bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resource Use and Costs Associated with Routine Management of Febrile Neutropenia in German Hospitals.
Authors: Ihbe-Heffinger Angela , Paessens Bernadette , Jacobs Volker R. , Ehlken Birgit , Shlaen Margarita , Berger Karin , Bernard Rudolf , Peschel Christian , Goertz Anita , von Schilling Christoph 
Published: October 2019

Abstract
Febrile neutropenia (FN) is the most frequent dose-limiting complication of myelosuppressive chemotherapy. To date little data is available on the economic consequences of FN management in Germany. Therefore resource use and costs associated with routine FN management were assessed. This was a prospective, multi-centre, observational, longitudinal cost-of-illness study. Patients were enrolled consecutively from 1/2005-12/2006 at the start of first or second line (immuno)chemotherapy (CT) treatment in 4 German hospitals. Patients receiving myeloablative chemotherapy with peripheral blood stem cells were excluded. Adverse drug reactions were monitored prospectively according to the NCI CTCAE v.3.0 and WHO causality criteria. FN was defined as fever above 38°C associated with an absolute neutrophile count <1x109/L. In case of non-availability of the nadir-ANC in daily clinical practice the occurrence of febrile leukopenia (FL) was assessed as leukocyte count <2x109/L and fever above 38°C. Clinical data and resource use were collected from pre-planned chart reviews. German tariffs & prices in €2007 and hospital databases were used to allocate costs to health care resources. Costs are presented from the provider perspective. 325 patients undergoing a total of 1285 chemotherapy cycles were evaluable. 68 episodes of FN/FL (FN: n=28; FL: n=40) occurred in 58 pts. (18%). 35 FN/FL pts. had lymphoma (54% treated with a CHOP-like CT), 9 NSCLC (80% treated with a platinum-based CT) and 14 breast cancer (100% treated with an adjuvant taxane- or anthracyline-based CT). Mean age was 58.1 years (SD 14.5); age≥65 years 38%; female 57%; ECOG≥2 10%. The table shows a comparison of FN/FL patient characteristics with all patients included. 55 FN/FL episodes (81%) were associated with at least one hospital stay (episodes with inpatient treatment: n=49, outpatient or day care: n=6). 5 episodes were treated in an intensive care unit. Mean length of inpatient stay was 8.9 (SD 5.9) days. In addition to concomitant drug use transfusions were necessary in n=15 episodes. Mean treatment cost per FN/FL episode requiring hospital treatment amounted to €3,950 SD 4,961 (range: €134–31,924) with highest mean cost for patients with lymphoma (€4,808). Hospital basic services and personnel accounted for 60% of the direct costs, followed by expenses for drugs (19%) and diagnostics (11%). In conclusion FN/FL induces significant resource use and associated cost. The main cost drivers are hospital basic services and staff. In lymphoma patients FN/FL is more costly than in NSCLC or breast cancer patients.
All pts. (n= 325) Pts. with FN/FL (n=58) Tumour type Lymphoma 153 (47%) 35 (60%) Breast 52 (16%) 14 (24%) NSCLC 120 (37%) 9 (16%) Age: mean (SD) 59.9 (12.7) 58.1 (14.5) Age ≥65 124 (38%) 22 (38%) Female 149 (46%) 33 (57%) ECOG ≥2 30 (9%) 6 (10%)
The ΔN Isoform of the p73 Gene Is Induced during the G0→G1 Transition in Primary Human T Cells.
Authors: Chronis Constantinos , Smith Alexander E. , Orr Stephen J. , Raj Kavita , Mufti Ghulam J. , Thomas N. Shaun B. 
Published: October 2019

Abstract
p73 is a member of the p53-family of transcription factors (p73, p53 and p63). A truncated form of p73 (ΔNp73) also exists that lacks the transcriptional activation domain and inhibits both p53 & p73. However, ΔNp73 transcripts have not been reported in normal tissues or peripheral blood. We now show for the first time that ΔNp73 mRNA and protein are not present in quiescent (G0), primary human T cells but are induced post the G0→G1 cell cycle commitment point following stimulation with anti-CD3/CD28 or PMA/ionomycin. The ΔNp73 transcript could be produced either by activation of a promoter in intron 3 or from the 5′ P1 promoter by alternative splicing. Bisulfite sequencing shows that the intron 3 promoter is hypermethylated in T cells in G0 and throughout the cell cycle while the 5′ P1 promoter remains largely unmethylated. 5′-RACE results with quiescent and stimulated T cells verify that ΔNp73 transcripts originate from the P1 promoter. Additionally, RT-PCR analyses show that the transcript originating from the P1 promoter is present in G0 and mature ΔNp73 mRNA is produced by cell cycle-dependent splicing during the G0→G1 transition. We investigated the function of ΔNp73 during G0→G1 by inhibiting its induction with two different siRNAs. Microarray analyses show that expression of mRNA encoding a number of cell cycle regulators like E2F1, TCFL2 and CDT1 during G0→G1 are dependent on ΔNp73 and ΔNp73 represses the expression of the pro-apoptotic PUMA, a known p73 target. We conclude that ΔNp73 is produced in normal, human T cells during cell cycle entry and regulates normal gene expression. Moreover, the intron 3 promoter is hypermethylated, the ΔNp73 transcript originates at the P1 promoter and ΔNp73 mRNA is produced by cell cycle-dependent splicing.
Peroxisome Proliferator-Activated Receptor Gamma Promotes Lymphocyte Survival Via a Mitochondrial Pathway Mediated by GSK-3 Beta.
Authors: Miao Qi , Song Zibo , Yang Chunyan , Wang Y. Lynn 
Published: October 2019

Abstract
Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear hormone receptor involved in maintaining glucose and fatty acid homeostasis. Besides its metabolic functions, the receptor has also been implicated in tumorigenesis. Ligands of PPAR gamma induce apoptosis in several types of tumor cells including lymphomas, leading to the proposal that these ligands may be used as anti-cancer agents. However, apoptosis induction requires high doses of ligands, suggesting the effect may not be receptor-dependent. Previously, we reported that PPAR gamma is expressed in human primary T cell lymphoma tissues and activation of PPAR gamma with low doses of ligands protects lymphoma cells from serum starvation-induced apoptosis. The prosurvival effect of PPAR gamma is linked to its actions on mitochondria. In serum-deprived cells, PPAR gamma attenuates the decline in ATP, reduces mitochondrial hyperpolarization and limits the amount of reactive oxygen species (ROS) in favor of cell survival (Yang et al, Am J Pathol, 170, 722–32, 2007). In the current study, we investigated the molecular mechanisms by which PPAR gamma maintains mitochondria homeostasis. We demonstrated that PPAR gamma modulates the activities of two key components of Wnt signaling pathway, Fzd4 and GSK-3 beta. The receptor up-regulates the mRNA expression of Fzd4, a cell surface receptor of Wnt, through a conserved PPAR-response element (PPRE) in the promoter region of the Fzd4 gene. Moreover, PPAR gamma suppresses the activation of GSK-3 beta, a downstream inhibitory serine/threonine kinase, by maintaining its phosphorylation at serine 9 and decreasing its association with mitochondria. Downregulation of GSK-3 beta activity results in maintenance of mitochondrial membrance potential and suppression of ROS production in growth factor-deprived cells. Our studies revealed a novel interaction between PPAR gamma and Wnt signaling in lymphocyte survival. Since Wnt signaling plays an important role in tumorigenesis, our studies highlight the need for further investigation into the role of PPAR gamma in cancer prior to widespread use of its agonists as anticancer therapeutics.
Arginine Diet for Sickle Transgenic Mice Reduces Endothelin-1-Stimulated Gardos Channel Activity.
Authors: Romero Jose R. , Rivera Alicia , Muñiz Adriana , Nagel Ronald , Fabry Mary E. 
Published: October 2019

Abstract
Arginine (ARG) supplementation (5% arginine in chow) restores plasma ARG levels in S+S-Antilles mice to that found in C57BL mice and is associated with a reduction in Ca++ activated K+ channel (Gardos channel) activity, MCHC and high density red cells (Romero, Blood 99(4):2002). However the mechanisms for these effects are not entirely clear. Endothelin-1 (ET) is a potent vasoconstrictor that has been shown to activate Gardos channel activity and reduce MCHC. We hypothesized that reduced ET could account for the decrease in Gardos channel activity. We report here that arginine diet reduced ET levels in mouse plasma from 137 ± 10 to 89 ± 17 pmol/ml using a modified HPLC technique originally proposed by Kumarathasan (Anal Biochem299:37, 2001). We measured Gardos channel activity in ex vivo red cells as the influx of 86Rb in the presence or absence 10μM clotrimazole. Consistent with our previous report, we observed that ARG supplementation was associated with a decrease in Gardos Channel activity. In addition, incubation of red cells with 500 nmol/L of ET for 15 min at 37°C stimulated an increase in Gardos channel activity in cells from both ARG supplemented vs non-supplemented mice that was sensitive to 1 mmol/L of the specific ET receptor B antagonist, BQ788 (9.4 ± 2.5 vs 14.6 ± 3.8 mmol/L cell x h, respectively). However, the maximal response of the Gardos channel activity to ET was significantly blunted in ARG supplemented vs non-supplemented mice (15.7 ± 2.8 vs 22.1 ± 2.2 mmol/L cell x h, p<0.03, n=5). We also performed QT-RT PCR using Taqman assays on aortas from these mice and observed that mRNA expression of both ET and ET receptor A levels were significantly decreased in ARG supplemented vs non-supplemented mice (p<0.05, n=5) while ET receptor B levels were not significantly affected (n=5). Thus, our results suggest that reduced ET is in part responsible for the blunted Gardos channel activity in arginine supplemented mice and raises the possibility that ET metabolism is modulated by arginine supplementation. We conclude that arginine supplementation of sickle cell patients may have multiple benefits including reduced polymer formation, reduced vasoconstriction, and reduced inflammatory response.
Biomarkers and Pulmonary Hypertension in Sickle Cell Disease.
Authors: Ataga Kenneth I. , Moore Charity G. , Park Hyeon A. , Orringer Eugene P. 
Published: October 2019

Abstract
Introduction: Pulmonary hypertension (PHT), a common complication in patients with sickle cell disease (SCD), is associated with an increased risk of mortality. Patients with SCD are typically screened for the presence of PHT using Doppler echocardiography, with the diagnosis confirmed by right-sided heart catheterization. Validated biomarkers could provide additional diagnostic and prognostic information in these patients. The purpose of this study is to determine the relationship between a variety of biomarkers and the presence of PHT in SCD patients.
Methods: Selected biomarkers were obtained from a cohort of 76 SCD patients evaluated for PHT. The pulmonary artery systolic pressure (PASP) was determined by Doppler echocardiography and PHT was then defined using an age-, sex- and BMI-adjusted reference range. Receiver-operating characteristic curves, sensitivities, specificities, positive (LR+) and negative likelihood ratios (LR-), and positive (PPV) and negative predictive values (NPV) of each of these biomarkers was then used to assess its relationship to PHT.
Results: Elevated levels of lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine, total bilirubin (T Bili), N-terminal pro-brain natriuretic peptide (NT-proBNP) and soluble vascular cell adhesion molecule-1 (sVCAM) are associated with PHT, while decreased levels of fetal hemoglobin (Hgb F) are associated with PHT. LDH and sVCAM are the most predictive biomarkers for the presence of PHT. An LDH level of 927 U/L (AUC 0.759, P = 0.0004) provides a sensitivity of 73%, a specificity of 72%, a LR+ of 2.61, a PPV of 59% and a NPV of 83%, while a sVCAM level of 865 ng/mL (AUC 0.712, P = 0.0026) provides a sensitivity of 63%, a specificity of 72%, a LR+ of 2.25, a PPV of 54% and a NPV of 79% The AUC, cut-off level, sensitivity, specificity, likelihood ratio, and PPV and NPV for each biomarker is shown in the table below.
Conclusion: Multiple biomarkers have different predictive capabilities for PHT in patients with SCD. Despite the small likelihood ratios, LDH appears to provide greater prediction for PHT than other measured biomarkers including NT-proBNP that has previously been reported to be independently associated with increased mortality in these patients. More studies are required to evaluate the predictability of combinations of biomarkers for PHT and to assess the relationship of biomarkers with mortality in this patient population.
Table 1 Variable AUC Cutpoint based on Youden index P value Sens (%) Spec (%) Likelihood Ratio (+)/(−) PPV/NPV (%) LDH 0.759 927 U/L 0.0004 73 72 2.61/0.38 59/83 BUN 0.665 14 mg/dL 0.015 50 84 3.13/0.60 62/76 Creatinine 0.622 1.3 mg/dL 0.01 38 94 6.33/0.66 77/75 Hgb F 0.669 4.3% 0.04 65 72 2.32/0.49 55/80 T Bili 0.685 2.6 mg/dL 0.017 54 80 2.7/0.58 58/77 NT-proBNP 0.66 103 pg/mL 0.06 65 60 1.63/0.58 47/76 sVCAM 0.712 865 ng/mL 0.0026 63 72 2.25/0.51 54/79
Durable Complete Responses Following Therapy with Epratuzumab Plus Rituximab: Final Efficacy Results of a Multicenter Study in Recurrent Indolent Non-Hodgkin’s Lymphoma (NHL).
Authors: Leonard John P. , Schuster Stephen J. , Emmanouilides Christos , Couture Felix , Teoh Nick , Wegener William A. , Goldenberg David M. 
Published: October 2019

Abstract
BACKGROUND: Epratuzumab, an anti-CD22 humanized monoclonal antibody, has shown clinical activity as a single-agent (Leonard et al, J Clin Oncol.2003; 21:3051–3059) and in combination with rituximab in relapsed/refractory B-cell NHL (Leonard et al, J Clin Oncol.2005; 23:5044–5051). To evaluate this combination regimen in a larger cohort of patients and to evaluate long-term efficacy, we conducted an international multicenter, open-label, single-arm study in patients with recurrent indolent NHL.
METHODS: Forty-nine patients (23F/26M, median age: 61, elevated LDH: 25%, bone marrow involvement: 49%) with chemotherapy-relapsed or refractory follicular NHL (n=41) or small lymphocytic lymphoma (n=7) (as well as one enrolled patient with histological evidence of follicular and diffuse large B-cell lymphoma) were evaluated. Thirty-five (71%) were rituximab-naive, with the remainder having previously received and responded to then relapsed from rituximab (single agent or with chemotherapy). Patients received 360 mg/m2 IV of epratuzumab, followed by 375 mg/m2 IV of rituximab, weekly for 4 consecutive weeks.
RESULTS: As preliminarily reported (Emmanouilides et al, Blood2003; 102/11:69a), the combination therapy was well tolerated, without notable additive toxicity over that expected with single-agent rituximab. Twenty-two of the 41 (54%, 95% CI: 37% – 69%) follicular NHL (FL) patients achieved an objective response (OR) using IWG response criteria, including 10 (24%) patients with complete responses (CR), half of whom remained in remission at the last evaluation with a median duration of follow-up of 44.3 months (range: 18.2 – 52.4 months). The median duration of response (DR) was 13.4 months (95% CI: 8.4 – 28.2 months) and the median progression-free survival (PFS) was 10.2 months (95% CI: 6.3 – 13.6 months), with a Kaplan-Meier estimated median DR of 33.4 months (range: 11.2 – 47.9 months) and an estimated median PFS of 35.1 months (range: 12.9 – 52.4 months) for the 10 patients who achieved CR. Importantly, 4/7 SLL patients (57%) experienced OR, including 2 CR, 1 CRu and 1 PR. Furthermore, while the rituximab-naive FL and SLL patients (n=34) showed an OR of 50% (26% CR/CRu, 24% PR), those patients who had responded to prior rituximab (n=14) had an OR of 64% (29% CR, 36% PR).
CONCLUSIONS: Overall, this study confirms that the combination of epratuzumab and rituximab, in addition to being well tolerated, demonstrates promising anti-lymphoma activity for indolent NHL, and can result in durable complete remissions in a subset of patients. Further evaluation of this combination regimen as initial therapy for indolent NHL is planned (CALGB 50701), and in diffuse large B cell lymphoma (CHOP + epratuzumab + rituximab) is ongoing (NCCTG N0489).
Primary Thyroid Lymphoma: A Retrospective IELSG and IIL Analysis of Clinical Characteristics, Prognostic Factors, Treatment Outcome and Somatic Hypermutation for Localized Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Cortelazzo Sergio , Gaidano Gianluca , Mian Michael , Conconi Annarita , Rossi Andrea , Cabrera Maria E. , Federico Massimo , Bellei Monica , Magrini Stefano , Martelli Maurizio , Gomez Henry , Lopez-Guillermo Armando , Pogliani Enrico M. , Rossini Fausto , Busetto Mario , Visco Carlo , Tsang Richard , Zucca Emanuele , Rambaldi Alessandro , Cavalli Franco 
Published: October 2019

Abstract
We compared clinical characteristics, prognostic factors and treatment outcome of primary thyroid DLBCL (PTL) with those of other locations of primary extranodal head and neck lymphomas (PEHNL) and we further analyzed somatic hypermutation in pts with PTL. From December 1990 to June 2004, 48 PTL out of 478 PEHNL patients (pts) (10%) were enrolled in this study, including 10 males and 38 females, with a median age of 73 years (range, 34–90 years). In comparison with other locations PTL cases had more frequently advanced age (>60 yrs), female sex, bulky disease, poor ECOG-PS, elevated LDH and >1 adverse factors according to stage-modified IPI (MIPI). The commonest treatment was a short course of anthracycline-based chemotherapy (CHT) ± involved field radiotherapy (IFRT). Forty-two percent of PTL pts also underwent surgery. Clonal IGHVDJ rearrangements were analyzed in 17/48 cases. The CR rate of PTL pts (85%) was comparable to those of other locations. After a median follow-up of 41 months (range 1–154.months), 5-yr OS, EFS and DFS were 51%, 46% and 86%, respectively. The OS compared unfavourably with other locations (75%), while the disease-specific survival rate was similar in both groups (80%). Moreover, MIPI was not predictive of survival, probably due to a high mortality unrelated to disease (19% Vs 7%). Regarding treatment PTL pts seem to benefit more from surgery in combination with chemotherapy and/or IFRT than from other treatments not including partial or complete thyroid resection (p=0.04). Somatic hypermutation of IGHV genes was observed in the majority of PTL cases, suggesting that they derive from germinal center experienced B-cell, while the unmutated status in a fraction of pts indicates a different histogenetic and pathogenetic pathway. The significant clustering of S and R mutations in CDRs and FRs in a fraction of cases with high homologous CDR3 suggests that antigen stimulation may have an important role in the pathogenesis of these lymphomas. In conclusion, in spite of more adverse features at presentation PTL pts showed a favorable disease-specific survival, comparable to that of other PEHN. Biological study in PTL pts suggests different histogenetic and pathogenetic pathway. The comparison of thyroid biological profile with that of other PEHNL could help to clarify the different clinical behaviour of this uncommon malignancy.
Efficacy of Dose-Dense R-CHOP-14 Chemoimmunotherapy Plus Pegfilgrastim for First-Line Treatment of Diffuse Large B-Cell Lymphoma (DLBCL) in Low Risk Patients: An Interim Analysis of an Open-Label Clinical Trial in Spain. On Behalf of GEL/TAMO (Spanish Group of Lymphoma).
Authors: Gonzalez-Barca Eva , Salar Antonio , Bargay Joan , Tomas Jose F. , Canales Miguel A. , Moraleda Jose M. , Vidal Maria Jesus , Ferrer Secundino , Briones Javier , Estany Cristina , Gardella Santiago , Llorente Andres , Caballero Dolores 
Published: October 2019

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most prevalent form of non-Hodgkin lymphoma. The addition of rituximab to the standard treatment with 3-weekly CHOP (R-CHOP) has notably improved the survival in DLBCL. However, it is unclear whether a dose-dense regimen of 2-weekly R-CHOP-14 is efficacious and well tolerated. The aim of the current study is to determine the efficacy and tolerability of 6 cycles of dose dense R-CHOP-14 for low risk DLBCL. This is an ongoing, open-label, multicentre, single-arm clinical trial. Eligible patients are aged 18–65 years, with CD20+ DLBCL, an international prognostic index (IPI) of 0–2 and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Six cycles of R-CHOP-14 are administered with pegfilgrastim 6 mg sc on day 2 of each cycle. Patients with tumor masses > 10 cm are allowed to receive radiotherapy with 30 Gy, and those at risk of central nervous system infiltration receive prophylactic liposomal cytarabine with each chemotherapy cycle. An interim analysis of efficacy was planned when the first 25 patients were included. Patients receiving ≥1 dose of study medication were included in the tolerability analysis, while 130-day follow-up was required for inclusion in the efficacy analysis. The first 25 patients were included between June 2006 and January 2007: mean age was 46.5 years, 56% were male. The characteristics of the disease at diagnosis were as follows: stage III-IV 40%, ECOG 0–1 96%, B-symptoms 12%, bulky disease 28%, extranodal involvement 56% (most frequently spleen and gastrointestinal system), elevated LDH 44%, elevated β2microglobulin 36%, IPI 0–1 60%. All patients completed 6 cycles of chemotherapy (150 cycles). Among the 125 cycles excluding the first one, there were 7 (5.5%) delays, 3 because of neutropenic fever, 2 because neutropenia, and 2 because of infection without neutropenia. Dose modification due to hematological toxicity occurred in 4 cycles (3.2%) all in the same patient. Twenty-two patients were included in the efficacy analysis. The global response rate, the complete remission rate and the partial remission rate were 91%, 81.8% and 9.1%, respectively. No patient exhibited disease progression or relapse, whereas 2 (9.1%) had stable disease. All 22 patients were alive at 130 days follow-up. In this interim analysis, high remission rates suggest that dose dense R-CHOP-14 with pegfilgrastim support is an efficacious treatment for low risk DLBCL in patients younger than 65. The regimen was well tolerated with most patients completing their full treatment schedule as planned.