bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Extracorporeal Photochemotherapy on the Clinical and Economical Management of Patients Affected with GVHD.
Authors: Perotti Cesare , Isernia Paola , Del Fante Claudia , Viarengo Gianluca , Bressan Daniela , Santini Tiziana , Salvaneschi Laura 
Published: October 2019

Abstract
Extracorporeal photochemotherapy (ECP) is an effective, relatively new technique, FDA approved for cutaneous T-cell lymphoma, employed as second-third line treatment in patients affected with GVHD not or poorely responsive to standard immunosuppressive drugs. Both aGVHD and cGVHD are the major complications after stem cell transplantation (till to 50% and 80% of the patients, respectively). Corticosteroids, cyclosporine, micofenolate, tacrolimus and various experimental monoclonal antibodies (anti CD40 ligand, anti TNFα etc) are the drugs employed to control GVHD and are burdened with important short and long term side effects. Recently we revised our data about 102 pts (children and adults) treated by ECP in our Institution. The overall response was 75%, permitting to taper or suspend the immunosuppressive therapy (IST) in 67.6% of the pts. The economical and social impact (cost analysis and quality of life) of ECP vs standard IST was calculated basing on the National Price List and on Short Form Quality of Life (QoL) Scoring System. The cost of ECP comprehensive of the leukapheresis procedure, waste matherials and dedicated personnel was estimated as 684.51 Euro/procedure. On the other side, when the solely costs of the most common IST drugs (corticosteroids, cyclosporine) were considered for 5 months of treatment, an evident and obvious economical advantage emerged (120,3 E). On the contrary, when the costs of hospitalisation and day hospital regimen derived from the most common side effects related to the solely use of IST were included in our cost analysis studies, an economical advantage for long term ECP treatment (calculated on 16 procedures) was demonstrated (14952.16 E vs 17553 E). Moreover, when the “real life implication” calculated on the QoL parameters were considered, the advantages were more evident. In conclusion, the tie of respecting strictly an imposed program of budget calculated on the short period may exert an inhibitory effect in introducing new diagnostic or therapeutic procedures ignoring that the improvement or the cure of the patient has always a positive economical counterpart, expecially when the impact of a new technology is considered in a long term view.
User Preference for 3 Hemophilia Factor Reconstitution Methods.
Authors: Mannix Sally , Brewster Jessica , Rentz Anne M. , Lloyd Andrew , Butler Regina , Larson Peter J. 
Published: October 2019

Abstract
Introduction: Treatment of hemophilia includes the reconstitution of lyophilized FVIII concentrates with diluent followed by intravenous injection. Several reconstitution devices exist for infusion of concentrates. The Bio-Set® (Biodome, Issoire France) is a new needleless device for reconstituting a factor VIII concentrate, Kogenate® FS (Bayer Healthcare, Elkhart, IN).
Objective: Comparison of preferences for reconstitution methods by hemophilia patients, caregivers to hemophilia patients, and care providers.
Methods: A total of 35 hemophilia A patients who infuse themselves, 67 caregivers, and 59 infusion nurses were recruited following an IRB-approved protocol. Infusion method names were blinded to participants to prevent brand recognition. Reconstitution methods used in this study were Bio-Set®, a conventional 2 vial, transfer needle reconstitution method, and Baxject (Baxter Healthcare, Westlake Village CA). Participants viewed a video demonstrating the three methods, watched the interviewer demonstrate each method, and then practiced each method once. Each participant performed 1 timed round with each method and completed preference questionnaires about each method. The preference questionnaire was scored into domains for safety/worry and ease/confidence, in addition to a total preference score. Participants’ comments about the reconstitution methods were also recorded.
Results: Participants preferred the Bio-Set® in terms of worry/safety, ease/confidence, and overall preference. These results were consistent across participant group. Participants agreed on their preferences for the Bio-Set® in terms of safety from needlesticks, amount of waste produced, and convenience for traveling (all p<0.0001). Analysis of the qualitative data indicated that exposure to needles and product contamination were issues commonly noted. Safety and complexity of instructions were also common issues for participants.
Conclusions: Results of this study show that patients, caregivers, and nurse providers prefer the Bio-Set® reconstitution device over other methods for preparing factor concentrates for infusion.
Comparable Survival in Newly Diagnosed Multiple Myeloma (MM) after VAD Induction with High Dose Therapy Using Melphalan 140mg/M2 + TBI 12 Gy (MEL+TBI) Versus Standard Therapy with VBMCP and No Benefit from Interferon (IFN) Maintenance: Final Clinical Results of Intergroup Trial S9321 in the Context of IFM 90 and MRC VII Trials.
Authors: Crowley John , Fonseca Rafael , Greipp Phillip , Jason McCoy , Bart Barlogie 
Published: October 2019

Abstract
ECOG, CALGB and SWOG (coordinating group) enrolled 899 patients with newly diagnosed MM to receive VAD x 4 (813 were considered eligible), followed by randomization to PBSC-supported MEL-TBI (n=261) versus VBMCP (n=255), using CTX 4.5g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or MEL-TBI were randomized to IFN (n=121) or no maintenance (n=121). With a median follow-up of alive patients of 60 mos, median EFS and OS from 1st randomization were 25 and 62 mos for MEL-TBI and 21 and 53 mos for VBMCP (p=.14 for EFS, p=.87 for OS). EFS and OS from IFN randomization were also identical at 23/59 mos for IFN versus 18/74 mos for observation (p=.2/.6). 87 VBMCP failures received salvage autotransplants, with a post-relapse median survival of 24 mos which was similar to the 27 mos observed among the remaining 83 VBMCP failures managed with standard salvage therapies. When examined in the context of 2 other randomized trials (IFM 90, MRC VII), OS from baseline of S932, limited to patients <60 yr (as in IFM 90 + MRC VII), is intermediate between the high dose arms of IFM 90/MRC VII and the standard dose arms of these two trials (randomization at baseline) (Figure 1). OS from the time of randomization to high or standard dose therapy on S9321 (again restricted to age <60 yr) was similar to OS timed from transplant for the high dose arms of IFM 90 and MRC VII. (Figure 2).
Figure Figure
The comparable outcome after high- versus standard-dose therapies on S9321, interpreted in the context of 2 other published randomized clinical trials, may relate to (1) higher dose intensity with VBMCP than with other standard regimens or (2) a detrimental effect of TBI in S9321. We conclude that with the current follow-up MEL-TBI is no better than VAD/VBMCP with the option of salvage transplant and that IFN maintenance is of no benefit in this maintenance setting. Data from this trial will be provided to MRC to be included in their on-going meta-analyses of high-dose therapies and IFN maintenance.
In Vivo Fate Tracing Studies Using the SCL Stem Cell Enhancer: Embryonic Hematopoietic Stem Cells Significantly Contribute to Adult Hematopoiesis.
Authors: Gothert Joachim R. , Gustin Sonja E. , Hall Mark A. , Green Anthony R. , Gottgens Berthold , Izon David J. , Begley C. Glenn 
Published: October 2019

Abstract
Evidence for the direct lineage relationship between embryonic and adult hematopoietic stem cells (HSCs) in the mouse is primarily indirect. In order to study this relationship in a direct manner we expressed the tamoxifen-inducible Cre-ERT-recombinase under the control of the SCL-stem-cell-enhancer in transgenic mice (HSC-SCL-Cre-ERT). To determine functionality, HSC-SCL-Cre-ERT transgenics were bred with the Cre-reporter-mice ROSA26R and R26R-EYFP. Flow-cytometric and transplantation studies revealed tamoxifen-dependent recombination occurring in more than 90% of adult long-term HSCs, whereas the targeted proportion within mature progenitor populations was significantly lower. Moreover, the transgene was able to irreversibly tag embryonic HSCs on days 10 and 11 of gestation. These cells contributed to bone marrow hematopoiesis five months later. In order to investigate whether the de novo HSC-generation is completed during embryogenesis, HSC-SCL-Cre-ERT marked fetal liver cells were transplanted into adult recipients. Strikingly, the proportion of marked cells within the transplanted and the in vivo-remaining HSC-compartment was not different, implying that no further HSC-generation occurred during late fetal and neonatal stages of development. These data demonstrate for the first time the direct lineage relationship between mid-gestation embryonic and adult HSCs in the mouse. Additionally, the HSC-SCL-Cre-ERT mice will provide a valuable tool to achieve temporally controlled genetic manipulation of HSCs.
Expression Profile of Aging Hematopoietic Stem Cells.
Authors: Chambers Stuart M. , Shaw Chad A. , Goodell Margaret A. 
Published: October 2019

Abstract
A decline in stem cell function has been suggested to contribute to vertebrate aging. Several labs have documented a reduction in transplant efficiency and skewing in lineage contribution when murine bone marrow or hematopoietic stem cells (HSC) from old donors were transplanted into young recipients. Paradoxically, evidence from several labs including ours has shown that the percentage of phenotypically defined HSC in C57Bl/6 mice increases with age (Fig. 1). Within the serum of aged animals, systemic inflammatory markers such as C reactive protein in humans and IL-1 in mice have been shown to steadily increase with age, however it is unclear if systemic inflammation plays a role in these age-related HSC phenotypes. In order to investigate what might account for these functional changes in HSC aging, we have characterized gene expression in aged HSC using Affymetrix microarrays, examining expression profiles of HSC purified from C57Bl/6 mice that are 2-, 6-, 12-, 21-months old. Using polynomial regression over the time course, we have found more than 700 genes that are 2-fold up-regulated and more than 400 genes that are down-regulated with time. We used the Gene Ontology to categorize age-regulated genes, and have identified the category of ‘inflammatory response’ to be significantly enriched in genes that are up-regulated with age. Strikingly, several NF-Kb regulated genes, previously associated in other tissues with aging and inflammation (e.g. P-selectin, Cox-2, and ICAM-1) are up-regulated in aged HSC. The expression patterns of more than 15 genes, including clusterin, serum deprivation response, and growth hormone receptor, have been validated by quantitative real-time PCR. Furthermore, expression of several surface markers, including P-selectin, a protein that plays a role in inflammation, has been validated at the protein level by flow cytometry. In order to determine if the gene expression changes observed in aged HSC is caused by intrinsic or extrinsic factors, we have transplanted HSC from 21-month-old mice into young recipients and are assessing changes in their expression profile compared to young transplanted HSC. These data demonstrate a role for inflammation in HSC-aging, and may identify genes involved in stem cell transplant efficiency, lineage specification, and the onset of organismal aging.
Figure 1: Sca-1 enriched Side Population cells at the indicated ages (in months). The percentage of cells residing within the SP increases 9-fold with age. Figure 1:. Sca-1 enriched Side Population cells at the indicated ages (in months). The percentage of cells residing within the SP increases 9-fold with age.
Single 4-Dose Rituximab Treatment for Low-Tumor Burden Follicular Lymphoma (FL): Survival Analyses with a Follow-Up (F/Up) of at Least 5 Years.
Authors: Solal-Celigny Philippe , Salles Gilles Andre , Brousse Nicole , Franchi-Rezgui Patricia , Soubeyran Pierre , Delwail Vincent , Deconinck Eric , Haioun Corinne , Foussard Charles , Sebban Catherine , Tilly Herve , Milpied Noel-Jean , Boue Francois , Karsenti Jean-Michel , Lederlin Pierre , Najman Albert , Thieblemont Catherine , Morschhauser Franck , Berriot-Varoqueaux Nathalie , Bergougnoux Loic , Colombat Philippe 
Published: October 2019

Abstract
Rituximab alone may be given as initial treatment for FL either as a single treatment or as an induction treatment followed by a maintenance. In 2002, we have reported the response rates and progression-free survival (PFS) of 49 patients (pts) treated with 4 weekly 375 mg/m² doses of rituximab (Blood2002; 97: 101–6). All patients had FL and a low-tumor burden according to the GELF criteria. These pts have been followed during at least 5 years. According to the Follicular Lymphoma International Prognostic Index (Blood, in press). 22 pts were in the low-risk group (45%), 20 (41%) in the intermediate risk group and 7 (14%) in the poor risk group.
Best response rate was 80% with 49% CR/CRu and 31% PR, and response was maintained in 34% without further treatment after at least 5 years. Median F/Up was 60 months. The median PFS was 18 months. Among these 49 pts, only 3 pts died (2 from NHL, 1 from lung carcinoma).
Among the 32 pts who were bcl-2 positive in the blood and/or the bone marrow before treatment with rituximab, 10 (33%) became negative and 20 (67%) remained positive at d50. 6 (60%) relapsed among the former and 15 (75%) among the latter. Median PFS was 37 months for pts who became bcl-2 negative and 14 months for those who remained positive (p[log-rank test] = 0.10). Among the 4 patients who had information on molecular biology who did not relapse after a 5-year F/Up, 3 were bcl-2 negative and 1 was bcl-2 positive.
The long F/Up of these pts (i) confirms the median PFS of 18 months for all pts and the median relapse-free survival of 27 months for best responders (ii) shows that some patients (i.e. 28% of all pts and 34 % of responders) may have a relapse-free survival longer than 5 years after a single first line treatment with rituximab in monotherapy ; (iii) shows an excellent overall survival (only 3 death (6%) during the study) in these FL pts. These results confirm the relevance of on-going trials comparing a maintenance treatment with rituximab and treatment at the time of relapse.
Patients with Follicular Lymphoma, Grade 3, Have a Prolonged Relapse-Free Survival Following Aggressive Combination Chemotherapy.
Authors: Ganti Apar Kishor , Weisenburger Dennis D. , Smith Lynette M. , Hans Christine P. , Bociek R. Gregory , Bierman Philip J. , Vose Julie M. , Armitage James O. ,   The Nebraska Lymphoma Study Group
Published: October 2019

Abstract
Clinical prognostic factors for grade 3 follicular lymphoma (FL3), using the new WHO classification, have not yet been clearly defined. Hence, we conducted a retrospective study to identify the outcome and clinical features predictive of survival in patients with FL3. Two hundred and two patients diagnosed with FL3 using the Berard criteria, who were staged and treated with various aggressive combination chemotherapy regimens containing either an anthracycline or mitoxantrone, are included in this study. After a median follow-up of 8.4 years (range, 0.5 – 19.5 years), 105 patients (52%) have died and 97 patients (48%) are alive at last contact. The estimated 10-yr event-free survival (EFS) and overall survival (OS) are 34% (95% CI: 26–41%) and 45% (95% CI: 37–53%), respectively. By multivariate analysis, older age (≥60 years; Figure 1) and a low hemoglobin (<12 gm/dL) were independent adverse predictors of OS (RR: 2.3, 95% CI: 1.5–3.7, p=0.0002; and RR: 1.9, 95% CI 1.2–3.0, p=0.0095, respectively). A low hemoglobin and advanced stage (III/IV) at presentation were independent adverse predictors of EFS (RR: 1.8, 95% CI: 1.2–2.8, p=0.0072; and RR: 1.7, 95% CI: 1.1–2.5, p=0.0096 respectively). When patients were compared based on age, there were no significant differences in the distribution of adverse prognostic factors among patients ≥60 years of age as compared to younger patients. There were also no differences in the frequency of relapse/progression (10-year rate of 50% in patients <60 years vs. 44% in patients ≥60 years, p=0.71) or lymphoma-specific/treatment-related deaths between the two age groups (10-year rate of 30% in patients <60 years vs. 35% in patients ≥60 years, p=0.17; Figure 2). Although younger patients (<60 years) had a significantly better OS and EFS as compared to older patients, there were no differences in the relapse/progression rates or lymphoma/treatment-related survival. Thus, aggressive combination chemotherapy led to durable remissions in 50–60% of patients with FL3.
Figure Figure Figure Figure
First Report of the Phase III North American Trial of Decitabine in Advanced Myelodysplastic Syndrome (MDS).
Authors: Saba Hussain , Rosenfeld Craig , Issa Jean-Pierre , DiPersio John , Raza Azra , Klimek Virginia , Slack James , de Castro Carlos , Mettinger Karl , Kantarjian Hagop 
Published: October 2019

Abstract
MDS is a disease of the elderly marked by dysplasia of hematopoetic cell lines resulting in cytopenias and AML progression. There is currently no treatment approved to alter the natural history of the disease. Aberrant methylation associated with cancer is a potential target for pharmacologic therapy, and DacogenTM (decitabine) for injection (SuperGen, Inc.), a cytosine analogue, indirectly depletes methylcytosine after incorporation into DNA with subsequent inactivation of DNA methyltransferases. We report the results of a Phase III trial of decitabine (DAC) vs. supportive care (Supp.Care) in adult MDS patients with IPSS Intermediate (Int)-1 (31%), Int-2 (44%) and high risk disease (26%). Secondary MDS (14%) and previously treated (27%) MDS patients were not excluded. Bone marrows were assessed by a blinded, independent pathologist. 170 patients (accrued from July 2001 through April 2003 at 23 centers) were randomized 1:1 to either Supp.Care or DAC (a 3 hr infusion of 15mg/m2/hr every 8 hrs on 3 consecutive days every 6 wks for up to 10 cycles. The groups were comparable for numerous risk factors, including time from diagnosis (median 29 weeks for DAC and 35 weeks for Supp.Care). Kaplan Meier (KM) curves for time to AML progression or death showed early and clinically meaningful separation (consistent with clinical benefit) in favor of DAC in all patients (intent to treat; ITT), Int-2/High Risk, and High Risk patients. Using the Cox proportional hazards model for the ITT population, the probability of progression to AML or death was 1.68-fold greater for Sup.Care than for DAC (p=0.023).
Median Time to AML or Death (Days)
MDS group (n) DAC Supp.Care p-value 1Protocol specified test. 2Preferred test for analysis of early separation of KM curves. n=89 n=81 Wilcoxon1,2 Log rank1 All Patients (170) 338 263 0.046 0.204 Int-2/High Risk (118) 334 189 0.005 0.040 High Risk (44) 260 79 0.001 0.006 Treatment naïve (124) 354 189 0.005 0.034
Figure Figure
Investigator reported response rate by International Working Group criteria was 25% (10% CR, 15% PR) for DAC vs. 0% for Supp.Care (p< 0.001), with responses equally distributed across baseline subgroups. Time to response was 100 days and median duration was estimated at >9 months. Responders (CR and PR) vs. non-responders had a median survival of 678 days vs. 406 days (p= 0.038 Wilcoxon). There were no treatment related deaths. As expected, grade 3–4 toxicity (including hematologic toxicity, febrile neutropenia) occurred in more DAC patients than in Supp.Care patients. Most patients tolerated treatment well. DAC appears a promising therapy for MDS with manageable toxicity. Final results of independently reviewed response rates and clinical benefit (transfusion independence; Quality of Life) will be presented.
Fixed-Dose, Weight-Adjusted, Unfractionated Heparin (UFH) Given Subcutaneously (sc) without Laboratory Monitoring for Acute Treatment of Venous Thromboembolism (VTE): Randomized Comparison with Low-Molecular-Weight-Heparin (LMWH).
Authors: Kearon Clive , Ginsberg Jeffrey J. , Julian Jim , Douketis James , Solymoss Susan , Ockelford Paul , Jackson Sharon , Turpie Graham , McCarty Donna , MacKinnon Betsy , Hirsh Jack , Gent Michael ,   (for the FIDO Investigators)
Published: October 2019

Abstract
Background: Treatment of VTE with UFH is usually by intravenous (iv) infusion with adjustment of dose in response to the activated partial thromboplastin time (APTT). However, (1) there is no evidence that adjusting UFH in response to APTT results reduces recurrent VTE or bleeding if patients are receiving an appropriate dose of UFH, and (2) sc UFH might be preferable to iv UFH. We hypothesized that UFH is as effective and safe as LMWH when each is administered sc in weight-adjusted, fixed-doses.
Methods: We performed a multicentre, randomized, open-label, trial that compared fixed-dose UFH (first dose 333 u/kg sc, then 250 u/kg sc twice-daily) with fixed-dose LMWH (100 u/kg sc twice-daily) for initial treatment of acute VTE. Patients were followed for 3 months during which they received warfarin (target INR 2.0–3.0). Outcomes were adjudicated by a blinded committee.
Results: 703 patients who presented with acute DVT (81%) or PE (19%) were enrolled and received study drug (68% entirely as outpatients). Of the 352 LMWH patients, 74% received dalteparin and 26% received enoxaparin. Recurrent VTE occurred in 13 (3.8%) UFH and 12 (3.4%) LMWH patients in the 3 months (difference of 0.3%; 95% CI, −2.6 to 3.3%). Major bleeding occurred in 4 (1.1%) UFH and 5 (1.4%) LMWH patients in the first 10 days (difference of −0.3%; 95% CI, −2.3 to 1.7%), and a total of 6 (1.7%) UFH and 12 (3.4%) LMWH patients at 3 months. 18 (5.2%) UFH and 22 (6.3%) LMWH patients died.
Conclusion: Fixed-dose sc UFH is as effective and as safe as fixed-dose sc LMWH for treatment of acute VTE. Our findings: (1) support the use of fixed-dose sc UFH as a convenient and inexpensive alternative to LMWH; and (2) question the need for APTT monitoring of UFH therapy.