bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Significance of Symptom Burden and Quality of Life Decrement in Cancer Patients with Mild Anemia.
Authors: Schwartzberg Lee S. , Fortner Barry V. , Houts Arthur C. 
Published: April 2020

Abstract
Background. Cancer related anemia (CRA) is associated with increased symptom burden and reduced quality of life (QoL) compared to non-anemic subjects. Standard treatment guidelines for CRA recomend treatment when hemoglobin (Hb) declines to ≤ 10 g/dl. We compared patients with mild anemia to those with normal Hb level to assess clinical significance of mild anemia. Methods. 3416 patients from a large community oncology database sorted by gender and Hb were retrospectively reviewed.
Patients receiving chemotherapy (&lt;30 days) and/or growth factor (&lt; 60 days) were excluded. Each case provided one Hb determination and same day self reported scores on the Cancer Care Monitor (CCM), a validated measure of symptom burden, functioning, and health related QoL comprising 6 scales. All CCM items are rated for symptom severity on a 0–10 scale. Effect sizes for male groups are calculated relative to normal males (Hb &gt; 14), and effect sizes for females are calculated relative to normal females (Hb &gt; 12). Positive effect size (Cohen’s exact d) values indicate greater symptom burden, and negative effect size values indicate lower quality of life.
Results. Group differences on CCM measures were not accounted for by demographic, cancer diagnosis, and chemotherapy history differences. Table 1 shows a pattern of greater symptom burden, lower functioning, and worse QOL for males and females with mild anemia (p &lt; .05). As compared to standards for minimal clinically important differences such as found with SF-36 (0.09 &lt; Cohen’s d &lt; 0.28). patients with mild anemia showed clinically significant differences in terms of effect size (0.11 &lt; Cohen’s d &lt; 0.61).
Conclusions. The QoL impact of mild CRA is significant and failure to treat mild anemia may result in unnecessary symptom burden and noteworthy decrements in health related quality of life.
Differences in QoL for Patients with Mild Anemia
M Hb12&lt;14 M Hb &gt;14 Effect Size F Hb 10&lt;12 F Hb &gt;12 Effect Size Cancer Care Monitor Measure* (n = 327) (n = 471) Males (n = 449) (n = 2169) Females Note. *Mean (SE) for each item or scale. Adjusted means with different subscripts across rows are significantly different (p &lt; .05) by Bryant Paulson comparisons. Fatigue Item 3.10 (0.16) b 2.27 (0.13) c 0.30 3.47 (0.13) b 2.65 (0.06) d 0.30 Physical Symptoms 49.54 (0.58) b 45.49 (0.48) c 0.38 49.32 (0.49) b 46.97 (0.22) d 0.22 General Distress 49.51 (0.57) b 47.07 (0.47) d 0.19 51.23 (0.49) c 49.85 (0.22) b 0.11 Despair 50.74 (0.52) b 48.58 (0.43) c 0.25 50.37 (0.44) b 49.13 (0.19) c 0.14 Impaired Performance 55.55 (0.87) b 49.78 (0.70) c 0.61 55.02 (0.73) b 49.90 (0.32) c 0.48 Quality of Life 49.41 (0.79) b 53.46 (0.64) c −0.45 48.95 (0.67) b 52.39 (0.29) c −0.35
Resource Utilization, Costs and Type of Malignancy Associated with Prolonged Length of Stay in Autologous Stem Cell Recipients.
Authors: Patchett Linda J. , Hill John M. , Fitzmaurice Thomas F. , Meehan Kenneth R. 
Published: April 2020

Abstract
In order to contain costs, MDs must first identify the clinical factors contributing to increased resource utilization associated with an autologous stem cell transplant.
We performed a retrospective clinical and cost analysis of all autologous transplants performed at Dartmouth- Hitchcock Medical Center over a 30 month period (2002-2004) and identified patients who had a prolonged length of stay &gt; 25 d (PLOS). We pinpointed the clinical characteristics and hospital course of each patient to identify trends. The hospital cost-accounting system highlighted resource utilization and costs of the transplants, allowing a comparison between patients with a PLOS and all other transplant patients.
PROLONGED LENGTH OF STAY (PLOS)
Results: All Patients LOS &lt; 25 days LOS &gt; 25 days # of patients 87(100%) 58 (67%) 29 (33%) LOS (days) Mean (Median) 24 (22) 20 (20) 31 (31) DISEASE (n = no. of patients) AML 14 9 5 HD/NHL 44 24 20 MM 28 25 3 Other (ITP) 1 1 ENGRAFTMENT (median) ANC &gt; 500 (Platelets &gt; 20K) 12 (18) 11 (16) 13 (27) TRANSFUSIONS UNITS /PT (median) RBC /Platelets &gt; 20 4 (3) 3 (2) 7 (7) PARENTAL NUTRITION (TPN) # of days (median) 9 6 14 TOXICITIES &gt;= GRADE 3 NCI (Common Toxicitity Criteria) Nausea and Vomiting 36% 77% Diarrhea 9% 45% Mucositis 36% 41% Anorexia 57% 83% INFECTION RATE 10% 34% ICU TRANSFER 3% 3%
Major contributors to costs included nursing/daily room charge costs (39%), pharmacy (39%), Blood Bank (6%), Laboratory (12%), and other costs (3%). The average daily costs are $4252.
The PLOS cohort had grade &gt; 3 toxicity, increased infection rate, engrafted later and required more transfusional support. 1 pt was transferred to the ICU for temporary management. Of the 29 patients identified with PLOS, none died and all were discharged from the hospital. 45% of NHL/HD patients experienced a prolonged LOS, representing 68% of the PLOS cohort. The median LOS&lt;25d is 20d and the median LOS&gt;25d is 30.5d. At an average daily cost of $4252, these additional 10.5 days of hospitalization costs are substantial. Based on these findings, identification of factors underlying PLOS in the NHL/HD cohort may provide the key to minimizing cost of autologous stem cell transplant. Accordingly, we are assessing the impact of age, number of pre-transplant treatment regimens, number of peripheral blood stem cells reinfused, use of IL-2 for post-transplant immune modulation, and the day 15 absolute lymphocyte count on LOS in this population.
Gelclair® for the Treatment of Chemotherapy-Induced Stomatitis in Transplant and Hematology Patients: An Interim Analysis.
Authors: Liewer Susanne E. , Hecht Keith A. , Smith Courtney F. , DeRemer David L. , Howard Dianna , Brown Randy A. , Herzig Roger H. , Adams Val R. 
Published: April 2020

Abstract
Patients receiving treatment for hematologic malignancies (HM) commonly experience stomatitis. While there is no standard therapy, pain management and infection prophylaxis are the cornerstones of treatment. Gelclair® a bioadherent gel has been shown to decrease pain associated with stomatitis but has yet to be evaluated in this patient population. This open label, single-arm study evaluates the effectiveness of Gelclair® administered every 8 hours to relieve pain associated with treatment-induced stomatitis in patients with HM. Efficacy was determined by obtaining hourly pain scores on a 10-point scale for the first 8 hours, then every 6 hours until resolution of symptoms, while controlling for stomatitis severity and opioid consumption. Secondary endpoints included quality of life [functional living index-cancer (FLIC)], ability to consume a soft diet, and ability to take oral medications. Fifteen of 30 planned patients have been enrolled, with 12 being transplant patients (8 auto, 4 allo). Melphalan was the most common therapy received and multiple myeloma was the most common patient diagnosis. The median time on study was 5 days. The median stomatitis severity was grade 2 with a range of 1 to 3 (NCI criteria). The mean pain score at baseline was 5.8 +/− 0.6, which declined to 3.8 +/− 0.6 one hour after Gelclair® application and remained below baseline for 8 hours. Over the first 72 hours, average daily pain scores, stomatitis severity, and opioid consumption all increased, while WBC decreased. The average FLIC score at baseline was essentially unchanged on day 1, 7 or at the end of study (102, 102, 98, and 101, respectively). Oral meds were administered and soft diet tolerated during 93% and 85% of treatment days. Adverse events were limited to nausea with or without vomiting in 2 patients. Interim analysis suggests Gelclair® improves pain scores quickly while allowing patients to continue oral medications. This improvement is sustained throughout the dosing interval. Data from all evaluable patients will be presented at the meeting.
Homodimerization of Retinoic Acid Receptor alpha through its Fusion Partners Underlies Pathogenesis of Acute Promyelocytic Leukemia.
Authors: Kogan Scott C. , Phan Vernon T. , Sternsdorf Thomas , Maunakea Mei Lin , Sohal Jastinder , Silletto Angela , Galimi Francesco , Evans Ronald M. 
Published: April 2020

Abstract
In almost all cases of acute promyelocytic leukemia (APL), t(15;17)(q22;q12) fuses the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene. In rare cases of APL, other genes are fused to RARA including PLZF, NPM, NuMA, and STAT5b. These chimeras are collectively referred to as X-RARA fusions. Common features of the X-RARα fusions include their ability to form dimers through the X domain proteins while retaining the ability to interact with rexinoid receptors (RXRs, the proteins with which RARα normally heterodimerizes). We previously created an artificial X-RARα: p50-RARα (a fusion of the dimerization interface of p50 NFκB with the portion of RARα found in naturally occurring X-RARα proteins). p50-RARα has effects similar to PML-RARα including (i) enhancing repression at retinoic acid response elements, due to impaired release of co-repressors at low levels of all-trans retinoic acid (ATRA), and (ii) inhibiting differentiation of myeloid cell lines. We generated transgenic mice expressing p50-RARα under the control of the MRP8 promoter. p50-RARα had a minimal effect on myelopoiesis and initiated myeloid leukemias at a rate of &lt;5% in the first year of observation. Nevertheless, transduction of p50-RARA transgenic bone marrow with a retrovirus expressing an activated cytokine receptor (βcV449E) generated leukemias with features of APL including therapeutic responsiveness to ATRA. Complementing our work with the p50-RARA transgenic mice, retroviral co-transduction of normal bone marrow with βcV449E plus either p50-RARA or PML-RARA generated APL-like myeloid leukemias. Although retrovirally generated βc/p50-RARα and βc/PML-RARα leukemias were nearly identical, the PML fusion appeared associated with a subtle decrease in differentiation relative to the p50 fusion. In contrast to these X-RARα fusions, preliminary experiments suggest that RCRα (a homodimeric form of RARα in which the dimerization interface of RARα has been replaced by the dimerization domain of the homodimeric COUP-TF transcription factor) does not readily cooperate with βcV449E to cause leukemia. This finding lends support to the hypothesis that the decreased binding site selectivity of X-RARα fusions contributes to APL pathogenesis. Furthermore, we have generated a novel X-RARα fusion, F3-RARα, in which three copies of the F36M mutant of the Rapamycin-binding protein have been fused to RARα. This protein mimics the in vitro effects of PML-RARα on transcription & differentiation, and de-dimerization of F3-RARα by rapamycin reverses these effects. Additional experiments in vivo with F3-RARα are expected to further confirm the importance of abnormal transcription factor dimerization in leukemia pathogenesis.
Pim Kinases Mediate Viability Signals Downstream of the Tyrosine Kinase Oncogenes BCR-ABL and FLT3-ITD.
Authors: Sattler Martin , Babendreier Emily , Chu Stephanie C. , Gramlich Jessica L. , Podar Klaus , Griffin James D. 
Published: April 2020

Abstract
Pim1 and Pim2 belong to a family of serine/threonine kinases that are overexpressed in many leukemias. Pim1 has previously been shown to cooperate with the v-myc oncogene to transform hematopoietic cells with murine transforming viruses and overexpression of Pim2 has been shown to induce growth factor independence in a factor dependent murine BaF3 cell line. Protein expression of both Pim1 and Pim2 is low or absent in non-transformed hematopoietic cells but was found to be rapidly increased upon transformation by BCR-ABL or FLT3 with an internal tandem duplication (ITD). The exact contribution of the Pim kinases to transformation in these cells is unknown. BaF3 cell lines were created that stably expressed either BCR-ABL or FLT3-ITD tyrosine kinases, and in which either Pim1 or Pim2 could be induced with doxycycline. Treatment of BCR-ABL or FLT3-ITD expressing cells with small molecule kinase inhibitors specific for either ABL or FLT3 led to inhibition of cell growth, increased apoptosis, and downregulation of Pim expression as expected. However, if Pim2, and to a lesser extent, Pim1 expression was maintained by doxycycline, there was a substantial increase in both viability and cell growth. The molecular mechanisms by which Pim proteins exhibit their effects on target cells are not known. Using parental growth factor dependent BaF3 cell lines with doxycycline inducible Pim1 and Pim2, we show that expression of either of the Pim proteins is sufficient, by itself, to reduce apoptosis and induce modest cell growth. The effects of Pim overexpression on several pathways known to be associated with viability were studied. We found that while Pim over-expression does not activate Akt, it does result in the phosphorylation of a known Akt target, GSK-3β, a regulator of cell cycle progression by targeting the stability of cyclin D proteins. This suggests that Pim proteins may mediate their biological effects through regulation of components in the phosphatidylinositol-3′ kinase signaling cascade, independent of Akt activation. These results further suggest that upregulation of Pim kinases significantly contributes to transformation. Inhibition of Pim kinases could have beneficial therapeutic effects in leukemias.
A Cell-Based Screening Method for Resistance of Bcr-Abl Positive Leukemia Identifies the Mutation Pattern for an Alternative Abl Kinase Inhibitor.
Authors: von Bubnoff Nikolas , Veach Darren R. , van der Kuip Heiko , Aulitzky Walter E. , Saenger Jana , Seipel Petra , Bornmann William G. , Peschel Christian , Clarkson Bayard , Duyster Justus 
Published: April 2020

Abstract
The increasing impact of targeted cancer treatment demands strategies to identify and evaluate resistance mechanisms toward kinase inhibitors prior to their therapeutic application. Point mutations within the Bcr-Abl kinase domain constitute the major mechanism of resistance toward imatinib mesylate in Philadelphia-positive (Ph+) leukemia. Using Bcr-Abl-transformed Ba/F3 cells, we established a cell-based screening strategy for the prediction of specific kinase mutations that cause resistance toward kinase inhibitors. With imatinib at clinically relevant concentrations, we generated 368 resistant Ba/F3 sublines that were derived from resistant colonies. Thirty-two different single point mutations within the kinase domain of Bcr-Abl were identified in twenty-five per cent (liquid culture conditions) and seventy-two per cent (solid culture conditions) of these lines at known and novel positions. Using imatinib, the pattern and relative frequency of mutations reflected matters observed in patients with imatinib resistance. We then applied this screen to the pyrido-pyrimidine PD166326 (PD16), an investigational Abl kinase inihibitor. Compared to imatinib, we observed a five to seven times lower frequency of resistant colonies with equipotent concentrations of PD16. In addition, PD16 produced a distinct pattern of Bcr-Abl mutations. P-loop, A-loop and the known imatinib contact site T315 were affected with both inhibitors, whereas C-helix and SH2 contact sites were affected in imatinib resistant colonies exclusively. In contrast to imatinib, where kinase domain mutations were still widely distributed over the kinase domain even at at 4μM, mutations observed with PD16 at a concentration of 100nM narrowed to the exchange at position T315 to iseulicine. We did not detect mutations outside the kinase domain. Some resistant sublines displayed increased Bcr-Abl activity. Mutations that were derived from the screen were cloned and examined for the extent of cross-resistance to both inhibitors. The majority of mutations were effectively suppressed by PD16 at 50–500nM. In contrast, only few mutations were inhibited by imatinib at 5–10μM. However, exchanges at position F317 mediated resistance toward PD16, but were inhibited by standard concentrations of imatinib. Since this cell-based system produced results that are clinically significant, it may be used to predict resistance mutations in Bcr-Abl and other oncogenic kinases like cKit, EGFR, FIP1L1-PDGFRalpha or FLT3 towards clinically applicated and investigational drugs. Thus, this robust and simple screening strategy provides a rational basis for combinatorial and sequential treatment strategies.
Prognostic Impact of Minimal Residual Disease (MRD) in Children Is Different in B or T Lineage Acute Lymphoblastic Leukemia: Results of Trial AIEOP-BFM ALL 2000.
Authors: Schrappe Martin , Rizzari Carmelo , Mann Georg , Möricke Anja , Valsecchi Maria Grazia , Zimmermann Martin , Bartram Claus R. , Panzer-Grümayer Renate , Schrauder André , Cazzaniga Gianni , Flohr Thomas , Parasole Rosanna , Reiter Alfred , Ludwig Wolf-Dieter , Nigro Luca Lo , Basso Giuseppe , De Rossi Giulio , Barisone Elena , Niggli Felix , Gadner Helmut , Conter Valentino 
Published: April 2020

Abstract
Slow early response indicates poor prognosis in childhood ALL. We aimed to evaluate if post-induction MRD levels had different prognostic impact in precursor B-cell (pB) or T-cell ALL. From 07/2000 to 06/2006, 4730 pts with ALL were enrolled in trial AIEOP-BFM ALL 2000. MRD levels were centrally measured by real-time quantitative polymerase chain reaction using the identification of clone-specific T-cell receptor and immunoglobulin gene rearrangements. MRD study time-points (TP) were treatment day 33 (TP1, end of induction) and day 78 (TP2, after consolidation). To define MRD negativity, two markers with a sensitivity of at least 10−4 were required. Patients were treated with BFM induction (protocol I-A), consolidation (I-B), extra-compartment/intensified consolidation (HD-MTX in non-high-risk patients, pulses in high-risk patients), reinduction, and maintenance. MRD analysis at one or two time points suceeded in 3707 pts; the immunophenotype was available from 3636 pts. MRD levels and corresponding estimated 5-year event-free survival (5y-pEFS) comparing pB- and T-ALL are shown in Table 1 (3yrs median follow-up). MRD response in T-ALL was slower than in pB-ALL resulting in a higher percentage of pts with high MRD load in T-ALL. In pB-ALL as well as T-ALL, high MRD levels at TP2 were well predictive to identify pts with poor prognosis. For prediction of good prognostic subgroups, TP1 was more appropriate identifying a subgroup with excellent 5y-pEFS of &gt;90% in case of MRD negativity. Specificity of TP1 was poor in T-ALL if the pB-ALL criteria of MRD negativity were applied. If MRD low positive and MRD negative T-ALL pts were combined, the discrimination was as good as in pB-ALL. The optimal choice of MRD evaluation time points depends on biological factors and treatment, and is most relevant for MRD-based risk stratification.
Table 1 pB-ALL T-ALL n % 5y-pEFS % (SE) n % 5y-pEFS % (SE) all 3177 100% 82.3 (1.0) 459 100% 77.2 (2.2) MRD TP1     neg 1399 44.1 92.5 (1.0) 75 16.4 94.3 (2.8)     10E-4/−5 1122 35.4 81.9 (1.7) 116 25.4 91.2 (2.8)     10E-3 393 12.4 66.4 (3.5) 110 24.1 75.3 (4.6)     ≥10E-2 256 8.1 53.2 (4.3) 156 34.1 59.8 (4.5) MRD TP2     neg 2464 77.6 87.7 (1.0) 220 47.9 91.9 (2.0)     10E-4/−5 523 16.5 68.9 (2.9) 143 31.2 76.6 (3.9)     10E-3 107 3.4 56.3 (6.5) 58 12.6 50.2 (8.1)     ≥10E-2 82 2.6 38.0 (7.3) 38 8.3 33.2 (8.3)
Evaluation of the Spectrin Compartment Size in Normal and Diseased Red Blood Cells by Single Particle Tracking.
Authors: Kodippili Gayani C. , Spector Jeff , Sullivan Caitlin , Labotka Richard , Ritchie Ken , Low Philip S. 
Published: April 2020

Abstract
In a process termed “hop diffusion”, membrane proteins diffuse randomly within a cytoskeletally-enclosed compartment over short time scales, periodically hopping from one compartment to the next. Band 3 diffuses in the erythrocyte membrane bilayer in a manner that is thought to be restricted by the size and stability of the spectrin network. Although a fraction of band 3 may exhibit reduced mobility due to its association with spectrin (mediated by proteins such as ankyrin and adducin), another subpopulation of band 3 is thought to diffuse freely within the spectrin compartments, hopping from one corral to the next by transient opening of the barrier (presumably a spectrin tetramer) separating adjacent corrals. Based on this hypothesis, measurement of the compartment size and hopping frequency of a band 3 molecule in the erythrocyte membrane can provide information on the structure and stability of the spectrin network. We have combined single particle tracking (SPT) techniques with high-speed video microscopy to determine the average compartment size and diffusion coefficient of the mobile fraction of band 3 in both normal and diseased red blood cells (RBCs). Streptavidin-linked quantum dots (525nm emission) and 40 nm fluorescent beads were attached to band 3 via a DIDS-biotin-linker, and fluorescence microscopy coupled to a high speed camera was used to determine the position of band 3 with a time resolution of 8 ms (120 fps). Labeling specificity was demonstrated by blotting with streptavidin-horseradish peroxidase, and flow cytometry studies established the binding constant of DIDS-biotin for band 3 in the intact cell of ∼1-2*10−5 M. For diffusion studies, RBCs were incubated with 10−11 M conjugate in order to attach only one or two streptavidin-quantum dots per cell. SPT data were collected on both healthy and pathologic human RBCs, including HbSS (sickle cells), HbSC (sickle cell hemoglobin C), HbSBo (sickle cell zero-beta-thalasamia), HbSB+ (sickle cell beta-plus-thalasamia), HS (hereditary spherocytosis), and HPP (hereditary pyropoikilocytosis). Movement within the observed compartments was found to be random, with an average diagonal length for the mobile fraction in healthy cells of ∼100nm and a diffusion coefficient of ∼1–2*10−10cm2/s. HbSS cells, however, displayed a comparatively smaller compartment size (∼60–80nm) with a lower diffusion coefficient (0.1−1*10−10cm2/s). In contrast, HPP cells exhibited an average compartment size of ∼133nm with a diffusion coefficient of 6*10−10cm2/s. SPT data further suggest the presence of multiple populations of band 3, exhibiting both free diffusion and restricted mobilities with different characteristics. Details of band 3 diffusion in all of the aforementioned diseased and normal blood cells will be provided, and a model accounting for the multiple populations of band 3 will be presented.