bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antifungal Prophylaxis with Itraconazole in Patients with Acute Leukemia and after Stem Cell Transplantation (SZT): High Plasma Concentrations with a Loading Dose Strategy.
Authors: Sandherr Michael , Vogeser Michael , Hartig Carsten , Aulmann Christoph , Fuhrmann Stefanie , Wondzinski Linda , Oruzio Daniel , Schlimok Guenter 
Published: October 2019

Abstract
Invasive fungal infection (IFI) is a major complication in the treatment of leukemia. Itraconazole (ITR) is an azole antifungal that has activity against both Candida species and molds. Its prophylactic use in patients at high risk for IFI has been shown to reduce invasive mold infections, but the antifungal efficacy depends on a sufficient plasma concentration early in the course of prophylaxis. We tested a loading dose strategy to reach plasma levels above 500 μg/l by 48 hours.
ITR plasma concentrations from 30 patients (pts) in 51 treatment courses were sampled on day 3, 7 and 11 of prophylaxis which started one day after conclusion of chemotherapy. It consisted of 400 mg oral solution and 400 mg intravenous ITR on day 1+2 and continued with 400 mg oral solution daily until an ANC count > 500/μl, limiting toxicity or the use of empirical antifungal treatment. Plasma concentrations were measured by LC-MS/MS. Two pts received an allogeneic, 4 pts an autologous stem cell graft. Underlying diseases were 43 AML, 4 CML blast crisis, 3 Hodgkin’s disease and 1 Ph+ ALL. In 45 courses chemotherapy was based on Cytarabine plus an anthracycline.
Data from 51 courses were analyzed. Median time of neutropenia (ANC < 500/μl) was 11 days (4–25 days), median time of ITR was 14 days (4–28 days). Median ITR plasma concentrations were 902 μg/l (176–5149) on day 3, 604 μg/l (145–1945) on day 7 and 942 μg/l (191–2987) on day 11. The desirable plasma level of > 500 μg/l after 48 hours of ITR was achieved in 86% of courses and remained above that level in 64% on d 7 and 75% on d 11. No proven or probable IFI could be observed. In 15% of courses empiric antifungal treatment with Amphotericin B and Voriconazole was initiated because of persisting neutropenic fever. Colonization with Candida species was found in 32% of courses. Nausea and vomiting grade 1/2 CTC was observed 39%, diarrhea in 14% of courses.
Sufficient plasma concentrations 48 hours after starting antifungal prophylaxis with ITR can be reached with a loading dose combining oral solution and intravenous formulation. Toxicity is mild with only 10% of patients refusing oral solution. Our strategy suggests a high prophylactic efficacy in terms of preventing IFI in this high-risk group of patients.
Clinical Use of Caspofungin in Immunocompromised Children: A Multicenter Survey.
Authors: Lehrnbecher Thomas , Attarbaschi Andishe , Schuster Friedhelm , Herzog Nadine , Grigull Lorenz , Dworzak Michael , Beutel Karin , Laws Hans-Jürgen , Groll Andreas H. 
Published: October 2019

Abstract
Background : Caspofungin (CAS) is a novel echinocandin, which is approved for several antifungal indications in adults. Although the compound is not licensed in pediatric patients (pts), it is being used in children with refractory infections or intolerance to standard antifungal agents.
Methods: We conducted a multicenter retrospective survey to obtain data on clinical use, safety, and outcome in immunocompromised pediatric pts who received therapy with CAS.
Results : The survey identified 71 immunocompromised children and adolescents [mean age (range) 11.4 years (5 months –26 years)]. Out of the 29 females and 42 males, 53 suffered from hematological malignancies, 10 from bone marrow failure syndromes, 3 from solid tumors, 2 from congenital immunodeficiency, and 3 from non-malignant hematological disorders. Forty-two pts (59%) had undergone allogeneic blood stem cell transplantation, and 36 pts (51%) had an ANC of less than 500/μL at baseline. CAS was administered for proven (n=18), probable (15), and possible (20) invasive fungal infection, or as empirical antifungal treatment (18). All but one pt had received prior systemic antifungal therapy with amphotericin B (52) and/or triazoles (41). The 71 pts received CAS for a mean duration of 43.5 days (range, 2–218) as single agent (22) or in combination with other antifungal agents (49). The mean maintenance dosage of CAS was 1.2 mg/kg (range, 0.4–2.9) or 34.8 mg/msqu (range, 16.3–57.5). In none of the pts, CAS was discontinued prematurely due to clinical or laboratory adverse events. Clinical adverse events were described in 35 children (49%), mostly fever (28), nausea and vomiting (18), diarrhea (8), and headache (5). Increases in hepatic or renal function parameters were frequent in these pts that received multiple other therapeutic compounds. Whereas at the end of treatment (EOT), mean GPT and GOT were slightly elevated (from 41 at baseline to 61 U/L at EOT; p=0.002 and from 29 to 80 U/L, p=0.001, respectively), mean serum creatinine, bilirubin, and alkaline phosphatase values were not different from baseline. Complete responses, partial responses, or stabilization were observed in 4/8/3 of 18 evaluable pts with proven, in 4/2/3 of 13 pts with probable, and in 3/8/2 of 15 pts with possible invasive fungal infection. Of 16 evaluable pts who received CAS empirically therapy, 10 successfully completed therapy. Overall survival was 74% at EOT and 67% at three months post EOT (65 and 60 evaluable pts, respectively).
Conclusions: The data of this retrospective survey show that CAS displays acceptable safety and tolerance and may have useful antifungal efficacy for second line treatment of severely immunocompromised pediatric patients.
Anticipated Diagnosis of Adverse Events after Stem Cell Transplantation Using Highly Sensitive STR-PCR for Chimerism Quantification.
Authors: Nava Paola , Simon Ainhoa , Gonzalez-Pardo Gema , Jimenez Jose L. , Gonzalez-Rivera Milagros , Balsalobre Pascual , Carrion Rafael , Serrano David , Gomez-Pineda Alfonso , Diez-Martin Jose L. , Buño Ismael 
Published: October 2019

Abstract
Introduction: The current gold standard for chimerism quantification after allo-stem cell transplantation (SCT) is based on the polymerase chain reaction of DNA short tandem repeats (STR-PCR). This methodology is sex-independent, highly informative and quantitatively accurate. However, this method has a moderate sensitivity (1–3%).
Objective: To test the usefulness of increasing the assay sensitivity by 3 different approaches in order to detect recipient residual cells.
Material and Methods: Two sets of 20 samples, belonging to artificial mixtures of male and female peripheral blood (PB) cells in different proportions (% male: 100, 75, 50, 25, 10, 5, 3, 1, 0.1, 0) were prepared to test the assay sensitivity and reproducibility. Additionally 58 samples from 10 selected patients showing different clinical evolution post-SCT were retrospectively studied. Chimerism was analyzed on genomic DNA (purified QIAamp DNA blood kit, Qiagen) by multiplex STR-PCR (AmpFlSTR SGM Plus revealed on capillary electrophoresis in an ABI Prism 3100 automated DNA sequencer; Applied Biosystems). Three different approaches aimed to increase the sensitivity of STR-PCR were tested: (1) Increasing DNA concentration in the PCR (1x, 2.5x, 5x), (2) Increasing the concentration of the PCR product for the capillary electrophoresis (1x, 2.5x, 5x) and (3) Increasing the sample injection time into the capillary for the electrophoresis (10s, standard time, 30s and 50s).
Results: The standard STR-PCR showed a sensitivity of 1% in both sets of male-female PB artificial mixtures. Both approaches increasing DNA concentration in the PCR and the PCR product in the capillary electrophoresis did not achieved better sensitivity. Moreover, appropriate analysis of the samples was frequently hampered due to fluorescence saturation. However, longer injection times (30s, 50s) showed that currently underrepresented DNA fragments were conspicuously overestimated, giving a one-log increase in the sensitivity of the STR-PCR assay, which reached a 0.1%. This approach was used to re-analyze the 23 SCT patient samples previously identified as in complete chimerism by standard STR-PCR. The 0.1% sensitivity methodological approach allowed to detect residual/reappearing recipient cells in three of the 23 analyzed samples. Therefore this new approach would have allowed to anticipate the detection of graft rejection and disease relapse in 2/10 patients, 7 and 77 days respectively.
Conclusion: Long injection times (30s and 50s) in the capillary electrophoresis after STR-PCR result in a one log sensitivity increase (from 1% to 0.1%). This would allow earlier diagnosis of adverse events after SCT favoring a prompt introduction of therapeutic interventions.
Late Onset Hemorrhagic Cystitis (LOHC) Following Stem Cell Transplant (SCT): Risk Factors and Outcomes.
Authors: Janbay Nasser , Amin Albish , Visweshar N. , Ojha Rakesh , Mohsen Reyad , Randhawa Devinderdal , Stives S. , Benn H. , Manna Pradeep , Nath Rajneesh 
Published: October 2019

Abstract
Background. Hemorrhagic cystitis (HC) following stem cell transplant (SCT) is classified into two types, based on causes and time of appearance. Early-onset HC occurs within 48 hours of preparative regimen, and is thought to be a complication of high-dose chemotherapy containing preparative regimen. Late-onset HC occurs beyond 48 hours from the preparative regimen and has been reported to be associated with viral infections.
Goals. To establish risk factors for predicting LOHC and the impact on the outcomes following SCT.
Subjects and methods. We retrospectively analyzed the clinical records of 41 patients who underwent SCT from June 2002-June 2004, the median age 54 years (range 20–74), including 28 males and 13 females. The patients had the following diagnosis: AML/MDS=15, ALL=4, CML=2, NHD/HD=14, MM=4, solid tumor=1, and AA=1. Twenty-two patients received allogeneic transplants (matched sibling-10, matched unrelated-2, cord blood -10), and 19 patients underwent autologous SCT. Conditioning regimens included the following: BEAM=8, BU+CY±Thiotepa=17, TBI+CY±others=4, Melphalan±Fludara=12. Sixteen patients were considered to have poor risk disease (those beyond first complete remission or in relapse) and 25 patients had good risk disease. LOHC was defined as: RBCs in the urine without any trauma and persistence of >7 days. All patients who developed LO HC were tested for BK virus, CMV, and adenovirus in the urine and blood, which were measured by a real-time PCR assay.
Results. LOHC was detected in 11 patients (26.8%), 8 of which had BK viruria. median of 23 days (range 13–60 days), None of these patients were detected to have CMV or adenovirus. Nine patients (90%) that received cord blood SCT developed LO HC, while only two patients (6.4%) who did not have cord blood SCT developed LO HC (P=0.0001). Ten patients (58.8%) who had BU+CY±Thiotepa developed HC compared to one patient (4.2%) who did not have the same regimen and developed LO HC (P=0.0002). Nine patients (56.2%) who had poor risk disease developed LOHC, while two patients (8%) who had good risk disease developed LOHC (P=0.001). Eight patients (72.7%) who developed LOHC died compared to only six patients (20%) who did not develop LOHC and died (P=0.003). Among the 28 males, 10 patients developed LOHC, compared to only one female patient who developed LOHC (P=0.126).
Conclusion. Three predisposing factors were identified for the development of LOHC: cord blood transplant (P=0.0001), Busulphan use for pre-transplant conditioning (P=0.0002), and poor risk group characteristics (P=0.001). The mortality rate was significantly higher among patients who developed LOHC.
The Influence of Human Plateley Antigen Match on the Success of Stem Cell Transplantation after Myeloablative or Reduced-Intensity Conditioning Regimen.
Authors: Leitner Gerda C. , Greinix Hildegard T. , Kalhs Peter , Paul Hoecker , Simon Panzer 
Published: October 2019

Abstract
Background: Mismatches between donor and recipient for human platelet antigens (HPA) may affect the success of transplantation due to: a) serving as minor histocompatibility antigens and therefore render recipients at risk for GvHD, b) inhibition of thrombopoiesis due to platelet antibodies.
Patients and Methods: We evaluated in 54 patients receiving hematopoietic stem cell transplantation (HSC T) from HLA matched siblings after a myeloablative conditioning regimen the occurrence of GvHD, transplant related mortality (TRM), and the need of platelet support by prospective analyzes of donor-recipient pairs for HPA -1, -2, -3, and -5 allotypes. Patients were screened for platelet antibodies prior to transplantation and in weekly intervals until day 100 after transplantation. Forty five patients receiving HSCT from related or unrelated donors after a reduced-intensity conditioning regimen (RIC) were enrolled retrospectively after a median observation time of 372 days.
Results: Neither the incidence of GvHD and TRM, nor the onset of thrombopoiesis, nor the CCI after platelet transfusions, nor the frequency of platelet transfusions were affected by HPA mismatches. TRM among patients receiving a RIC was higher when grafts were from unrelated donors with 2 or more mismatches. Six of 7 patients who died due to TRM had 2 mismatches in the HPA system, although TRM was not significantly associated with mismatched HPA (p = 0.06). However, within donor-recipient pairs with more than one HPA mismatch TRM occurred when grafts were from unrelated donors (p = 0.03).
Conclusion: Thus, the HPA match does not affect the success of transplantation.
Diverse Functional Implications of ADAMTS13 Gene Mutations in Patients with TTP and Congenital Deficiency.
Authors: Donadelli Roberta , Banterla Federica , Capoferri Cristina , Galbusera Miriam , Ruggeri Zaverio M. , Bucchioni Sara , Noris Marina , Remuzzi Giuseppe 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the VWF cleaving protease ADAMTS13, causing life-threatening disseminated microvascular thrombosis. Here we report four missense mutations (V88M, G1239V, R1219W, R1123C) in three patients with congenital ADAMTS13 deficiency. The three subjects carrying the mutations had less than 10% normal ADAMTS13 plasma antigen levels (measured by ELISA), which is consistent with previously reported data showing that most ADAMTS13 mutations in TTP patients result in impaired secretion of the protein. To evaluate whether the small amount of the mutant protease present in patients’ plasma had proteolytic activity, we cloned the ADAMTS13 cDNA in the pMT/Bip/His Drosophila expression vector and introduced the respective mutations by directed mutagenesis technique using wild-type cDNA as a template. These wild-type and mutant constructs were stably transfected into S2 Drosophila cells under the influence of the Drosophila BiP protein signal sequence, which allows the protein to be secreted into the medium and overcomes impaired secretion caused by the mutations. The induction of the histidine-tagged ADAMTS13 recombinants following the addition of copper was analyzed by Western blotting using an anti-hexahistidine monoclonal antibody. Equal amounts of recombinant ADAMTS13 proteins were used to evaluate proteolytic activity of recombinant proteins by cleavage of the rVWF A1-A2-A3 substrate. The proteolytic carboxyl terminal product of about 30 kDa was visualized by Western blot with a mouse monoclonal antibody directed against an epitope contained within the A3 domain of VWF. All the four missense mutations exhibited reduced activity: V88M:40%, G1239V: 66%, R1219W: 62% and R1123C: 64% of wild type activity . The results were also confirmed by collagen binding assay. For the the V88M mutation (located in the metalloprotease domain), decreased activity was confirmed by kinetic studies. In conclusion, mutant ADAMTS13 proteins found in patients with TTP, besides defective secretion, also have reduced protease activity. The mechanisms of the deficiency will be the matter of further studies.
Favorable Outcomes with Acceptable Toxicity Using a Reduced Intensity Conditioning Regimen for Patients Otherwise Ineligible for Related Donor Allogeneic Stem Cell Transplantation.
Authors: Westervelt Peter , Holmes Wendy , Emmons Robert , Becker Pamela , Lowry Phil , Traynor Ann , Ballen Karen 
Published: October 2019

Abstract
Allogeneic stem cell transplantation represents a potentially curative treatment modality for patients with advanced hematologic malignancies. However, the toxicity associated with fully myeloablative conditioning regimens has historically limited its use to younger, otherwise healthy patients. To investigate the feasibility of allogeneic stem cell transplantation in older (over 55 years) or otherwise higher risk patients (eg, prior transplant) with fully HLA-matched sibling donors, a reduced intensity conditioning regimen consisting of fludarabine (30 mg/M2 IV qd X 6, day −8 to −3), ATGAM 10 mg/kg IV qod X 4, day −7/−5/−3/−1) and melphalan (100 mg/M2 IV X 1, day −2) was employed in a single institution setting. GVHD prophylaxis consisted of cyclosporine (2 mg/kg IV bid, adjusted, beginning day −1) and methotrexate (10 mg/m2 IV, day +1/+3/+6).
RESULTS: 21 patients with a variety of hematologic malignancies (AML=4, MDS=5, NHL=5, CML/MPD=3, HD=2, MM=1, CLL=1) were enrolled. Mean age was 54 years (range 28–66). 7 patients had undergone prior autologous transplants. Median followup among surviving patients was 42 months (range 3–58 months). Peripheral blood chimerism at day +100 was >95% donor in 16/18 patients, 80% (with subsequent conversion to 95%) in one patient, and >95% recipient (with documented relapse) in one patient. Acute GVHD grade 1–2 was seen in 52% and grade 3–4 in 10% of patients. Chronic GVHD was observed in 9/20 evaluable patients (45%). Infectious complications included documented bacteremia (6 cases), candida albicans fungemia (1), aspergillus pneumonitis (3), nocardia pneumonitis (2), CMV viremia (6), CMV colitis (1). Veno-occlusive disease (self-limited, grade 1–2) was observed in 4/21 patients (19%). Relapse was observed in 5/21 patients (24%) at a median 249 days post-transplant (range 97–328 days). Event-free survival was 90% (19/21) at 100 days, 58% (11/19) at 1 year and 47% (8/17) at 3 years. Overall survival was 95% (20/21) at 100 days, 68% (13/19) at 1 year and 47% (8/17) at 3 years. Primary causes of death were relapse (4/9), infection (4/9), and idiopathic pneumonitis/multi-organ failure (1/9). Chronic GVHD was a significant contributing factor in 3/4 fatal infections. PTLD was observed in one patient, who subsequently died of CMV infection/sepsis syndrome.
CONCLUSIONS. Allogeneic BM/SCT using a reduced intensity conditioning regimen is feasible among older patients, and those who are otherwise poor candidates for myeloablative BM/SCT regimens; however, GVHD, infection, and relapse remain formidable obstacles to achieving successful outcomes.
Impact of Allogeneic Stem Cell Transplantation (ASCT) on Outcome of Biphenotypic Acute Leukemia (BAL):.
Authors: Krishnan Amrita Y. , Chang Karen L. , Fung Henry C. , O’Donnell Margaret , Bhatia Ravi , Spielberger Ricardo , Pullarkat Vinod , Stein Anthony , Kogut Neil , Kirschbaum Mark , Bolotin Ellen , SarkodeeAdoo Clarence , Dagis Andrew , Cheng Nigel , Forman Stephen J. 
Published: October 2019

Abstract
Biphenotypic acute leukemia is a rare disease accounting for approximately 10% of acute leukemias using the new scoring system. No standard therapeutic approach exists for this entity. In addition, the prognosis for these patients (pts) is poor and thought to be worse than for acute myelogenous leukemia (AML). ASCT may provide improved disease free survival for patients with high risk AML, but its role in BAL is unknown. We undertook a retrospective study of pts with BAL to determine if outcome was similar following ASCT to pts with AML in first remission. Between 7/93 and 2/04, nine patients with BAL who underwent ASCT were identified. Criteria for the diagnosis of BAL was based on the scoring system adapted from the European Group of Immunological Classification of Leukemia. Pts with Philadelphia positive acute lymphoblastic leukemia (ALL) were excluded. Cytogenetics at presentation included 1 pt with deletion7 and trisomy 8, 1 with 11q23, 2 with complex karytoype, 4 with normal cytogenetics ,1 unknown. Six pts were treated with an AML induction of Idarubicin/Cytarabine, two with an ALL regimen Daunorubicin/Vincristine/Prednisone and one with an Idarubicin- AML based first induction, and then a combination of an ALL/AML reinduction at first relapse. Eight pts were in first complete remission (CR) and one pt in second CR at ASCT. Median age at ASCT was 34 years (range 11–60). Median time from diagnosis to ASCT was 3.4 mos (range 1.5–5.2). Seven pts received sibling donor (SIB) and two received unrelated donor (URD) stem cells. Two pts received marrow and seven received peripheral stem cells. The conditioning regimen consisted of 1320cGy total body irradiation (TBI)+VP16 60mg/kg in 6 pts, 1320cGy TBI+Cyclophosphamide 120mg/kg in 1 pt, Fludarabine125mg/m2+Melphalan 140mg/m2 in 2 pts. Seven received a Cyclosporin- based graft versus host disease prophylaxis regimen (GVHD) and two a Tacrolimus- based regimen. Six pts developed grade III GVHD. Two patients died of pulmonary toxicity, one of GVHD, one from infection and one from disease relapse. One year overall survival (OS) is 39%( 95% CI 13–73). The relapse rate at one year was 20%. In conclusion, despite unfavorable cytogenetics in many patients, relapse rates are low following ASCT for BAL and comparable to pts undergoing ASCT for AML. Future approaches include methods to reduce transplant related mortality which was the major cause of reduced survival in this series.
Improved Disease Survival without Increased GVHD Using Low Dose Cyclosporine and Prednisone in Allogeneic Stem Cell Transplantation - a Case Control Study.
Authors: Moore John J. , Ma David D. , Dodds Tony , Milliken Sam , Fay Keith , Concannon Alan , Smith Ian Nivison 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (HSCT) can cure numerous malignant and non-malignant diseases but this is offset by significant morbidity and mortality from graft versus host disease (GVHD). The standard prophylactic regimen contains cyclosporine, methotrexate and/or prednisone however doses and the timing of tapering remain unclear. Recently Ruutu et al demonstrated reduced GVHD using a prednisone based prophylactic regimen without a survival benefit whereas Baclgalupo et al demonstrated an increased survival benefit with 1mg/kg cyclosporine over 3mg/kg which strongly correlated with cyclosporine levels. Since early 2002 we have adopted both these strategies in an attempt to reduce GVHD in myeloblative HSCT but still maintain disease free survival. Consecutive myeloblative allogeneic HSCT patients (n=47, median age 41 yrs, 28 sibling or family, 19 unrelated) underwent HSCT using cyclosporine 1mg/kg, standard dose methotrexate and prednisone commencing at D14 0.5mg/kg, according to Ruutu et al. All sibling allograft patients underwent conditioning with Bu/Cy whereas unrelated recipients received Cy/TBI. This group was compared with 94 historical controls for age and disease status (median age 36 yrs, 63 sibling or family, 31 unrelated). At a median of 1 year follow up (range 100–600 days), overall and disease free survival is significantly increased in the low dose cyclosporine/prednisone arm (OS: 75% vs 50% at 1 yr, p=0.04). Acute GVHD (II–IV) was similar in both arms at D100 with a trend to less GVHD in the low dose cyclosporine/prednisone arm (20% vs 30%, p=0.1). These results suggest that the low dose cyclosporine/prednisone regimen has controlled GVHD whilst maintaining an adequate GVL effect. Randomised trials using this regimen may be warranted to fully determine its place in allogeneic HSCT prophylaxis.