromboembolism. In conclusion, inherited PS deficiency type I, but not type III showed to be a strong risk factor for venous thromboembolism. This difference was due to lower free PS levels in type I deficient subjects and a free PS cut-off level that was half of the lower limit of its normal range.