bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxygen Desaturation at Rest and after Exercise in Pediatric Sickle Cell Disease Patients: Correlations with Hemolysis and Elevated Tricuspid Regurgitant Jet Velocity.
Authors: Campbell Andrew D. , Minniti Caterina , Rana Sohail R , Onyekwere Onyinye C. , Nouraie Mehdi , Arteta Manuel , Sable Craig , Ensing Gregory , Dham Niti , Darbari Deepika S. , Luchtman-Jones Lori , Kato Gregory J. , Gladwin Mark , Castro Oswaldo , Gordeuk Victor R. 
Published: April 2020

Abstract
Background. As a part of a multicenter, observational study in determining the prevalence and risk factors of elevated tricuspid regurgitant jet velocity (TRV) in children, oxygen desaturation correlated with TRV. We further investigated the risk factors and clinical associations of oxygen desaturation at rest and after execrcise in children at steady state. Methods. 310 children and adolescents with sickle cell disease were studied under basal conditions. Pulse oximetry was determined at rest and after a six minute walk test. The relationships of oxygen saturation at rest and desaturation during exercise to the available clinical and laboratory variables were investigated. Results. Among 300 patients with available baseline oxygen saturations, 30 (10%) had saturation &lt;95 percent, 129 (43%) had saturation of 95–98 percent, and 141 (47%) had saturation &gt;98 percent. Twenty-three (9%) of 244 patients had &gt;3 percentage point reduction in oxygen saturation during a six minute walk; the median (interquartile range) baseline saturation was 96 (95– 99) percent among these patients versus 98 (97–100) percent among those with less or no reduction in saturation during the walk (P = 0.0009). Hemoglobin (p&lt;0.0001), creatinine (p=0.014) and total lung capacity (p=0.042) were also lower in patients with declines in saturations &gt;3 percentage points during the walk while a hemolytic index (p&lt;0.0001), tricuspid regurgitant jet velocity (p=0.030), pulmonary insufficiency end diastolic velocity (PIEDV) (p=0.019), left ventricular mass index (LVMI) (p=0.0006) and left ventricular internal diameter z score (LVIDD z score) (p=0.0001) were higher. In 3 separate logistic regression models (clinical variables, echocardiographic parameters, and pulmonary function testing), lower hemoglobin, hemolytic index, PIEDV, LVIDD z score, and low TLC were independent predictors of six-minute-walk desaturation of &gt;3 percentage points. Conclusion. Markers of hemolysis, low hemoglobin, PIEDV, LVMI, LVIDD z score, lower TLC, and elevated TRV velocities are associated with ≥3% reduction in oxygen desaturation during six minute walk in children and adolescents with sickle cell disease. A high degree of oxygen desaturation during the six minute walk in sickle cell disease patients might serve as an early biomarker for pulmonary hypertension. Exercise induced changes in oxygen saturation in sickle cell disease children may provide insight into the development of pulmonary hypertension as adults.
Analysis of FDG PET Diffuse Bone Marrow Uptake in Staging of Hodgkin’s Disease: A Reflect of Disease Infiltration or Just Inflammation?.
Authors: Salaun Pierre Y , Gastine Thomas , Campion Loic , Cambefort Pierre , Bodet-Milin Caroline , Moreau Anne , Le Gouil Steven , Harousseau Jean-Luc , Kraeber-Bodéré Françoise 
Published: April 2020

Abstract
FDG-PET has been successfully evaluated in the management of Hodgkin’s lymphoma (HL) and the most recent international guidelines recommended FDG-PET for initial staging and final therapeutic assessment. However, FDG PET diffuse bone marrow uptake (BMU) is frequently observed and remains difficult to analyse. The aim of this study was to evaluate the correlation between bone marrow involvement and BMU in HD. Methods: 106 HD patients (median age was 31 years range from 9 to 81; male gender in 23 cases) who underwent FDG PET/CT were retrospectively analysis. BMU level was graduated according to liver uptake. In addition, as semi-quantitative reference SUVmax was assessed upon sacral promontory. These data were compared with patient characteristics including age, Ann Arbor staging, bulky disease (Tumor burden &gt; 10 cm), presence of B symptoms, bone foci on PET (n=106), bone marrow biopsy (n=75), leukocyte count (n=74), LDH (n=87) and inflammatory parameters measured in the serum (C-Reactive Protein (CRP) (n=83) and fibrinogen (n=60)). Univariate and multivariate analysis were performed. A Fisher’s exact test and a Kruskal-Wallis equality of population rank test were used to analyse qualitative and quantitative parameters, respectively. Results: No statistical link was found between BMU and stage, bulky disease, bone marrow involvement (BMI), bone foci on PET or LDH. In contrast, univariate analysis showed correlation between BMU and age (p =0.0001), B symptoms (p =0.028 for clinical), CRP (p=0.0001), fibrinogen (p=0.0111) and leukocyte (p=0.0024). Multivariate parameters analysis found independent correlation between BMU and CRP level (p&lt;0.0001). Sacrum SUV was correlated with inflammatory parameters as BMU and with disease extension parameters like stage (p=0.0001), BMI on biopsy (p=0.0127) and bone foci on PET (p=0.0498). No BMI was found in patients presented with SUVmax below 3.5. Conclusion: This study demonstrates that the intensity of FDG-PET bone marrow uptake in HD is not correlated to BMI but related to inflammatory parameters probably reflecting the cellular activation within the BM. Semi-quantitative analysis of SUV could be useful to improve bone uptake interpretation because no infiltration is found under a SUV level.
Prognostic Value of Immunohistochemical Angiogenic and Invasion Markers in Hodgkin Lymphoma.
Authors: Mestre Francisco , Gutierrez Antonio , Ramos Rafael , Casasus M. , Nicolau C. , Martinez Jordi , Besalduch Juan , Rifa Julio , Garcia Juan Fernando , Rodriguez Jose 
Published: April 2020

Abstract
Microenvironment has and important role in sustaining the malignant cells by providing survival signals and promoting angiogenesis and invasion. Vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), metalloproteinase-2 (MM2) and laminin are involved in angiogenesis, growth and metastatic invasion potential of malignancies. Numerous studies have demonstrated up-regulation of this protein at both mRNA and protein level in various tumours and a correlation with advanced stage and prognosis has been demonstrated in several solid tumors and hematologic malignancies such as multiple myeloma or non-Hodgkin lymphomas. There is evidence that also the neoplastic Hodgkin-Reed-Stenberg cells express VEGF and that VEGF expression both in macrophages and the extracellular matrix might facilitate tumour progression. To analyze the role of these markers in the prognosis we retrospectively examined their immunohistochemical expression using a tissue array in a series of 62 cases of Hodgkin’s disease uniformly treated with the standard ABVD regimen (3–6 cycles, in function of clinical prognostic factors). Median age was 30 years (14–71). Prognostic factors were as follows: 35% Ann Arbor stage III–IV, 23% adjusted-international prognostic index &gt;1 and 11% Hasenclever &gt; 3. Median follow-up was 90 months. Relapses were significantly higher in patients with strong VEGF staining (50% vs 19%; p=0.04) with a significant worst progression-free survival (60% vs 84%; p = 0.01). COX-2, MM2 and laminin showed a non-significant trend towards a lower relapse rate and PFS. Conclusion: The presence of VEGF strong staining in Hodgkin-Reed-Stenberg cells or reactive macrophages and the extracellular matrix might facilitate tumour progression as it was related to a shorter PFS. The trend towards a worst prognosis in higher COX-2, MM2 and laminin staining warrants further investigation of their role in the prognosis of patients with Hodgkin lymphoma.
Mannose-Binding Lectin Deficiency - a Risk Factor for Invasive Aspergillosis in Immunocompromised Patients.
Authors: Lambourne Jonathan , Agranoff Dan , Buchbinder Aby , Troke Peter F , Herbrecht Raoul , Lindsay Jodi , Harrison Thomas 
Published: April 2020

Abstract
Invasive aspergillosis is a devastating infection with 30–40% mortality. Immune mechanisms involved in recognition and elimination of aspergillus are incompletely understood. Mannose-binding lectin (MBL) deficiency occurs in 10–15% of the population and has been identified as a susceptibility factor in animal models of aspergillosis. We hypothesise there is an association between human MBL deficiency and invasive aspergillosis.
In this multi-centre case-control study, serum MBL concentrations were measured in 65 patients with probable or proven invasive aspergillosis (as defined by the 2002 EORTC/NIH-MSG criteria) and in 79 immunocompromised controls with fever not due to aspergillosis. MBL concentrations were measured using a commercially available, technically straightforward solid phase ELISA (Hycult Biotechnology, The Netherlands). Median MBL concentrations and the frequency of MBL deficiency were compared using the Mann-Whitney and Fisher’s exact tests.
Cases and controls were well matched in terms of age, gender, ethnicity and cause of immunocompromise. The assay performed well with a mean coefficient of variation of 7%. Patients with invasive aspergillosis had significantly lower MBL concentrations and a greater frequency of MBL deficiency than controls (65% vs. 33%, p = 0.0002, MBL deficiency cut-off 500ng/ml). MBL deficiency was significantly more frequent in cases than in controls at all MBL concentrations ≤500ng/ml. This is the first study to identify a strong association between MBL deficiency and invasive aspergillosis in immunocompromised patients. Because MBL concentrations do not consistently change during acute infection we conclude that MBL deficiency predisposes to invasive aspergillosis. Routine measurement of MBL levels is within the capability of most diagnostic laboratories. These data suggest that replacement therapy with recombinant human MBL may be an opportunity to prevent or mitigate the poor outcome of invasive aspergillosis.
Long-Term Follow-up of Rituximab and Infusional Cyclophosphamide, Doxorubicin, and Etoposide (cde) in Combination with HAART in HIVRelated Non-Hodgkin’s Lymphomas (NHL).
Authors: Spina Michele , Simonelli Cecilia , Vaccher Emanuela , Jaeger Ulrich , Sparano Joseph , Talamini Renato , Tirelli Umberto 
Published: April 2020

Abstract
Background: The combination of Rituximab plus chemotherapy (CT) is more effective than CT alone in the treatment of high grade NHL.
Objective: To report the long-term follow-up of CDE plus Rituximab in HIV-NHL.
Methods: In June 1998, we started a phase II study using infusional CDE (Cyclophosphamide 187.5 mg/m2/day, Doxorubicin 12.5 mg/m2/day and Etoposide 60 mg/m2/day) administered by continuous intravenous infusion for 4 days every 4 weeks and Rituximab 375 mg/m2 i.v. on day 1. HAART was given concomitantly with CT.
Results: Seventy-four patients (pts) have been enrolled. The median CD4+ cell count was 161 (range 3–691) and the median Performance Status was 1 (range 0–3). Diffuse large B-cell NHL was diagnosed in 72% of pts and Burkitt in 28%. Seventy per cent of pts had advanced stage (III–IV) disease and 57% of pts had an age-adjusted international prognostic index ³2. Fifty-two out of 74 pts (70%) achieved a complete remission (cr), 4/74 (5%) had a partial remission and 18 pts progressed. With a median follow-up of 61 months, only 17% of CRs have relapsed and 41/74 pts are alive. The overall survival, disease free survival and time to treatment failure (TTF) at 5 years were 56%, 81% and 52%, respectively. Only one secondary tumor (acute leukemia) has been observed. No case of late pulmonary or cardiac toxicity has been reported.
Conclusions: The combination of Rituximab and CDE in HIV-NHL treated concomitantly with HAART is very active. CR rate (70%) and TTF at 5 years (52%) are comparable to those observed in high grade NHL of the general population. Our data confirm that in HAART era a high proportion of HIV-NHL can be cured. This study was supported by ISS grants.
In Vivo Genetic Mutations Define Predominant Functions of the Human T-Cell Leukemia/Lymphoma Virus p12I Protein.
Authors: Franchini Genoveffa , Fukumoto Risaku , Andresen Vibeke , Bialuk Izabela , Cecchinato Valentina , Walser Jean Claude , Valeri Valerio William , Nauroth Julie M , Gessain Antoine , Nicot Christophe 
Published: April 2020

Abstract
The human T-cell leukemia/lymphoma virus Type 1 (HTLV-1) ORF-I encodes, a ninety-nine amino acid hydrophobic membrane protein, p12I that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12I. The removal of a non-canonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12I is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8 kDa protein. The 8 kDa protein in turn traffics to the cell surface, is recruited to the immunological synapse following T-cell receptor (TCR) ligation and down-regulates TCR proximal signaling. The uncleaved 12 kDa form of p12I resides in the ER and interacts with the β and γc chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1-infected patients reveals predominant amino acid substitutions within ORF-I that inhibits proteolytic cleavage, suggesting that ER associated functions of p12I may contribute to the survival and proliferation of the infected T-cells in the host.
Acute Lymphoblastic Leukemia (ALL) with t(8;14)(q11.2;q32): B-Lineage Disease with High Proportion of Down Syndrome. A Children’s Oncology Group (COG) Study.
Authors: Messinger Yoav H. , Higgins Rodney , Devidas Meenakshi , Hunger Stephen P. , Carroll Andrew J. , Heerema Nyla A. 
Published: April 2020

Abstract
Recurrent chromosome translocations play a critical role in the pathogenesis of ALL and many translocations have important prognostic significance. The t(8;14)(q11.2;q32) is a recurrent translocation that fuses the chromosome 8 CEBPD (CCAAT enhancer binding protein delta) gene to the IgH (immunoglobulin heavy chain) gene, leading most likely to deregulated CEPD expression. We previously reported the clinical data of 10 such patients (Leukemia, 2000;14:238–240). Using the COG ALL cytogenetics database we expand the report to include 22 patients (13 females and 9 males) with the t(8;14)(q11.2;q32). All patients with available immunophenotyping data (n=20) had B-lineage ALL. The median age at diagnosis was 9.2 years (range: 1.6 months – 17.1 years). Median diagnostic white blood cell count (WBC) was 9,950 (range: 700–172,000). Of the 22 patients, 7 were NCI standard risk and 15 were high risk. The most common additional cytogenetic abnormality was trisomy 21. Of the ten cases with trisomy 21, seven were constitutional (Down Syndrome), thus confirming previous reports that a significant fraction of t(8;14) patients (7/22; 31.8%) have Down Syndrome, which is much higher than the 3% (80/2811) overall rate of children with Down Syndrome in a recent COG ALL trial (p&lt;0.0001). In addition to the Down Syndrome cases, one case with phenotypic Turner syndrome had a mosaic constitutional r(Y)(p11q11.2); thus, eight cases (36%) had constitutional abnormalities. Secondary abnormalities included additional X (n=5); additional 5 (n=3); Philadelphia chromosome (n=1). Two cases had a second der(14)t(8;14) and two had loss of the der(8) t(8;14), consistent with the der(14)t(8;14) as the significant abnormality. Four cases (18%) had 9p deletions compared with 11% in the overall ALL population, and two cases (9%) had abnormalities of 13q compared with 2% in the overall population. Numerically, the cases were pseudodiploid (n=12) and hyperdiploid (n=10). Children with Down Syndrome had superior estimated 5-year event-free survival of 100%, compared to non-Down patients with 50.1±17.7% (p=0.04). Overall survival was also different but did not reach statistical significance: 100% vs. 60.9±17.0% (p=0.088). In summary, the rare t(8;14)(q11.2;q32) is associated with B-lineage phenotype and occurs with greatly increased frequency in children with Down Syndrome, who have an excellent outcome with standard COG therapy as compared to non-Down Syndrome patients with this translocation.
Stimulation of B-Cell Lymphoproliferations with CpG-Oligonucleotide DSP30 Plus IL-2 Is More Effective than with TPA to Detect Clonal Abnormalities.
Authors: Struski Stéphanie , Gervais Carine , Helias Catherine , Herbrecht Raoul , Audhuy Bruno , Mauvieux Laurent 
Published: April 2020

Abstract
Conventional cytogenetics (CC) of B-cell lymphoproliferations remains difficult because of low mitotic in vitro activity of the leukemic cells. Therefore, mitogen stimulation of B-cells is required to analyze an adequate number of metaphases. Chromosome abnormalities using CC with TPA can be detected in up to 50% of chronic lymphocytic leukemia (CLL), but the development of FISH techniques has allowed the detection of selected chromosome abnormalities in more than 80% of CLL. However, FISH is restricted, since information is only available for the genes/loci for which probes are used. So, for a comprehensive genetic analysis, CC is essential because it provides an overview of all microscopically visible chromosome abnormalities important as prognostic factors. The use of the immunostimulatory CpG-oligonucleotide DSP30 to effectively induce cell cycle progression of CLL cells in vitro has been reported. This proliferation is markedly enhanced upon addition of Interleukine-2 to cultures. To our knowledge and to date, there has been no direct comparison of classical TPA versus DSP30+IL-2. DSP30+IL-2 stimulation has been successfully tested in CLL but no data are available for other lymphoproliferations. We cultured 132 B-cell lymphoproliferations (80 CLL and 52 other B-cell lymphoid neoplasms (BCLN)) in parallel, in presence of TPA or DSP30+IL-2. The objective of this study was to evaluate the suitability of DSP30+IL-2 as a routine B-cell mitogen for metaphase cytogenetics. CC successfully analyzed 94.9% of CLL and 98.1% of BCNL with more than 80% abnormal karyotypes. For CLL, failures of karyotypes were more frequent in cultures with DSP30+IL-2 (14%) than in those with TPA (4%). The rate of failures were similar for BCLN (6% versus 4%). For CLL, there were significantly fewer metaphases in DSP30+IL-2 than in TPA spreads (mean of 50 versus 72 metaphases per slide respectively, p=0.0007), as well as for BCLN (mean of 50 versus 71 metaphases per slide respectively, p=0.009). However, the proportion of abnormal metaphases was significantly higher in DSP30+IL-2 (mean of 59%) compared to TPA cultures (mean of 26%, p=0.00265) for CLL and for BCLN (mean of 57% versus 33%, p=0.0065). Stimulation with DSP30+IL-2 allowed to detect more abnormalities, more abnormal subclones and more complex karyotypes in CLL and in the majority of BCLN. Though FISH exploration using a large probe panel has yielded valuable results in lymphoproliferative diseases, it underestimates the heterogeneity of chromosomal aberrations. Complexity of chromosomal changes, recently associated to unfavorable outcomes, can only be assessed with CC. In conclusion, our results in both CLL and BCLN indicate that the immunostimulatory oligonucleotide DSP30 in combination with IL-2 is an easy and efficient stimulus in metaphase generation for routine chromosomal banding.
High-Resolution Genomic Profiling (array-CGH) of Childhood T-ALL Identifies Deletions at 6q15-16.1 as a Predictive Marker for Early Treatment Response.
Authors: Remke Marc , Pfister Stefan , Stanulla Martin , Schrappe Martin , Muckenthaler Martina Ulrike , Lichter Peter , Kulozik Andreas 
Published: April 2020

Abstract
Purpose: Precursor T-cell lymphoblastic leukemia (T-ALL) accounts for approximately 15% of pediatric ALL and represents a particular clinical challenge, because relapses are usually fatal. In T-ALL, monitoring treatment response (prednisone prephase; MRD kinetics) provides a powerful tool for risk assessment. We now aimed to identify DNA-based predictive biomarkers that allow risk assessment and treatment stratification at the time of diagnosis. We thus performed a genome-wide analysis for DNA copy-number aberrations to detect circumscribed gains and losses that are specific for molecular and prognostic subgroups.
Experimental design: Samples of 77 T-ALL patients enrolled in BFM-ALL protocols were analyzed by array-based comparative genomic hybridization (array-CGH) on an 8k BAC array allowing for an average resolution of 0.5 megabases. After using a Hidden Markov Model for bioinformatic analysis, our findings were correlated with minimal residual disease (MRD) data. Frequently affected pathways were identified using Babelomics software. This approach was complemented by genomic sequencing and the analysis of mRNA abundance for interesting candidate genes in a subset of leukemias.
Results: Several circumscribed genomic alterations affecting key regulators and downstream intermediates of TGF-β and PI3K-AKT signalling were identified thus suggesting an important role of these pathways in T-ALL leukemogenesis. Furthermore, deletions at chromosome band 6q15-16.1 haboring the caspase 8-associated protein 2 (CASP8AP2) gene were overrepresented in patients with unfavorable MRD. QRT-PCR revealed a marked gene-dosage effect resulting in reduced expression of CASP8AP2 mRNA in samples with 6q15-16.1 deletions (p=0.01). Fisher’s exact test revealed that deletions at 6q15-16.1 constitute a powerful marker for poor early treatment response (p=0.03), which is likely related to the reduced expression of the pro-apoptotic CASP8AP2 gene.
Conclusions: Array-CGH analyses indicate a novel role of TGF-β and PI3K-AKT signalling in T-ALL leukemogenesis. Moreover, deletions at 6q15-16.1 resulting in the reduced expression of the pro-apoptotic CASP8AP2 candidate gene identify a subgroup of T-ALL patients with poor treatment response. Prospective studies will now have to validate the usefulness of DNA-based molecular markers to clinically stratify the individual risk profile in pediatric T-ALL.