bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of Ganciclovir Following Oral Valganciclovir Versus Intravenous Ganciclovir in Allogeneic Hematopoietic Stem-Cell Transplant Patients with Stable Graft-Versus-Host Disease of the Gastrointestinal Tract.
Authors: Winston Drew J. , Ratanatharathorn Voravit , Baden Lindsey , Emmanouilides Christos , Gabriel Don , Li Sherry , Lange W. Robert 
Published: October 2019

Abstract
Cytomegalovirus (CMV) disease can be effectively prevented in allogeneic hematopoietic stem cell transplant (HSCT) patients by ganciclovir (GCV) given as prophylaxis or preemptive therapy. Due to the low bioavailability of oral GCV capsules, GCV is usually administered intravenously (IV) to HSCT patients. Valganciclovir (VGCV) is the valine ester prodrug of ganciclovir. In healthy subjects, HIV-infected patients, and solid-organ transplants, the oral bioavailability of VGCV is about 60%, or 10-fold higher than oral GCV capsules. The bioavailability and total GCV exposure provided by oral VGCV relative to IV GCV in HSCT patients with gastrointestinal (GI) GHVD has not been established.
METHODS: HSCT patients were eligible for the study if the following criteria were satisfied: 1) ≥16 years of age; 2) biopsy-proven GHVD of GI tract with nausea and/or diarrhea (300–1500 ml/day) or proven GVHD of skin or liver plus diarrhea with no other explanation; 3) no active CMV infection or disease; 4) neutrophil count ≥1000/μL; 5)creatinine clearance >60 ml/min. Following a standardized breakfast, eligible patients were randomized to receive a single dose of open-label study drug (900 mg of oral VGCV or 5 mg/kg of IV GCV). After a minimum 48 hr. washout period, patients were crossovered to alternate study drug. Blood for levels of GCV and VGCV were obtained predose and then over the 24 hours after dosing. Pharmacokinetic (PK) parameters were derived by noncompartmental methods.
RESULTS: Data from 16 patients are currently available. Patient demographics include mean age 45 yrs (range 23 to 58 yrs); males 13, females 3; mean weight 80kg (range 52 to 107 kg); mean creatinine clearance 96 ml/min (range 62 to 184 ml/min). Median time after transplant for study was 303 days (range 102 to 988 days). Mean GCV PK parameters are summarized in the following table.
Mean GCV Value (Coefficient of variation in %)
Oral VGCV-900 mg IV GCV-5mg/kg Parameter N = 16 N = 16 AUC o -τ (μg•hr/mL) 43.58 (37) 46.74 (40) AUC o-∞ (μg•hr/mL) 46.03 (41) 48.89 (43) C(max) μg/mL) ( 6.45 (30) 12.53 (30) T max (hr) 3.13 (22) 0.97 (8) T½ (hr) 4.97 (31) 5.09 (29)
GCV AUC values were similar, although maximum GCV concentrations were higher and acheived earlier with IV GCV. Terminal elimination half-life of GCV with oral VGCV and IV GCV were similar. After 900 mg of oral VGCV, mean plasma Cmax for VGCV was low (0.22 μg/mL), which is consistent with rapid and almost complete metabolism of VGCV to GCV.
CONCLUSION: These preliminary results suggest that systemic exposure to GCV after 900 mg of oral VGCV is comparable to that achieved with IV GCV in HSCT patients with stable GI GVHD. Oral VGCV could be a useful alternative to IV GCV in certain HSCT patients requiring prophylaxis or preemptive therapy for CMV.
Cidofovir Is Safe and Effective in the Treatment of Adenoviral Infection in Pediatric Hematopoietic Stem Cell Transplantation.
Authors: Yusuf Usman , Hale Gregory , Woodard Paul , Benaim Ely , Kasow Kimberly , Horwitz Edwin , Leung Wing , Srivastava Deo , Handgretinger Rupert , Haden Randy 
Published: October 2019

Abstract
Adenovirus (ADV) infections are increasingly recognized as significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Early diagnosis and prompt initiation of effective treatment are important in preventing often fatal disseminated ADV disease.
We report our experience with using cidofovir (CDV) for the treatment of adenovirus infection in 57 HSCT patients, median age 8 years (range 0.5–26). Fifty-four patients received allogeneic HSCT, 35 of whom were T-cell depleted with 3 patients receiving autologous marrow. Blood was tested weekly for ADV by quantitative real-time PCR, with viral culture performed on urine, stool and throat swabs. Antiviral therapy was initiated immediately upon detection of ADV by PCR, culture or tissue histopathology. Cidofovir was given at 5mg/kg once weekly for 2 weeks, then every 2 weeks untill 3 negative PCR or cultures were documented. ADV was first detected at a median of 53 days (range 6–319 days) after HSCT. The most common clinical manifestations were diarrhea (53%), fever (21%), hemorrhagic cystitis (12%), and pneumonitis (11%). Fourteen (25%) patients were asymptomatic and four (7%) patients had exacerbation of an ongoing GVHD.
The virus was isolated from stool 53%, blood 50%, urine 16%, respiratory specimens 16% and the cerebrospinal fluid in 1 patient. Twenty (35%) patients had the virus isolated from more than 2 sites. Of the 30 patients who initially had ADV only in stool, 77% of them became PCR-positive in the blood while on CDV therapy, at a median of 10 days after ADV was first detected from the stool. The median duration of therapy was 60 days (range 1–270), with a median of 5 doses given (range 1–22). CDV treatment was associated with resolution of diarrhea, hemorrhagic cystitis, fever and pneumonitis in 56 patients in whom the virus became undetectable by both cultures and quantitative PCR. There was one adenovirus-related death due to pneumonitis and ARDS. No cases of dose-limiting nephrotoxicity were observed. Cidofovir was demonstrated to be safe and effective for the treatment of ADV infection in this predominantly pediatric HSCT patient population. Vigilant surveillance for ADV and early treatment with CDV can prevent the poor outcomes associated with ADV disease. A larger prospective study will be needed to further determine the role of CDV in the treatment of ADV in patients after HSCT.
Pharmakokinetics of Valganciclovir after AlloSCT: A Fixed Oral Dose Can Be Used for Preemptive Therapy in Patients with Normal Body Weight - Even with Intestinal GVHD.
Authors: Einsele Hermann , Reusser Pierre , Hebart Holger , Hertenstein Bernd , Bornhaeuser Martin , Ehninger Gerhard , Kroeger Nikolaus , Kahls Peter , Chalandon Yves , Rohde Frank 
Published: October 2019

Abstract
Background: After alloSCT, oral valganciclovir (VALGCV) is a promising alternative to IV GCV against CMV but its pharmacokinetics (PK) have not been studied.
Methods: We investigated the PK of GCV after VALGCV in a randomized, crossover phase II-study of 48 patients (pts) after alloSCT. Pts who had >400 copies/ml of CMV DNA in plasma measured by quantitative PCR were randomized to receive a fixed dose of VALGCV 900 mg BID (adjusted for renal function) for 7 days, followed by IV GCV as 1-h-infusion at 5mg/kg every 12 h for another 7 days, or to receive the inverse sequence of study drug administration. The PK of GCV were assessed on days 4 and 11. Safety monitoring was done until day 84 after alloSCT.
Results: 28 pts were fully assessable for PK analyses. Among the 22 pts without intestinal graft-versus-host disease (GVHD), the mean±SD AUC 0–12 (mg/L*h) was 53.8±18.0 on VALGCV vs 39.5±13.9 on IV GCV (mean difference 14.3 [95% CI 7.6 to 20.9]); Cmax (mg/L) was 8.8±2.4 vs 10.3±2.1; tmax was 2.7±0.8 vs 1.1±0.6; and t1/2 was 4.2±1.1 vs 3.4±0.8. Among the 6 pts with intestinal GVHD, the mean±SD AUC 0–12 (mg/L*h) was 46.6±24.9 on VALGCV vs 35.3±12.8 on IV GCV (mean difference 11.3 [95% CI −13.4 to 35.9]); Cmax (mg/L) was 7.1±3.6 vs 11.1±3.1; tmax (h) was 2.7±0.8 vs 1.2±0.4; and t1/2 (h) was 5.6±2.0 vs 3.3±0.7. The bioavailability of GCV after VALGCV was 53%. Using a VALGCV fixed oral dose (1.800mg) for preemptive therapy in pts with low body weight led to a sharp increase of the VALGCV / IV GCV ratio (i.e. 50kg = 1.9). With a limited number of pts with low body weight included in this study no severe GCV associated toxicity was seen in these pts. Non-fatal CMV pneumonia developed in 2 pts during follow-up after antiviral therapy, and servere neutropenia < 500/μl occurred in 3 pts. Clearance of CMV DNA was equally effective in both arms.
Conclusions: In alloSCT, exposure to GCV after preemptive therapy using VALGCV is higher compared to that with IV GCV in patients with and without intestinal GVHD. In addition to patients with renal dysfunction patients with low body weight < 60kg and normal renal function should be treated very carefully to avoid over-exposure to GCV. Although no severe toxicity was demonstrated in this pk-study a further study to address the safety and efficacy of VALGCV in alloSCT is needed.
B Cell Development in the Absence of PU.1.
Authors: Ye Min , Ermaermakova-Cirilli Olga , Graf Thomas 
Published: October 2019

Abstract
Mice deficient of the ETS-family transcription factor PU.1 lack B cells as well as macrophages. While most macrophage specific genes are known to be regulated by high levels of PU.1, the reason for the defect in B cell formation is not known. Here we analyzed a mouse strain in which a floxed version of the PU.1 gene, surrounding exon 4 and 5, which encode the DNA, binding and PEST domains (developed by C. Somoza and D. Tenen), was excised by Cre mediated recombination. As expected, this strain lacks both B cells and macrophages and die at birth. Surprisingly, however, we were able to establish lymphoid cell lines from fetal livers of these mice (day 14 to day 18), which proliferated on S17 stromal cells supplemented with IL-7 and stem cell factor. These cells expressed the B lineage cell surface markers CD19, CD43, BP-1 and CD24, but not B220. They also expressed B cell transcription factors, EBF, E47, Pax5, and their target genes, Rag1, IL7R, λ5 and v-preB, as detected by RT-PCR, exhibited DJ and VDJ immunoglobulin heavy chain rearrangements, and expressed IgM after IL-7 withdrawal. We then tested the effect of PU.1 deletion in B cells in adult animals by crossing the floxed PU.1 strain with a CD19 Cre mouse line. The spleen and peripheral blood (but not bone marrow) of these mice contained B cells that were CD19+ IgMlow, IgDhigh but B220 negative and instead expressed CD43. Thus PU.1 is not essential for immunoglobulin production and late B cell development. Although PU.1−/− fetal liver cells can give rise to cells, resembling Pre-B in vitro, the process of B cell formation was delayed by almost 12 days, compared with wt fetal liver, and the efficiency was reduced approximately 25-fold. In addition, PU.1 deficient B cells demonstrated an impaired ability to engraft into the bone marrow, when injected into irradiated SCID mice. We have found that PU.1 deficient B progenitors showed reduced or undetectable levels of the SDF1 receptor CXCR4, a receptor that has been implicated in B cell homing. Taken together, our observations suggest that PU.1 plays two different roles during B cell development: for early B cell formation and for proper migration and engraftment, which might be mediated through regulation of CXCR4 expression.
Tissue Iron Overload Is Common Post Transplantation (Allo BMT) and Is Associated with Red Cell Transfusion Load and HFE Genotype.
Authors: Carradice Duncan , Shuttleworth Peter , Szer Jeffrey , Roberts Andrew , Grigg Andrew 
Published: October 2019

Abstract
In order to analyse the incidence of iron overload after allo BMT and assess the role of venesection in preventing complications, we retrospectively analysed 168 consecutive patients undergoing allo BMT at our institution from 1998–2003 surviving at least one year. Iron studies were performed routinely pre-BMT, at D100, one & two years post BMT. Iron overload was defined by at least one of the following criteria i)liver biopsy (n=24), one of : a) dry weight iron concentration >80μmol/g; b) iron index >1.9; c) Perl’s stain grade 3 or 4, ii) CT liver iron >1.0mg/ml (n=13) iii) raised ferritin >1000 μg/L and transferrin saturation >55% on 2 occasions, persisting >6/12 post BMT (n=11), iv) venesection >5g iron (n=1). Using these criteria, iron overload occurred in 49/168 (29%) pts. 12/119 in the non-overloaded group had further investigation but did not meet the criteria; liver biopsy (n=10) or CT (n=2). Elevated ferritin, particularly early post-transplant, did not reliably predict for iron overload, with 55/91 evaluable patients having values >1000μg/L at D100 not fulfilling the criteria for iron overload. There was no difference between overloaded and non-overloaded patients with respect to age or sex. Acute (15/49 vs. 26/113) or chronic liver GVHD (25/46 vs. 47/105) was not different between the two groups (both p>0.05). Only 3 patients were hepatitis B sAg+ or hepatitis C Ab+. The iron overloaded group was more likely to i) have been transplanted for acute leukaemia (29/49 vs. 33/119; p 0.0002) ii) be C282Y heterozygotes (11/46 vs. 10/110, p 0.02) (iii) been transfused more units of red cells (mean 42 vs. 19; p<0.0001) and iv) have persistently abnormal liver function post-transplant, ALT (IU/ml; normal <55) at 1 year 77 vs. 52 and at 2 years 67 vs. 37 (all p<0.05). There was no effect of hetero- or homozygosity for H63D. 63 patients were analysed for the S65C, V59M and Q283P mutations. One patient was heterozygous for the S65C mutation (non-overloaded group). A mean of 12.3 units were venesected in 22 patients (range 2–46), all of whom had received >25 units of red cells. ALT fell significantly (mean pre venesection 189 IU/ml, post 36, p<0.05), as did transferrin saturation (mean pre venesection 68%, post 29%, p<0.05). We conclude that tissue iron overload is common after BMT, that biochemical measures of iron stores (ferritin and transferrin saturation) may be unreliable in this context, particularly in the early post BMT period and that radiological or histological assessment to distinguish hyperferritinaemia due to inflammation from true tissue iron overload may be required. Patients at risk of iron overload (transfusions >25 units, C282Y heterozygotes) should be closely monitored and early venesection therapy instituted to minimise organ damage.
Primary Central Nervous System Lymphomas (PCNSL) Are Distinct from Systemic DLBCL for Expression Pattern of Germinal Center and Activation B-Cell Markers. A GOELAMS Study.
Authors: Camilleri-Broet Sophie , Delwail Vincent , Moreau Anne , Gardembas Martine , Raphael Martine , Lamy Thierry , Sautes-Fridman Catherine , Colombat Philippe , Martin Antoine 
Published: October 2019

Abstract
Most of the PCNSL of immunocompetent patients are diffuse large B-cell lymphomas (DLBCL). They differ from systemic DLBCL in their outcome, a poor survival in most cases contrasting with a lack of systemic dissemination. Concerning their histogenic derivation, a germinal center B (GCB) cell origin has been hypothesized, based on BCL-6 expression and ongoing mutational activity. Using cDNA microarrays, two main prognostic subgroups have been described in systemic DLBCL: the favorable GCB-cell like subgroup and the activated-B cell like, characterized by a non-favorable outcome. These prognostic subgroups are defined accurately by immunohistochemistry, using a panel of GC B-cell (CD10, Bcl-6) and activation (MUM1/IRF4, CD138) markers. The goal of the present study was to determined the immunoprofile of PCNSLs and its potential prognostic significance by analyzing retrospectively 28 cases included in two clinical trials from the GOELAMS (Groupe Ouest Est des Leucémies et Autres Maladies du Sang). According to the pathological panel review, all cases were classified as DLBCL, not associated with Epstein-Barr virus as shown by in situ hybridization. Immunohistochemistry was performed for CD10, BCL-6 and MUM1/IRF4 and CD138 on paraffin-embedded sections. Labelings were interpreted independently by two pathologists without knowledge of clinical data with 10% increments. Cases were considered positive when positive tumor cells accounted for more than 30%. CD10 was expressed in 1 out of the 28 cases. BCL-6 was expressed in more than 30% of tumor cells in 15/28 cases (54%). Strong nuclear expression of IRF-4 was found in almost all cases (26/28; 93%) and none of the tested cases expressed CD138. Thus, only one case was subclassified in the favorable GCB-cell like subgroup (CD10+/BCL-6+/IRF4−/CD138−). The other cases, classified in the non favorable activated-B cell like prognostic subgroup. The latter may be divided in two patterns: an activated or “late” GC B-cell pattern (CD10−/BCL-6+/IRF4+/CD138-) and an activated non-GC pattern (CD10−/BCL-6−/IRF4+/CD138−) observed in 54% and in 42 % of the cases, respectively. This study shows that PCNSL display an relatively homogeneous immunoprofile, corresponding to an activated late GC or early post-GC stage of B cell maturation, different from that published in systemic DLBCL. This result may partly explain the usual poor prognosis of PCNSL and raises the question of considering PCNSL as a separate biological entity, distinct from systemic DLBCL.
Follicular Lymphoma: Design of a Protein-Based Survival Predictor Using Tissue-Microarrays (TMA).
Authors: Camacho Francisca I. , Arranz-Saez Reyes , Caleo Alessia , Cannata Jimena , Cereceda Laura , Gonzalez Leocricia , Perez-Martin Mª Elena , Sanchez-Verde Lydia , Montalban Carlos , Garcia Juan F. , Piris Miguel A. , Bellas Carmen 
Published: October 2019

Abstract
Follicular lymphoma (FL) is the most common type of low-grade non-Hodgkin’s lymphoma. A subset of FL patients shows a favorable treatment response, and remains in complete remission with long-term follow-up, while another subset of patients has a clinical course characterized by frequent relapses and a shorter survival. Survival predictors for FL are mainly based on clinical data, and they seem to lack accuracy enough predicting survival among patients with advanced stage disease. The aim of this study is to build a survival predictor based on a set of biological markers using Tissue Micro Arrays (TMA). To this purpose, we have retrospectively analysed the expression of a group of 40 selected genes - related with apoptosis control, cell cycle, B-cell differentiation and signaling- in a series of 192 FLs using TMA. The association of these molecules with survival, and their usefulness to discriminate among FLIPI groups was evaluated. Results were quantified using different tools; singularly nuclear markers were scanned using the Bliss system and the quantitative expression was measured using the TMAscore v.1.0 image analysis software (Bacus Laboratories, Inc.). The mean overall survival (OS) was 74 months, and 38 months for progression-free survival (PFS). Statistically significant differences in OS were found with the Follicular Lymphoma International Prognostic Index (FLIPI) score (p < 0.01). No significant OS or PFS differences were observed between FL grades 1–3, between grades 3a and 3b, or using Ki67 expression. Univariate analysis revealed several TMA markers with capacity to predict OS and PFS. After multivariate analysis, a set of 4 apoptosis and cell-cycle markers was integrated into a FLIPI-independent clinical predictor, with the capacity to recognize two groups of FL patients with statistically significant differences in OS (83% versus 43% of OS at 120 months; p< 0.001). Then, patients were classified into low-risk (FLIPI: 0–2) and high-risk groups (FLIPI: 3–5), and the protein-based predictor model was used in both groups. High-risk FLIPI patients were stratified by the protein-based predictor into two groups with OS probability of 79,3% versus 14,2% at 120 months, p < 0.001, and low-risk FLIPI patients were also separated into two groups with OS probability of 100% versus 60,4% at 120 months, p < 0.01. The model is now being validated in a blind set. These results suggest that an integrated use of the FLIPI and the protein-based model could reach a higher accuracy predicting survival in FL.
High Resolution Screening of Genomic Aberrations in Follicular Lymphoma Using Microarray Based Comparative Genomic Hybridization (MATRIX-CGH).
Authors: Schwaenen Carsten , Wessendorf Swen , Viardot Andreas , Ruf Sandra , Enz Martina , Kohlhammer Holger , Kestler Hans A. , Barth Thomas F.E. , Moeller Peter , Doehner Hartmut , Lichter Peter , Bentz Martin 
Published: October 2019

Abstract
Follicular Lymphoma (FL), one of the most frequent lymphoma entities in the western world, is characterized by a highly variable clinical course reaching from rapid progression with fatal outcome to cases with long term survival. In a recent study applying chromosomal comparative hybridization (CGH) to FL, in 70% of the cases genomic aberrations were detectable and a loss of genomic material on chromosomal bands 6q25-q27 was the strongest predictor for short overall survival. However, limitations of CGH as a screening method are a restricted genomic resolution to 3–10 Mbp and demanding non-automated evaluation procedures. Thus, high throughput analysis of genomic alterations for risk adapted patient stratification and monitoring within treatment trials should rely on efficient and automated diagnostic techniques. In this study, we used array CGH to a novel generation of DNA Chips containing 2800 genomic DNA probes. Target clones comprised i) contigs mapping to genomic regions of possible pathogenetic relevance in lymphoma (n=610 target clones mapping to e.g. 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q, X); ii) selected oncogenes and tumor suppressor genes (n=686) potentially relevant in hematologic neoplasms; and iii) a large genome-wide cluster of 1502 target DNA clones covering the genome at a distance of app. 2 Mbp (part of the golden path clone set). This chip represents a median genomic resolution of app. 1.5 Mbp.
In total, DNAs from 70 FL samples were analyzed and results were compared to data from chromosomal CGH experiments and clinical data sets. The sensitivity of array CGH was considerably higher compared to chromosomal CGH (aberrations in 95% of cases vs 70% of cases). Most frequent aberrations were gain mapping to chromosome arms 2p (21%), 7p (24%), 7q (30%), 12p (17%), 12q (21%), 18p (21%) and 18q (34%) as well as losses mapping to chromosome arms 1p (19%), 6q (23%), 7p (20%), 11q (26%) and 17p (20%). In addition, several genomic aberrations were identified which have not been described before in FL. Currently, these aberrations are characterized in more detail and results will be correlated with the clinical data set. Moreover, three recurrent sites of genomic polymorphisms in human beings affecting chromosomes 5q, 14q and 15q were identified. In conclusion, these data underline the potential of array CGH for the sensitive detection of genomic imbalances in FL.