bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Amyloid A Induces G-CSF Expression and Granulocytosis Via Toll-Like Receptor 2.
Authors: He Rong L. , Zhou Jian , Hanson Crystal L. , Chen Jia , Ye Richard D.
Published: October 2019

As a major acute-phase protein, serum amyloid A (SAA) is commonly used as a marker for inflammatory diseases; however, its precise role in inflammation and infection, which often result in granulocytosis or neutrophilia, remains ambiguous. In this study, we demonstrate that SAA is a potent endogenous stimulator of granulocyte colony-stimulated factor (G-CSF), a principle cytokine regulating granulocytosis, and this effect of SAA is mediated by Toll-like receptor 2 (TLR2). Our data showed that in mouse macrophages, the elevation of the G-CSF mRNA level was observed within the first two hours of SAA stimulation while the secretion of the G-CSF protein was significantly increased after eight hours and sustained for 24 hours. The induction of G-CSF by SAA was blocked by the specific anti-TLR2 antibody and significantly decreased in TLR2 knockout mouse macrophages. We also showed that SAA-stimulated G-CSF expression correlates with the activation of nuclear factor κB (NF-κB), the p65 subunit of which was bound to the CK-1 element of the G-CSF promoter region within 30 minutes of the stimulation. In addition, the SAA increased production of G-CSF was tested to be sensitive to heat, yet insensitive to polymyxin B treatment, indicating that the induction is a direct effect of SAA. Furthermore, our in vivo studies confirmed that SAA significantly increases the plasma concentration of G-CSF and the number of neutrophils in the blood circulation while such phenomenon vanishes in G-CSF or TLR2 knockout mice.
Cyclic Neutropenia Is Not Associated with Transformation to MDS and AML.
Authors: Dale David C. , Bolyard Audrey Anna , Newburger Peter E. , Bonilla Mary Ann , Kannourakis George , Dror Yigal , Link Daniel C. , Alter Blanche P. , Rosenberg Philip S. , Boxer Laurence A.
Published: October 2019

Cyclic neutropenia is a rare hematological disorder characterized by recurrent severe neutropenia, mouth ulcers, fever and infections beginning soon after birth. The diagnosis depends primarily on observing regular periods of severe neutropenia (neutrophils <500/μL, usually <200/μL) lasting for 2–4 days at approximately 21-day intervals, documented by serial blood counts (a minimum of 2–3 complete blood counts per week for at least six weeks). Severe congenital neutropenia is a similar, but usually more severe disease. Mutations of the ELA2 gene are regarded as the cause of most cases of both cyclic neutropenia and severe congenital neutropenia. However, only patients with severe congenital neutropenia, not cyclic neutropenia, are thought to be at risk of evolution to MDS/AML. Since its founding in 1994, the Severe Chronic Neutropenia International Registry (SCNIR) has utilized data from previous studies and enrolled patients with cyclic neutropenia based on the clinical information from their treating physicians. We reviewed 190 cases of cyclic neutropenia (including 30 families) enrolled for 0.5 to 19.9 years, (median 11 years) with a total of 2,035 patient years of observation. 173 of 190 patients were treated with G-CSF (median dose 2.82 mcg/kg/day). We identified three patients who were reported to have developed MDS/AML. Further analysis by three experts from the SCNIR revealed that all three patients lacked sufficient serial blood count data to show well-defined neutrophil cycles prior to G-CSF. Two of the three patients lacked a clinical history of mouth ulcers and fevers consistent with the diagnosis, and the bone marrow evaluation was not consistent with cyclic neutropenia in all three cases. One of two patients tested did not have an ELA2 mutation. Thus, using standard criteria for the diagnosis of cyclic neutropenia, none of the three patients fully satisfied the criteria for this diagnosis. In addition, previous family studies, reviews of the published literature, and personal experience of the authors have revealed only one case of leukemia. This case of CML emerged in a 35 year-old patient, who was never treated with G-CSF, 31 years after the diagnosis of cyclic neutropenia. Based upon the review of these cases, we believe it is extremely important to make the diagnosis of cyclic neutropenia by careful analysis of serial blood counts. When the diagnosis is made confidently, it is also important to assure patients that with or without G-CSF treatment, the possibility of evolution to leukemia is unlikely.
Ongoing Strong Improvement in Survival after Diagnosis with Childhood Hematologic Malignancies.
Authors: Pulte Dianne , Gondos Adam , Brenner Hermann
Published: October 2019

PURPOSE: Advances in the treatment of childhood hematologic malignancies have led to improvements in survival in several of these conditions during the past few decades. Here we use the novel method of modeled period analysis to disclose most recent trends in survival among patients diagnosed with hematologic malignancies at less than 15 years of age1.

METHODS: We estimated trends in 5-, 10-, and 25-year survival in children with common hematologic malignancies in the US over three 5-year intervals: 1990–94, 1995–99, and 2000–04, using data from the Surveillance, Epidemiology, and End Results program. Expected survival for 2005–09 was estimated by modeling from trends in the preceding intervals2.

RESULTS: Major improvements in 5- and 10-year relative survival between 1990–94 and 2000–04 were seen in acute lymphoblastic leukemia (ALL) (+7.3 and +10.4% points, respectively), acute non-lymphoblastic leukemia (ANLL) (+18.0 and +20.4% points) and non-Hodgkin lymphoma (NHL) (+11.1 and +13.9% points). Improvements in survival for patients with ALL were particularly strong in older patients, so that the significance of age as a prognostic factor decreased for children diagnosed with ALL in the early 21st century. For Hodgkin’s disease (HD), 5 and 10-year survival were as high as 96.1% and 94.1% in 1990–94 and did not show recent changes. However, it is notable that the 5- and 10-year survivals for HD in 2000–04 were identical, that is, no further deaths occurred between 5 and 10 years. Twenty-five year survival was lower for all of the malignancies examined, with 25-year survivals of about 80% for ALL, HD, and NHL and about 50% for ANLL. Projected 10-year survivals for children diagnosed in 2005–09 are 88.0%, 63.9%, 90.6%, and 94.3% for ALL, ANLL, NHL, and HD, respectively.

CONCLUSION: Application of period analysis to a population-based study of hematologic malignancies reveals ongoing strong improvement in 3 of the 4 common childhood hematologic malignancies. Projections for 2005–09 suggest chances of 10-year survival to be close to 90% or higher for children with ALL, HD, or NHL and to approach 65% for children with ANLL. Long term outcomes remain problematic, with some excess loss of life occurring as late as 25 years after diagnosis.

Period estimates of 10-year survival for childhood hematologic malignancies Malignancy 1990–94 (SE) 1995–99 (SE) 2000–04 (SE) Difference P-val Projected for 2005–09 (SE) ALL-total 73.4 (1.5) 81.0 (1.3) 83.8 (1.2) +10.4 <0.0001 88.0 (1.4) ALL-0-2 yr 72.3 (3.3) 80.9 (2.9) 83.4 (2.8) +11.1 0.01 87.9 (3.0) ALL-3–4 yr 80.9 (2.4) 84.9 (2.1) 88.9 (1.8) +8.0 0.006 91.6 (2.0) ALL-5–9 yr 71.4 (2.7) 80.4 (2.4) 81.4 (2.2) +10.0 0.004 86.1 (2.6) ALL-10–14 yr 61.3 (2.1) 72.3 (4.1) 78.2 (3.6) +16.9 0.007 83.9 (4.0) ANLL 38.7 (4.0) 42.7 (3.8) 59.1 (3.7) +20.4 0.0005 63.9 (4.8) HD 94.4 (2.1) 90.8 (2.6) 95.4 (1.8) +1.0 0.79 94.3 (3.0) NHL 73.0 (4.0) 81.7 (3.4) 86.9 (2.6) +13.9 0.005 90.6 (2.8)
Utilization of Resources and Overall Outcome in Patients Undergoing Hematopoietic Stem Cell Transplantation Related to Psychosocial Factors as Measured by the Transplant Evaluation Rating Scale (TERS).
Authors: Speckhart Dawn S. , Holland H.K. , Solomon Scott R. , Morris Lawrence E. , Bashey Asad
Published: October 2019

Several studies have begun to examine the relationship between psychosocial variables and outcome in hematopoietic stem cell transplantation (HSCT). Data presented at the 2006 ASH Convention, demonstrated a significant relationship between psychosocial variables, such as those assessed on the Transplant Evaluation Rating Scale (TERS), and objective outcomes, such as length of hospitalization and survival. The 2006 data included 200 consecutive patients (136 autologous, 65 allogeneic) undergoing HSCT. Based on the patient’s TERS score, each patient was stratified into one of two groups (low/moderate risk (n=173) vs. high risk (n=28)) based on their predicted psychosocial risk for problems during transplant. With the addition of 166 patients (Current N=366: 239 autologous, 127 allogeneic) the difference in length of hospitalization between low/moderate risk (10 days) versus high risk (19 days) patients remains significant (p<.02). For allogeneic patients (N=127), there continues to be an improved overall survival in low/moderate risk patients in the first 12 to 18 months following HSCT compared to high risk patients (p = .246). To determine whether similar factors impact utilization of resources in patients undergoing HSCT, we prospectively conducted psychosocial assessments on 112 consecutive allogeneic HSCT patients. An analysis of cost was completed for all patients in both the low/moderate risk group and high risk group. The mean cost differential for high risk patients is noted to be 27% higher than those patients in the low/moderate risk group (p = .122). This trend reinforces earlier data presented and suggests a correlation between pre-transplant psychosocial risk factors and resource utilization in HSCT.

Overall Survival Overall Survival
Economic Evaluation of Posaconazole Versus Standard Azole Prophylaxis in High Risk Neutropenic Patients in The Netherlands.
Authors: Stam Wiro B. , O’Sullivan Amy K. , Rijnders Bart , Lugtenburg Elly , Span Lambert F. , Janssen Jeroen J. , Jansen Jeroen P.
Published: October 2019

Background: Acute leukemia and high risk myelodysplastic syndrome patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of acquiring potentially fatal invasive fungal infections (IFI). Pharmacoeconomic analysis is considered a valuable tool to justify the significant costs involved in managing these fungal infections. The present study evaluates the cost-effectiveness of posaconazole versus standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands.

Methods: A decision-tree model was developed that starts with the choice of antifungal prophylaxis: posaconazole or standard azole treatment (fluconazole or itraconazole). The decision tree was estimated using data from a recently published prospective, randomized, double blind, multi-center trial that compared both treatments in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., 2007). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI related death, and death from other causes. It is assumed that patients surviving the prophylactic period will have a life expectancy that reflects that of the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include incremental cost per IFI avoided, incremental cost per life years saved and incremental cost per QALYs gained.

Results: The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to €4,566 (95% uncertainty interval €3,574 –€5,769), which is €63 (−€1,552 - €1,903) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.1 (0.03 – 0.15) QALYs gained in comparison to prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 87% probability that the cost per QALY gained with posaconazole is below €20,000, a commonly accepted threshold for cost-effectiveness. Additional scenario analyses with different assumptions confirmed these findings.

Conclusion: Given the underlying data and assumptions, our economic evaluation demonstrated that posaconazole prophylaxis is cost and QALY saving compared to fluconazole / itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.
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

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

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

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.
Hematopoietic Progenitor Cell Transplantation from Parental Donors for Children with Sickle Cell Anemia and Stroke.
Authors: Woodard Paul , Hale Gregory , Leung Wing , Barfield Raymond , Kasow Kimberly , Madden Renee , Handgretinger Rupert , Cunningham John , Ware Russell
Published: October 2019

Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sickle cell anemia (SCA), most patients lack an HLA matched sibling donor or matched unrelated donor. A 2002 multidisciplinary conference held at St. Jude Children’s Research Hospital reached consensus that pilot studies using parental donors were reasonable and ethical. Subsequently, eight children with a history of clinically overt stroke were transplanted on two sequential pilot studies. Peripheral blood progenitor cells were obtained from parents with sickle cell trait. Conditioning was i.v. busulfan (targeted to Css 900 ng/ml) q 6 hours x 4 days, fludarabine 150–200 mg/m2, and OKT3/methylprednisolone and infusion of CD34+ HPCT for 3 patients. Five patients received i.v. busulfan (targeted to Css 900 ng/ml) x 4 days, cyclophosphamide 200 mg/kg, thiotepa 10 mg/kg, OKT3/methylprednisolone, and infusion of both CD34+ cells and CD3+ cells with a fixed T-cell addback of 1.0–1.5 x 105 CD3+ cells/kg. Six children received pre-transplant immunosuppression with hydroxyurea and azathioprine. The median follow-up of eight patients is 1.4 years (range 2 months–4 years). Five of eight had durable donor engraftment,4 of whom are alive and free of SCA post-HPCT. Rejection occurred in 4 patients and was successfully reversed with additional CD34+ cells in one of three patients. GVHD occurred in patients receiving a fixed T-cell addback or DLI: two patients had grade II acute graft-versus-host disease (aGVHD), one grade III aGVHD, and three patients developed chronic GVHD, including a fatal case of bronchiolitis obliterans organizing pneumonia (BOOP) and fungal sepsis. One engrafted patient developed medulloblastoma 2 years post-HPCT and is in remission after treatment. Further investigation revealed that this child inherited a novel germline p53 mutation. In this preliminary experience, haploidentical HPCT for children with SCA and stroke was associated with significant graft rejection and chronic GVHD. The addition of pre-transplant hydroxyurea and azathioprine, increased intensity of conditioning, and the use of T-cell addback to the graft did not improve engraftment in the second cohort. While offering the possibility of cure, haploidentical HPCT for SCA as performed in this experience is associated with significant toxicity and should only be pursued in the context of a rigorously designed and controlled prospective clinical trial.
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

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

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

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

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

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.
Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma: Results of a Phase II Study.
Authors: Advani Ranjana , Hymes K. , Pohlman B. , Jacobsen E. , McDonnell J. , Belt R. , Lerner A. , Kim Y. , Mundis R. , Mansfield T. , Buhl-Jensen P. , Ooi C.E. , Duvic M. , Foss F.
Published: October 2019

Background: Belinostat (PXD101) is a hydroxamate pan-histone deacetylase inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. Phase I studies have shown that belinostat is well-tolerated.

Methods: This Phase II trial evaluated the activity of belinostat in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Belinostat (1000 mg/m2) was administered as a 30-min IV infusion on Days 1–5 of a 3-wk cycle. The primary endpoint was objective response (OR) rate analyzed separately for PTCL and CTCL using the Cheson criteria and Severity Weighted Assessment Tool (SWAT), respectively. For each arm, a Simon 2-stage design was used based on target OR rate of 25%, with expansion to 34 pts if ≥ 2/13 OR were observed.

Results: In the PTCL arm, 12 pts (9 with stage III/IV disease) were enrolled; (7 PTCL-unspecified (PTCL-U), 2 anaplastic large cell lymphoma (ALCL), 2 angioimmunoblastic T-cell lymphoma and 1 NK-T-cell lymphoma), treated for a median of 2 cycles (range 1–8). Of 11 evaluable pts, 2 achieved a CR and 5 pts had SD. The two CR (11+ and 15+ wks) were both in pts with PTCL-U. A third pt with PTCL-U had SD lasting 14 wks and discontinued treatment due to an adverse event (AE). Both pts with ALCL had durable SD (20+ and 14 wks). In the CTCL arm, 16 pts were enrolled (9 Mycosis Fungoides (MF), 5 Sezary Syndrome (SS), 2 primary cutaneous ALCL) and treated for a median of 2 cycles (range 1–6). Four ORs were observed (25%): 1 CR (ALCL) and 3 PR (MF/SS). The median duration of the OR was 10 wks (range 7 to 39+ wks). Four additional pts had a 25 – 50% decrease in SWAT. Improvement in pruritus score by ≥ 3 on a visual analog scale was reported in 5/6 patients with significant pruritus at baseline. Overall in both study arms the drug was well-tolerated and most AE were grade 1/2 (nausea, fatigue, constipation, diarrhea, and vomiting). Grade 3 AE attributed to the study drug was reported in 7 pts and included peripheral edema, apraxia, adynamic ileus, pruritus, rash, and infections. Only 1 treatment related Grade 4 AE was noted (thrombocytopenia). One patient with progressive PTCL died 6 days after last belinostat dose with ventricular fibrillation and drug causality could not be excluded.

Conclusions: Belinostat (PXD101) is generally well tolerated and demonstrates encouraging clinical activity in recurrent or refractory PTCL and CTCL. The objective response rate in both arms has met the pre-defined criteria for study expansion to stage II of enrollment.
Unlike Imatinib, Dasatinib Uptake into Chronic Myeloid Leukaemia Cells Is Independent of hOCT1 Expression.
Authors: Giannoudis Athina , Davies Andrea , Lucas Claire M. , Harris Robert J. , Pirmohamed Munir , Clark Richard E.
Published: October 2019

In chronic myeloid leukaemia (CML), resistance to imatinib is an important clinical issue. We have previously shown that imatinib uptake into CML cells and cell lines is dependent on the uptake transporter human Organic Cation Transporter 1 (hOCT1; SLCA22). Furthermore, in clinical samples, low hOCT1 expression is an important mechanism of imatinib resistance (Wang L et al, Clinical Pharmacology and Therapeutics; epub June 13th 2007). Dasatinib is a second generation novel tyrosine kinase inhibitor that is effective in many imatinib-resistant patients. Its mechanism of transport into and out of CML cells has not been previously investigated. We hypothesised that dasatinib might be transported differently to imatinib, which might account for its favourable effects in imatinib-resistant patients. The CML cell line KCL22 was selected for transfection work as it has a particularly low basal level of hOCT1 expression. KCL22 cells were transfected with pcDNA3-hOCT1 plasmid (kind gift of D Gründemann, Germany) and stable lines were selected with high hOCT1 expression. The uptake of radiolabelled dasatinib (kind gift from Bristol Myers Squibb) was greater in high-hOCT1 expressing cells than in mock transfected cells (p=0.0149, n=3). However, prazosin and amantadine, both inhibitors of hOCT transport, did not decrease dasatinib uptake into mock transfected KCL22 cells, in sharp contrast to the block on imatinib uptake seen with both these inhibitors. Dasatinib decreased the level of phosphorylated CRKL (surrogate marker for BCR-ABL) by 49.9% in mock transfected KCL22 cells and 40.3% in high-hOCT1 expressing cells. The distribution coefficient (logD) of dasatinib between 1-octanol and HEPES medium was 2.05, compared with 0.81 for imatinib, demonstrating that dasatinib is more lipophilic. The efflux of dasatinib was investigated in confluent monolayers of Madin-Darby canine kidney (MDCKII) cells on a semipermeable membrane. These cells stably express ABCB1 (MDR1) on their apical but not their basal aspect. Both dasatinib and imatinib were transported from the basal to the apical layer, indicating ABCB1 transporter-mediated efflux of both drugs (p=0.001, p<0.0001, respectively). Addition of the ABCB1 inhibitor PSC833 blocked transport of both drugs (p=0.0013, p<0.0001 respectively). Taken together, the data are consistent with the view that dasatinib, unlike imatinib, may achieve adequate intracellular levels and BCR-ABL suppression even in cells with low or blocked hOCT1 function. However, in cells with high hOCT1 expression, dasatinib uptake may be augmented. Efflux of dasatinib and imatinib appear similar and via ABCB1. Dasatinib may be useful therapeutically in patients with imatinib resistance related to low hOCT1 expression.
Characterization of Acute Myeloid Leukemia with PTPN11 Mutation - The Mutation Is Closely Associated with NPM1 Mutation but Inversely Related to FLT3/ITD.
Authors: Hou Hsin-An , Chou Wen-Chien , Chen Chien-Yuan , Lin Liang-In , Tang Jih-Luh , Tseng Mei-Hsuan , Huang Chi-Fei , Chiou Rong-Jing , Lee Fen-Yu , Liu Ming-Chih , Tien Hwei-Fang
Published: October 2019

The development of acute myeloid leukemia (AML) is a multistep process. Recently, somatic mutations of PTPN11, the gene encoding non-receptor protein tyrosine phosphatase SHP-2, were observed in some hematological malignancies. However, the characteristics of adult AML with PTPN11 mutations have not been comprehensively studied, and the specific genetic alteration cooperative with a PTPN11 mutation in the leukemogenesis remains largely unknown. In this study, PTPN11 mutation and its association with other gene aberrations were analysed for 272 adult patients with de novo AML. Missense mutations were identified in 14 individuals (5.1%). The PTPN11 mutation was closely associated with old age (P=0.036), FAB M4/M5 subtypes (P=0.049), CD14 expression (P=0.026), a normal karyotype (P=0.044) and NPM1 mutation (P=0.037), but negatively associated with FLT3/ITD (P = 0.025). In addition, four patients revealed simultaneous mutations of PTPN11 and AML1 (n=3) or MLL (n=1). We observed a shorter overall survival for patients with PTPN11 mutation than those without amongst NPM1-wild patients (P=0.001), but not amongst NPM1-mutated patients (P=0.738). Our findings provide evidence that AML patients with PTPN11 mutations had some distinct biological and clinical characteristics, and the mutation may cooperate with other gene alterations to lead to AML in a subset of patients.
Prognostic Significance of FLT3/ITD Mutation in AML1/ETO-Associated Acute Myeloid Leukemia.
Authors: Kim Yeo-Kyeoung , Kim Hee-Nam , Lee Il-Kwon , Bang Soo-Mee , Jo Deog-Yeon , Won Jong-Ho , Yim Chang-Yeol , Yang Deok-Hwan , Lee Je-Jung , Kim Hyeoung-Joon
Published: October 2019

Background: AML1-ETO fusion gene in acute myeloid leukemia (AML) usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. An internal tandem duplication of the FLT3 gene (FLT3/ITDs) is known to be associated with poor outcome after standard induction chemotherapy in AML patients with normal cytogenetics. However, this mutation is reported to be rarely found in cases with AML1/ETO positive and it remains a matter of debate as to whether these mutations play an independent role in the prognosis of AML patients with AML1/ETO fusion gene.

Aims: To determine the prevalence and the prognostic role of FLT3/ITD in patients with AML1/ETO positive AML.

Methods: FLT3/ITD and NPM1 mutation status was evaluated by performing DNA polymerase chain reaction assays on 39 bone marrow samples obtained at initial diagnosis from the patients with AML1/ETO fusion gene positive AML. GeneScan analysis was performed to confirm the FLT3/ITD mutation and to measure mutant levels.

Results: Of total 39 patients, 11 patients (28.2%) demonstrated the aberrant FLT3/ITD mutations. The median age of patients was 40 years (range, 17–75 years). There were 24 males (61.5%) and 15 females (38.5%). There was no statistically significant difference in age, gender, leukocyte count, hemoglobin level, platelet count and percentage of peripheral or bone marrow blasts between the patients with or without FLT3/ITD. No NPM1 mutation was found in these AML Patients. To analyze the response to or outcome of therapy, we evaluated 34 patients who received intensive induction chemotherapy containing cytarabine. In univariate analysis, there was no significant difference in complete response rate (FLT3/ITD+: 100% vs. FLT3/ITD−: 95.6%, p = 0.48). However, the presence of FLT3/ITD was associated with higher relapse rate in these patients (FLT3/ITD+: 72.7% vs. FLT3/ITD−: 27.3%, p = 0.01).Significant shorter leukemic-free survival (LFS) was observed in patients with FLT3/ITD compared with those without FLT3/ITD (6.9±1.0 ms vs. 18.9±10.9 ms, p = 0.01), but there was no statistical significance in overall survival (OS) (10.6±0.6 ms vs. 16.5± NA ms, p = 0.56).

Conclusions: This study demonstrates that the presence of FLT3/ITD mutations is a significantly higher relapse rate and shorter LFS in AML1/ETO positive patients. Therefore, a stratified treatment plan such as stem cell transplantation may be warranted for the AML1/ETO positive AML harvoring FLT3/ITD mutation.