bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frascati , a Mitochondrial Solute Transporter, and Its Role in Vertebrate Erythropoiesis.
Authors: Paw Barry H. , Shaw George C. , Cope John J. , Corson Kenneth , Hersey Candace , Wingert Rebecca , Ackermann Gabriele E. , Traver David , Trede Nikolaus S. , Barut Bruce A. , Zon Leonard I. 
Published: April 2020

Abstract
Acquired and congenital defects in iron metabolism from either deficiency or excess are one of the most common human diseases. Here we present the characterization of the zebrafish frascati mutation, which results in a profound hypochromic anemia and a developmental arrest at the pro-erythroblast stage. Using a positional cloning strategy, we have identified the gene disrupted frascati in mutants as a novel member of the mitochondrial solute transporter family. Members of this family of solute carriers have related tripartite sequence and structure. They function in transporting various metabolites and substrates across the inner mitochondrial membrane. We have verified the identity of the gene in zebrafish by the following criteria: (a) tissue-restricted expression in erythroid progenitors, (b) identification of missense mutations from the frascati five alleles, (c) rescue of anemia by over-expression frascati of cRNA in mutant embryos, and (d) mimicry of anemia using inactivating antisense morpholinos in wildtype embryos. We have also identified the functional ortholog in the mouse which has an analogous tissue and developmental expression pattern. The frascati ortholog in the mouse is highly expressed in fetal liver and adult bone marrow and spleen. The murine frascati transcript and protein are induced during terminal erythroid differentiation in MEL cells treated with either DMSO or HMBA. The over-expression of the mouse frascati cRNA in zebrafish frascati mutant embryos rescued their anemia with equal efficacy as the zebrafish clone. Given the identity of the gene and the requirement for iron in heme biosynthesis in the mitochondria of the developing erythron, we injected exogenous iron-dextran into frascati embryos. The embryos injected with iron-dextran were allowed to develop to 3 days post-fertilization, then stained for hemoglobinized cells with o-dianisidine and genotyped. Using this assay, the anemia caused by frascati the mutation could be partially rescued with exogenous iron supplementation. We therefore propose that the frascati gene functions as the essential transporter for iron importation into the mitochondria for heme biosynthesis and subsequent hemoglobin production in developing erythroid progenitors. Insight into the function of frascati the gene will be directly relevant to our understanding of human disorders of iron deficiency anemia and iron-overload sideroblastic anemia.
Osteonecrosis of the Jaw Associated with Pamidronate Therapy.
Authors: Zarychanski Ryan , Elphee Erin , Embil John , Walton Paul , Johnston James B. 
Published: April 2020

Abstract
BACKGROUND: Bisphosphonates, as a class of medication, fulfill an essential role serving to modify the natural history of bone disease associated with multiple myeloma and other neoplasms that infiltrate bone. They are also commonly used for the prevention and treatment of osteoperosis. Bisphosphonates are generally well tolerated and associated with minimal adverse effects; however, there exists a growing concern that bisphosphonate use may be associated with osteonecrosis of the jaw.
CASE PRESENTATION: We report the occurrence of osteonecrosis of the jaw associated with pamidronate therapy in 4 patients undergoing treatment for multiple myeloma. At the onset of jaw osteonecrosis, pamidronate therapy was the single medication common to all 4 patients. The duration of therapy varied from 18 to 65 months before osteonecrosis was observed. All cases involved the posterior mandible and have been refractory to a variety of medical therapies including surgical debridement and systemic antibiotics. Biopsies available from two patients revealed inflammation consistent with osteomyelitis. In one biopsy Actinomyces spp. were recovered from culture, but treatment with an extended course of clindamycin conferred no clinical benefit. The persistence of exposed bone remains a significant source of morbidity and pain for each patient. Discontinuation of pamidronate therapy has not helped to reverse the presence of osteonecrosis and surgical manipulation of the involved site appears to worsen the underlying bone pathology.
CONCLUSIONS: Osteonecrosis of the jaw is an important adverse outcome associated with bisphosphonate therapy. The unremitting nature of this clinical development, and the long lasting morbidity associated with it suggests that patients should be counseled regarding the possible occurrence of osteonecrosis prior to initiating therapy with pamidronate.
GvHD and Engraftment after Haploidentical Stem Cell Transplantation. A Comparison of 3 Immunomagnetic Selection Procedures.
Authors: Lang Peter , Schumm Michael , Greil Johann , Bader Peter , Handgretinger Rupert , Klingebiel Thomas , Schlegel Paul Gerhard , Niethammer Dietrich 
Published: April 2020

Abstract
Profound depletion of T and B cells is a fundamental prerequisite for haploidentical transplantation. Here, we compare hematopoietic engraftment and occurrence of GvHD after two different positive selection procedures (with anti-CD34 coated or anti-CD133 coated beads) and after a direct depletion procedure with CD3/CD19 coated microbeads in children with leukemias (ALL, AML, CML) and lymphomas. Median purity of stem cells was comparable after CD34+ selection and CD133+ selection, whereas stem cells were only slightly enriched after CD3+/CD19+ depletion (97.5%, 93.4% and 1.02%). Indirect depletion of T cells was better after CD34+ selection than after CD133+ selection (4.1log vs. 3.75log, p&lt;0.001). Direct T cell depletion with anti-CD3 coated microbeads produced results comparable to CD34+ selection. Those grafts comprised also remarkable amounts of effector cells such as NK cells (median number: 40 x106/kg), dendritic cells and monocytes (median number: 120 x106/kg). Recovery of stem cells was similar in all three methods (77.3%, 80.6%, and 70% respectively).
Primary engraftment occurred in 85% (44/52) of patients with CD34+ selected stem cells and in 78% (11/14) of patients with CD133+ selected cells. After reconditioning, sustained engraftment was achieved in 98% and 100%. All patients (10/10) with CD3+/CD19+ depleted grafts had primary engraftment. Recovery of platelets was rapid especially in patients with CD133+ selected grafts (median time to reach independence from substitution = 14.5 days). GvHD grade II occurred in 6%, 7% and 25%, respectively. Only one patient had severe GvHD grade III-IV (CD34+).Conclusions: CD34+ selection and CD133+ selection resulted in similar engraftment and GvHD rates. CD3+/CD19+ depletion resulted in better engraftment but produced slightly more GvHD. Thus, the methods may be individually used according to the patient’s requirements.
Fludarabine Phosphate-Based Nonmyeloablative Stem Cell Transplantation in the Elderly Patients: A BHS Study.
Authors: Bron Dominique , Zachée Pierre , Maertens Johan , Theunissen Koen , Ferrant Augustin , Martiat Philippe , Doyen Chantal , Noens Luc , Schroyens Wilfried , Sellesslag Dominique , Demuynck Hilde , Schots Rick , De Meuter Anne , Boogaerts Marc 
Published: April 2020

Abstract
Background: Fludarabine phosphate (F)-based nonmyeloablative conditioning regimens are associated with reduced transplant-related toxicity and allow transplantation in patients (pts) above 55 y.o.
Aims: We prospectively studied the role of ATG to control the development of graft-versus-host-disease (GVHD), accelerate donor engraftment and maintain GVT effects in pts not eligible for classical allogeneic transplant. The subgroup of pts with 60 yo or more was analysed and compared with the younger population.
Population: A total of 113 pts were enrolled in the phase II study. Pts with lymphoid malignancies were conditioned with F (30 mg/m²/day for 4 days) plus cyclophosphamide (1g/m²/day for 3 days) or cytarabine (Ara-C, 2g/m²/day) for myeloid malignancies. All pts received cyclosporine (3–5 mg/kg IV, daily) and ATG (10 mg/kg/day for 4 days - [ATG-4, n= 36] or 2 days - [ATG-2, n=67] ). Chimerism analyses were performed on d30, 45, 60 and 90.
Results: 29 pts had 60 y.o. or more.Diagnoses were as follows: 9 MM, 5 NHL, 3 CLL, 5 AML, 4 MDS, 2 CML, 1 WM. The median age was 63 (range 60–74) years. The median follow-up was 24 months. Prior to transplantation, 35% of pts were in complete remission. 65% had poor prognostic disease(PR, RR or PD). Engraftment rate was 100% of the evaluable pts. Treatment-related mortality was 48%,much higher than in the younger population (15%) and due primarily to infectious complications. Grade II-IV acute GVHD (aGVHD) at d90 were similar in both populations (35%). Chronic GVHD rates were similar in both groups (40%). At d90, 23 pts were evaluable for T-cell chimerism analysis. Full (&gt;90%) donor chimerism was achieved in 20/23 pts. Overall survival was higher in patients with good prognostic diseases (60% vs. 48%). No pts developed veno-occlusive disease.
Conclusion: These results confirm the feasibility of F-based nonmyeloablative conditioning in elderly population but infectious complications remain a concern compared to younger population.
Less Treatment Related Mortality with Variable Intensity Conditioning Than Non-Myeloablative Conditioning in Unrelated and Related Adult Allogeneic Transplant Recipients.
Authors: Bigelow Carolyn L. , Elkins Stephanie , Hardy Cheryl L. , Files Joe Clark 
Published: April 2020

Abstract
For the past four years our adult allogeneic transplant program has employed two alternative approaches to standard recipient conditioning, the use of non-myeloablative “mini” conditioning and variable intensity conditioning. We now report a retrospective comparison of relapse, day +100 and one year survival, engraftment and grades I-II and III-IV acute GVHD in unrelated as well as related recipients in these two preparative regimen groups. Patients with a variety of malignancies were not randomized to receive either non-myeloablative (Group 1) or variable intensity (Group 2) conditioning. Twenty patients with a median age of 49 (range 27–64, Group 1) and 17 patients also with a median age of 49 (range 24–58, Group 2) received either marrow or peripheral blood stem cells, usually with a 6/6 match grade; one recipient in Group 2 received a cord blood transplant (4/6 match). Group 1 regimen consisted of fludarabine 30 mg/m2 x 3d and TBI 200 cGY. Group 2 regimen consisted of Campath 20 mg/d either 5 or 3 days, fludarabine x 5d and melphalan 140 mg/m2 x 1d. GVHD prophylaxis was the same in both groups (standard dose cyclosporine or tacrolimus and MMF.) All patients received an adequate CD34+ cell dose and none of the products was manipulated. Relapse rate was 37% in Group 1 and 53% in Group 2. Day+100 survival and one year survival were 55% and 20%, respectively, in Group 1 vs 69% and 33% in Group 2. Only one patient in Group 2 had acute GVHD, grades I-II; none had grades III-IV. However, in Group 1, 6 patients had grades I-II and 8 had grades III-IV (40%). Graft failure occurred in five patients in Group 1, while no patients in Group 2 experienced it. We conclude, first, that in our program the application of variable intensity conditioning has been quite successful in unrelated transplant recipients, as well as in related. Second, significant treatment related mortality in the form of graft failure and acute GVHD occurred less frequently in recipients who received this conditioning than in those receiving non-myeloablative conditioning. This regimen requires some further modification to enhance its tumoricidal properties; however, its treatment-related toxicity is minimal and allows us to offer this therapy to patients with co-morbid conditions and older age.
Valganciclovir for the Early Prophylaxis of Cytomegalovirus (CMV) Infection after Allogeneic Stem Cell Transplantation.
Authors: Bachier Carlos , Shaughnessy Paul , Wall Donna , Grimley Michael , Carrum George , Freytes Cesar , Callander Natalie , Walsh Tracey , LeMaistre C. Fred 
Published: April 2020

Abstract
Despite improvements in methods for the early diagnosis of CMV infection, 5% of HSCT patients receiving preemptive therapy develop CMV disease. In addition, the use of highly immunosuppressive therapies prior to and after transplant and the use of matched unrelated (MUD) and mismatched related (MRD) donors have increased the incidence of CMV infection and disease. We designed a prospective trial examining the safety and efficacy of valganciclovir for the prophylaxis of early CMV infection.
Methods: CMV seropositive patients or CMV seronegative patients receiving CMV seropositive stem cell products with an estimated creatinine clearance of ≥ 50 mL/min, platelet count ≥ 50,000/μL, and WBC count ≥ 1,000/μL are eligible. Patients receive valganciclovir 900 mg daily Mondays through Fridays starting 21 to 35 days after transplant and continuing through Day 100, with dosage adjustments for myelosuppression and/or reduced creatinine clearance. Patients are monitored with weekly CMV PCR analysis at a central lab according to the Roche assay.
Results: Twenty four (24) out of 50 planned subjects have been enrolled to date (MUD 9, MRD 15). All were CMV seropositive at the time of transplant. Stem cell source included peripheral blood = 21, bone marrow = 3. A total of 7 patients required corticosteroids for treatment of graft versus host disease. Three patients developed myeloid toxicity related to valganciclovir (absolute neutrophil count &lt; 1,000/μL = 1, platelets &lt; 50,000/μL = 2). All three (3) patients recovered their counts and restarted valganciclovir with dose adjustments. A total of 11 patients required dose adjustments due to myelosuppression (3), creatinine clearance (4), weight (1), institutional decision (3). Twelve (12) patients have not completed therapy due to: progressive disease or death before day +100 = 4, CMV infection =2, too early for analysis = 6. CMV infection occurred in 2/24 and CMV disease occurred in 0/24. The two (2) patients with positive CMV-PCR developed infection one (Day 40) and two (Day 36) weeks after starting valganciclovir. These two (2) patients were successfully treated with IV ganciclovir. Ten (10) patients have been followed between day +100 and 6 months post transplant. Three (3) of these 10 patients continued valganciclovir off study and had no evidence of CMV infection. Two (2) of the 10 patients who were not receiving valganciclovir developed CMV infection but were successfully treated with valganciclovir. Survival is 80% (16/20) at day +100 and 82% (9/11) at 6 months post transplant.
Conclusions: We conclude that valganciclovir at the dose used in this study is well tolerated with minimal reversible myelosuppression. These preliminary findings suggest that prophylaxis with oral valganciclovir appears to be a promising strategy to prevent CMV infection and disease.
Results of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia of the FAB M0 Subtype in First Complete Remission: A Survey of the Acute Leukemia Working Party of the European Bone Marrow Transplant Group (EBMT).
Authors: Herr Andree-Laure , Labopin Myriam , Reiffers Rosy , Bunjes Donald , Blaise Didier , Hurtenstein Bernard , Gorin Norbert C. , Gluckman Eliane , Rocha Vanderson 
Published: April 2020

Abstract
Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with acute myeloid leukemia (AML). AML of the FAB M0 subtype is rare, often associated with a complex karyotype and a poor prognosis. Results of HSCT for this AML subtype have never been reported separately from other subtypes. We did a survey of the results of 274 HSCT in adults with M0 AML in first complete remission (CR1), performed in EBMT centres since January 1990 until 2002. One hundred fifty patients were transplanted with an HLA identical donor (HLA-id), 30 with an HLA-matched unrelated donor (MUD) and 94 received an autologous transplant (auto). The median age was 45 years (16–71), the median interval from diagnosis to HSCT was 4 months for HLA-id, 6 months for MUD and 5 months for auto HSCT. The median follow-up time (range) was 20 months (1–109), 12 (2–53) and 10 months (1–96) for HLA-id, MUD and auto-HSCT respectively. The source of stem cells was peripheral blood stem cells for 67% of cases, and bone marrow for the remaining. The majority of grafts were non-T-cell depleted. Acute GVHD (grade I–IV) occurred in 56% of HLA-id and in 64% of MUD cases. The table shows the outcomes at two years according to the type of transplant. In conclusion, outcomes after HLA identical HSCT and MUD in adult patients with AML FAB subtype M0 in CR1 are encouraging. In comparison to allogeneic transplant cases, LFS is decreased in patients receiving an autologous transplant due to a high relapse incidence, reflecting the probable role of a graft-versus-leukemia effect in this FAB subtype.
Results of HSCT in AML M0 CR1 patients
Outcomes HLA-id n=150 MUD n= 30 Auto n=94 LFS: leukemia free survival; OS: overall survival; RI: relapse incidence; TRM: treatment-related mortality 2y LFS 50% 45% 33% 2y OS 58% 50% 49% 2y RI 25% 40% 57% 2y TRM 24% 14% 9%
Reduced-Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Patients Older Than 60 Years.
Authors: Busca Alessandro , Locatelli Franco , Santarone Stella , Narni Franco , Morello Enrico , Rambaldi Alessandro , Mordini Nicola , Bruno Benedetto , Bacigalupo Andrea , Falda Michele 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with hematological malignancies but its use is limited to young patients without comorbidities.
The aim of present study was to evaluate the efficacy of a reduced-intensity conditioning (RIC) consisting of fludarabine and TBI in older patients aged 60 to 70 years.
Methods: between March 2000 and May 2003, 22 patients (median age 62 years; range 59–70) with hematological malignancies (n=18 AML/MDS; n=1 ALL; n=1 CLL; n=1 myelofibrosis) and solid tumor (n=1 renal cell carcinoma) were treated with a RIC regimen based on fludarabine (30 mg/m2 x 3–5 days) and 200 cCy TBI followed by alloHSCT from a matched-sibling donor. GVHD prophylaxis consisted of cyclosporine and mycophenolate. The source of stem cell was blood in all patients. The median CD34+ content of the grafts was 5.7 x 106/kg (range 3.1–8.7). Three patients had received a prior allograft. Eleven patients had active disease at transplantation, 5 patients were untreated and 6 were allografted in complete remission (CR).
Results: neutrophil recovery occurred in 15 patients (68%) at a median time of 16 days (range 8–33). One patient who died early after transplantation (day +5) and 4 patients who experienced an autologous reconstitution, failed to reach this threshold; 2 patients did not become granulocytopenic. Fifty-eight percent of the patients had &gt; 90% donor chimerism on day +30. Twelve of 17 evaluable patients (70%) developed acute GVHD (n=5 grade I; n=6 grade II; n=1 grade III), whereas chronic GVHD was observed in 11 of 13 patients (85%) surviving more than 100 days (limited in 7 cases and extensive in 4 cases). The probability of acute GVHD grades II–IV and extensive chronic GVHD was 43% and 31% respectively. Two patients died of treatment-related complications: 1 patient died of toxic encephalopathy on day 5 after transplantation and 1 patient of thrombotic thrombocytopenic purpura on day 915. The 100-day nonrelapse mortality for the whole population was 5%.Ten patients (45%) died as a result of relapse. With a median follow-up of 586 days (range 50–1128) 10 patients are alive (9 with CR and 1 with relapsed disease).The probability of overall survival at 2 years was 86% for patients treated in CR or at diagnosis and 9% for patients transplanted in advanced phase of disease (p= 0.0008).
Conclusion: Our analysis would suggest that for patients older than 60, this RIC regimen is well tolerated and associated with a low incidence of transplant-related mortality and serious acute and chronic GVHD. The leukemic burden at time of transplant has proven to be the most important risk factor for the outcome.
Economic Analysis of Reduced-Intensity Cord Blood Transplantation.
Authors: Yuji Koichiro , Miyakoshi Shigesaburo , Myojo Tomohiro , Miura Yuji , Kato Daisuke , Imataki Osamu , Narimatsu Hiroto , Kusumi Eiji , Matsumura Tomoko , Kami Masahiro , Masuoka Kazuhiro , Ueyama Junichi , Wake Atsushi , Morinaga Shinichi , Taniguchi Shuichi 
Published: April 2020

Abstract
[Background] Non-myeloablative regimens have been proven to allow engraftment following allogeneic stem cells transplantation with minimal procedure-related toxicity and lower costs. Cord blood has emerged as an appealing alternative source of hematopoietic stem cells for unrelated donor transplantation, but delayed engraftment and frequent transfusion were reported. No studies have formally evaluated the cost of reduced-intensity cord blood transplantation (RICBT).
[Purpose] To evaluate the relationship among costs, baseline patient characteristics, and major complications of RICBT, we performed an economic analysis of data in a clinical trial of RICBT for hematologic diseases at a single institution.
[Patients and Methods] Ninety-three patients with hematological diseases (median age, 55y; range, 17–79: median body weight, 53kg; range, 38–75) underwent RICBT from March 2002 to May 2004 in Toranomon Hospital. Mean follow-up period was 77 days (range, 13–863). Data on resource use, including hospitalizations, medical procedures, medications, and diagnostic tests, were abstracted from subjects’ clinical trial records. Resources were valued using the Japanese national insurance reimbursement system for inpatient costs at one hospital and average wholesale prices for medications. Monthly costs were calculated and stratified by treatment group and clinical phase.
[Results] The median initial inpatient cost was $80,400 (range, 41,300–154,700). When baseline variables were considered, disease status was significant predictor of costs. When clinical events were considered, in-hospital death was associated with higher costs. The mean length of total inpatient days was 78 days (range, 31–222), and the mean length of inpatient days post transplant was 51 days (range, 15–131). The mean units of transfused RBC, Platelet, and FFP were 27u, 224u, and 27u, respectively.
[Discussion] This study firstly demonstrates that the cost of RICBT was much higher as compared to previous RIST using peripheral blood or bone marrow. RICBT is an attractive therapy, however, economic problem lies before prevalence of RICBT. The increased numbers of transfusions and supportive care would have effects on costs. The association between mortality and higher costs suggest that prevention of clinical complication may have significant economic benefits. Interventions that decrease these complications may have favorable cost-benefit ratios, and will be the focus of future investigation.