bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Chronic Opiates Pain Therapy in Sickle Cell Anemia.
Authors: Jonassaint Charles R. , Jonassaint Jude C. , Ashley-Koch Allison , Adam Soheir S. , Telen Marilyn J. , De Castro Laura M. 
Published: October 2019

Abstract
Sickle cell disease (SCD) patients experience high rates of morbidity and early mortality. Hydroxyurea (HU) therapy is associated with decreased morbidity and mortality as well as improved patient health outcomes (Charache et al, 1995 and Steinberg et al, 2003). However, the effect of chronic opiate pain management on HU treatment outcomes is unknown. In the current study, we evaluated the effects of HU and chronic long acting opiate therapy-OxyContin, methadone, fentanyl and MS Contin-on the following laboratory parameters: white blood cell count (WBC), hemoglobin (Hb), and mean corpuscular volume (MCV). Changes in these variables are known to be linked with HU effects on morbidity and mortality in SCD. 142 homozygous sickle cell anemia patients (75 females and 67 males) from the outpatient clinic at Duke University Medical Center were included in this study. Clinical data were collected by patient interview as well as review of medical records after informed consent. Patients were classified in 4 groups based on report of chronic daily use of long acting opiates and/or HU (current therapy with HU) as follows: No HU or opiates (None); opiates only; HU only; and HU and opiates. ANOVAs were used to identify combined effects of opiate therapy, HU therapy and the 3 laboratory parameters. Overall, we found that patients on HU (n=76, 54%), had lower WBC and higher Hb and MCV than the no HU patients (n=66, 46%), with p<.01 for all associations, as could be expected. In contrast to the positive effects of HU, patients on opiates had higher WBC than non opiate patients (p<.01). Surprisingly, when adjusting for gender and age, opiate therapy appeared to moderate the effect of HU treatment on WBC (p=.05) and MCV (p=.04). Patients who were on HU and opiates concurrently exhibited 17% higher WBC and 6% lower MCV than patients who were on HU alone, suggesting that opiate therapy may be attenuating the positive effects of HU. The findings from the current study confirm that HU treatment is associated with better patient health indices, i.e. lower WBC, higher Hb and MCV. In contrast, chronic opiate pain management, often a concomitant therapy with HU, was associated with poorer patient laboratory indices, both with or without concurrent HU treatment. Overall, these data indicate that the chronic use of opiates may decrease the efficacy of HU treatment in this patient population. Further studies are needed to study the mechanism of drug interaction between opiate and HU in SCD patients. The previously suggested inhibitory effect of HU on the cytochrome P450 CYP3A, an important cytochrome in the metabolism of some opiates (Reardon et al, 2005), should be considered for future studies of drug-drug interaction in SCD.
Figure Figure
Asthma Is Associated with Acute Chest Syndrome, but Not an Increase Rate of Hospitalization for Pain among Children with Sickle Cell Anemia: A Retrospective Cohort Study.
Authors: Bernaudin Francoise , Strunk Robert C. , Kamdem Annie , Arnaud Cecile , An Ping , Torres Martine , Delacourt Christophe , DeBaun Michael R. 
Published: October 2019

Abstract
Introduction In this study, we sought to validate the previous findings that asthma increases the incidence of acute chest syndrome (ACS) and pain in children with sickle cell anemia (SCA).
Methods A retrospective cohort was comprised of children with SCA evaluated for at least six months from a single medical center. Asthma was defined as being present when the first wheezing episode was heard by a physician after the age of 2 years or after 3 episodes of bronchiolitis before the age of 2 years. ACS was defined as a recent abnormal X-ray of the lungs associated with fever, respiratory signs or thoracic pain. A painful episode was defined as pain that resulted in hospitalization. Therapeutic intervention (hydroxyurea, blood transfusion therapy or transplant) was uniformly applied to all children with three or more episodes of pain that required hospitalization within a 12 month period. Patient years were accumulated from birth until death, lost to follow up, last visit to the center or a therapeutic intervention, whichever came first.
Results A total of 297 children with SCA were evaluable for a doctor diagnosis of asthma for a total of 1,805 patient-years. The mean length of follow-up was 6.1 patient-years. A doctor diagnosis of asthma was present in 8.4% (25 of 297). Among the children with asthma 75% (19 of 25) were consistently prescribed a beta 2 agonist or inhaled corticosteroids. After adjustment for the effect of age, asthma was significantly associated with ACS event (p = 0.03) but pain was not (>0.05).
Conclusion Among children with SCA, asthma is associated with an increased incidence of ACS, but not pain that required hositalization. The absence of an association between asthma and pain may be related to uniform therapeutic intervention for children with repetitive painful episodes that require hospitalizations coupled with active treatment for asthma in most of the children.
Continued Late Conversion to Complete Remission (CR/CRu) and Durability of Remission (DUR) in Pts with B-Cell Follicular Lymphoma (FL) Treated with Rituximab Followed by Mitumprotimut-T (Id-KLH, FavId®) Active Immunotherapy.
Authors: Koc Omer N. , Redfern Charles , Wiernik Peter H. , Rosenfelt Fred , Winter Jane N. , Guthrie Troy H. , Kaplan Lawrence , Holman Peter , Densmore John , Hainsworth John , Lin Thomas S. , Castillo Rene A. , Janakiraman Nalini , Ghalie Richard G. 
Published: October 2019

Abstract
Background: We have previously reported results from a Phase 2 trial in which both treatment naïve (TN) and relapsed/refractory (R/R) pts with stable disease (SD) or a clinical response (PR or CR/CRu) following 4 weekly doses of rituximab received mitumprotimut-T active immunotherapy (Koc et al, Blood2006; 108: #691). We report here 4-year follow up of conversion of pts into complete remission (CR/CRu) and an assessment of the DUR in this population.
Treatment: Pts received rituximab (375mg/m2 iv weekly x 4) and those with ≥SD assessed at Week 11 received mitumprotimut-T, 1 mg sq every month (mo) x 6 starting on Week 12 along with Leukine (sargramostim, GM-CSF), 250 mcg, sq on Days 1–4. Pts continued to receive booster injections on a reduced schedule (every 2 mos x 6, then quarterly) until disease progression. Radiological scans were performed every 3 mos for the first 2 years then every 6 mos, and reviewed centrally. Objective response and progression were assessed using modified IWG criteria.
Results: 89 pts (54 RR, 35 TN) had ≥SD following rituximab received mitumprotimut-T + Leukine. Two pts (RR) achieved a CR following rituximab and prior to receiving mitumprotimut-T. As shown in Fig. 1, an additional 16 pts (9 TN, 7 RR) converted to CR/CRu over the next 31 mos. At a median follow-up of 42 mos, only 6 (3 TN, 3 RR) of the 18 CR pts have relapsed (Fig. 2).
Discussion: Long-term follow-up has shown a continuing conversion of pts into CR occurring as late as 31 mos. These data suggest clinical activity of mitumprotimut-T in these pts as determined by the increasing CR rate and the durability of this response. These data are of particular interest since a blinded interim analysis of best response in an ongoing controlled Phase 3 study of single agent rituximab vs. rituximab followed by mitumprotimut-T showed 47% of pts in this study to be in CR/CRu with 12–18 mos of follow-up (Freedman et al, Blood2006; 108: #2756).
Figure Figure Figure Figure
Relapse from Complete Remission More Than 5 Years after Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): Relapse Histology Most Commonly DLBCL with a Germinal Center B-Cell (GCB) Phenotype.
Authors: Vose Julie M. , Chan John C. , Bierman Philip J. , Arevalo Alejandro , Loberiza Fausto , Fu Kai , Weisenburger Dennis , Bociek Robert G. , Bast Martin , Armitage James O. 
Published: October 2019

Abstract
Although many patients are successfully treated for DLBCL, relapses can occur especially in the higher risk patients. Relapses in successfully treated DLBCL patients most frequently occur within the first 2–3 years. However in a small number of patients, relapses occurring after 5 years do happen and have been frequently reported to be a relapse of follicular lymphoma. We evaluated 805 patients with DLBCL treated with an anthracycline based chemotherapy through the Nebraska Lymphoma Study Group from 1983–1998. The patients were treated prior to the use of rituximab in this patient population. Two hundred and three patients relapsed from a documented complete remission. Of these, 30 (15%) relapsed more than 5 years after treatment (range 5.3 – 14.5 years, median 6.8 years). The median age at relapse was 71 years (range 32 – 85) and 58% were male. Patients with late relapses had relatively good prognostic features at the time of diagnosis. None had a low performance status, 71% were stage I/II, 78% had no systemic symptoms, 78% had a normal LDH, and 67% had an IPI of 0/1. All patients had biopsies to document relapse. Eighty one percent of the relapses were documented DLBCL, 11% had composite lymphoma with DLBCL and follicular grade 3 (FL3) lymphoma, 4% had FL3 alone, and 4% had follicular grade 1 (FL1). Using immunohistochemistry to predict GCB vs. non-GCB origin, 72% of the patients had a GCB phenotype at diagnosis and 90% had a GCB phenotype at relapse. Four patients had no therapy at relapse and 2 patients had radiotherapy. The remaining patients received a variety of combination chemotherapy regimens with or without rituximab and 2 patients underwent autologous stem cell transplantation. Seven patients had durable complete remissions to their second line chemotherapy regimens (4 with chemo + rituximab and 2 autologous stem cell transplantation). Three of these survivors died of unrelated causes and 4 are alive in remission 19–119 months after the salvage therapy or autologous transplantation.
Conclusions: Most patients with late relapses of DLBCL initially present with good prognostic characteristics at the time of the origninal diagnosis. Unlike previous studies, the most common type of histology in this study at the time of late relapse was DLBCL and not follicular lymphoma. However, the vast majority of the late relapse DLBCL patients had a GCB phenotype both at diagnosis and at relapse. Patients with late relapses usually do respond to salvage therapy and can have second prolonged remissions with chemotherapy and/or autologous stem cell transplantation.
C-MYC Correlates with Expression of Multidrug Transporters ABCC1 and ABCC4.
Authors: Ho Lye Lin , Chong Li , Ling Silvia , Lau Diana , Lau Edwin , Iland Harry , Joshua Douglas E. , Allen John 
Published: October 2019

Abstract
C-MYC is an oncogene with protean effects and there is some speculation that aberrant overexpression in cancer may be associated with drug resistance by increased expression of the Multi-Drug Resistance Transporters, for example ABCC4 (MRP4) and ABCC1 (MRP1). A relationship between N-MYC and these transporters has been established in the limited context of childhood neuroblastoma and it would be tantalising to extrapolate this to the wider scope of adult tumours. The corollory would be that modulating the levels of C-MYC might have a beneficial secondary effect of making a tumour more sensitive to chemotherapeutic treatments. We have determined that the ABCC4 promoter directly responds in vitro to C-MYC and N-MYC contransfection and that this effect can be abolished by the progressive disruption of the C-MYC binding sites i.e. mutation of the E-boxes. Transient or stable overexpression of C-MYC or N-MYC did not increase multidrug transporter protein expression in 5 tumour cell lines, possibly due to the methylation status of the E-boxes or that the transporters present are already maximally expressed. However, knocking-down C-MYC by shRNA results in a concomitant reduction in ABCC1 and ABCC4. Together, these results suggest both direct and indirect regulation may be important in the functional control of these transporters. A survey was performed of Chronic Myeloid Leukaemias (CML, n=26) and Myelomas (n=23), assessing the expression of C-MYC, ABCC4 and ABCC1 by quantitative RT-PCR. The genes of interest were normalised to housekeeping genes and linear regression applied to examine the relationship of C-MYC levels to transporter expression. In CML, a direct relationship was seen between C-MYC and both ABCC4 and ABCC1. In Myeloma, a correlation was noted between C-MYC and ABCC1 but was not seen with ABCC4, as the levels detected were very low. The inference is that high levels of C-MYC may be associated with elevated multidrug transporter levels in other tumours and may be of use in predicting transporter-mediated drug resistance.
Pharmacogenetic Study on Multiple Myeloma Patients Treated with DAV Regimen and Autologous Stem Cell Transplantation.
Authors: Buda Gabriele , Maggini Valentina , Orciuolo Enrico , Galimberti Sara , Martino Alessandro , Morabito Fortunato , Barale Roberto , Rossi Anna Maria , Petrini Mario 
Published: October 2019

Abstract
As previously reported, genetic variability in xenobiotic metabolism (GSTP1 and NQO1), multidrug resistance (MDR1), folate transport (SLC19A1) and DNA synthesis (TYMS) can influence the outcome after chemotherapy and autologous transplantation in patients with multiple myeloma (MM) (Maggini et., Leuk Res 2007 in press; Buda et al., Leuk Res 2007, 31(8):1029–30; Buda et al., BJH 2007, 137(5):454–6; Maggini et al., Leukemia 2007, 21(1):176–8). To test the reciprocal influence of the examined polymorphisms on the outcome, multivariate analyses were performed on 98 patients receiving DAV regimen, followed by conditioning regimen with melphalan and autologous stem cell transplantation (ASCT) in 84 cases. As shown in table I, a worse outcome following DAV therapy was significantly associated with GSTP1 G/G, SLC19A1 T/T and TYMS A/A genotypes. Only a borderline effect was seen for NQO1 T/T carriers. After ASCT, no significant influence of the analysed polymorphisms was observed, but a higher percentage of responders presented the SLC19A1 T/T genotype. A significantly improved overall survival (OS) was found in patients carrying SLC19A1 T/T genotype or MDR1 T allele (Cox regression analysis, p=0.01). Multivariate analyses confirmed the previously reported findings: the estimated effects are comparable, even though the significance resulted slightly reduced as expected for multiple comparisons. These preliminary results, if sustained by extended analyses, suggest that these polymorphisms could be regarded as pharmacogenetic markers and as prognostic factor in order to predict the outcome of MM patients.
Table I Multiple genotype testing of MM patients are responders (R) versus non-reponders (NR) to DAV therapy (CT) or ASCT by unconditional logistic regression analysis.
Myeloperoxidase Is Required for the Combined Apoptotic Effects of Arsenic Trioxide with Ascorbic Acid or Epigallocatechin-3-Gallate in Myeloid Leukemia Cells.
Authors: Xia Lijuan , Lu Min , Chen Duo , Waxman Samuel , Jing Yongkui 
Published: October 2019

Abstract
Arsenic trioxide (As2O3) is a drug used world-wide that selectively causes the death of acute promyelocytic leukemia (APL) cells by novel mechanisms and induces complete clinical remission in 90% of patients without significant toxicity. The outstanding success of As2O3 therapy in relapsed APL patients has not been replicated by an equivalent success in other types of acute myeloid leukemia (AML). We have studied As2O3 mechanism(s) of action and identified agents to use in combination to improve the use of As2O3 as a treatment for other types of AML. As2O3 produces higher levels of H2O2 and apoptosis in APL NB4 cells than in other AML cells at therapeutic concentrations of 1-2 uM. As2O3 does not induce apoptosis in HL-60 cells but is synergistic with ascorbic acid (AA) or epigallocatechin-3-gallate (EGCG). Both AA and EGCG produce H2O2 which is augmented by the addition of As2O3. Apoptosis induction by As2O3 in combination with AA or EGCG is inhibited by catalase and the antioxidant N-acetylcysteine. Myeloperoxidase (MPO), a major neutrophil enzyme, augments H2O2-induced apoptosis by converting it into more potent reactive oxygen species. HL-60, NB4, SKNO-1 and PLB985 cells which express high level of MPO, but not U937 and K562 cells without expression of MPO, are responsive to As2O3 plus AA or EGCG-induced apoptosis. HP-100 cells, a subclone of HL-60 cells without MPO expression, are resistant to both combination treatments. MPO stable transfection sensitizes K562 cells to apoptosis following treatment with As2O3 and AA or EGCG. NADPH oxidase is an enzyme complex which generates O2− and H2O2 in neutrophils. In APL NB4 cells, As2O3 induces expression of NADPH oxidase members and is thought to participate in H2O2 production required for As2O3 response. X-CGD cells, a subclone of PLB-985 with targeted disruption of the gp91phox gene (Zhen et al, PNAS90:9832, 1993) and loss of NADPH oxidase activity but with high levels of MPO activity, are responsive to treatment with As2O3 and AA or EGCG. These results suggest that AA and EGCG enhance As2O3-induced apoptosis through a synergistic production of H2O2 which is independent NADPH oxidase activation in non-APL AML cells. MPO augments the apoptotic effect of H2O2 produced by As2O3 plus AA or EGCG and it could be used as a marker to predict the sensitivity of AML cells to both combination treatments.
Prognostic Value of Minimal Residual Disease by Real-Time Quantitative PCR in AML with CBFB-MYH11 Rearrangement: The French Experience.
Authors: Guièze Romain , Renneville Aline , Cayuela Jean-Michel , Abdelali Raouf Ben , Boissel Nicolas , Rubio Marie-Thérèse , Mazingue Françoise , Macintyre Elizabeth A. , Sigaux François , Fenaux Pierre , Dombret Hervé , Preudhomme Claude 
Published: October 2019

Abstract
Background. Despite the favorable prognosis of AML patients with inv(16)/t(16;16) leading to CBFB-MYH11 rearrangement, relapses still occur in about 40% of the cases. With the possible exception of receptor tyrosine kinase mutations, no pretreatment-factor can strongly predict risk of relapse.
Methods. To explore minimal residual disease (MRD) prognostic impact, we prospectively monitored CBFB-MYH11 rearrangement by real-time quantitative PCR (RQ-PCR) in patients with inv(16)/t(16;16) treated in French cooperative trials; most patients were treated in Acute Leukemia French Association (ALFA) trials and Leucémies Aiguës Myéloblastiques de l’Enfant (LAME) Cooperative Groups trials. RQ-PCR was performed in three molecular French labs (CHU of Lille, Necker Hospital and St-Louis Hospital) according to the EAC procedure and results are expressed as CBFB-MYH11/100 ABL copies(%).
Results. 61 AML patients with inv(16)/t(16;16) who had reached CR with one of the anthracyclin-aracytin regimens were analyzed. Median age was 37.5 years (range 2.1–76.5) and median baseline WBC 46 G/L (range 1.8–246). With a median follow-up of 23.3 months, median overall DFS was 23 months and median OS not reached (93.5% of patients alive). No initial clinical or hematological characteristic including age, gender and initial WBC was predictive of relapse in adults, but children had poorer DFS than adults (17.6 months vs not reached, p=0.03). Regarding chromosomal abnormalities in addition to inv(16)/t(16;16), trisomy 22 was the most frequent but no significant prognostic impact was observed. Of the 61 patients, MRD monitoring could be performed sequentially in 45. Pretreatment CBFB-MYH11 transcript level had no impact on DFS. However, after induction therapy, transcript levels >0.5% were significant predictors of poorer DFS (median 16.4 months vs not reached if <0.5%, p=0.002). Likewise, after first consolidation therapy course, transcript level >0.001% was also predictive of poorer DFS (median 22 months when >0.001% vs not reached when <0.001%; p=0.03). 34 paired analyses of bone marrow (BM) and peripheral blood (PB) samples revealed only moderate correlation (R2=0.86); especially for low MRD levels, CBFB-MYH11 transcript expression being generally higher (up to 78-fold) in BM samples than in PB samples.
Conclusion. MRD monitoring by RQ-PCR appears to be a major prognostic factor of DFS in AML with CBFB-MYH11 rearrangement and could be a powerful tool to early identify good and bad responders which could have an impact on therapeutic decisions for consolidation therapy.
DFS according to MRD level after first consolidation treatment DFS according to MRD level after first consolidation treatment
IL-6 Enhances C-myc Translation in Myeloma Cells Via Activation of the Myc Internal Ribosomal Entry Site (IRES) and an IRES-Binding Trans Factor, hnRNP A1.
Authors: Shi Yijiang , Gera Joseph , Lichtenstein Alan 
Published: October 2019

Abstract
Dysregulated c-myc expression in multiple myeloma (MM) can be due to a translocation with juxtaposition of the myc gene to the Ig enhancer resulting in constitutive transcription. However, myc protein levels can also be increased in MM cells when it is due to heightened translation. Activated translation can be mediated via an mTOR-mediated, cap-dependent mechanism, thus named because the translation initiation complex utilizes the cap structure on mRNA to recruit the ribosomal subunit. However, an alternative mechanism is cap-independent where the ribosomal subunit binds a transcript via an IRES in the RNA’s 5′UTR. IRES function is regulated by IRES trans activating factors (ITAFs) which bind to the 5′UTR. We studied myc expression in ANBL-6 wild type and activated K-RAS-transfected MM cells which proliferatively respond to IL-6 but do not contain myc translocations. IL-6 increased myc protein expression in both cell lines in a concentration and time-dependent fashion but RNA expression was only enhanced in the wild type cells. The increased protein expression in K-RAS mutant cells was unaffected by rapamycin, indicating independence from mTOR and cap-dependent mechanisms. Using an IRES-dependent reporter vector, reporter expression was shown to be increased by IL-6, confirming IL-6 activates myc IRES activity. This was also demonstrated in the IL-6 autocrine U266 MM cell line where myc IRES-dependent reporter expression was ablated following exposure to anti-IL-6 antibodies. In addition, primary MM cells treated with IL-6 also demonstrated an increase in myc IRES activity. Since a yeast three-hybrid screen for proteins specifically binding to the myc IRES identified several clones encoding hnRNP A1, we evaluated hnRNP A1 as a mediator of myc IRES activity. IL-6 increased the cytoplasmic localization of hnRNP A1 in ANBL-6 MM cells. Furthermore, in MM cells where hnRNP A1 expression was knocked down, myc IRES activity was greatly diminished and there was no enhancement with addition of IL-6. These results indicate that IL-6 can enhance c-myc translation in MM cells via activation of the myc IRES and that hnRNP A1 is a critical myc ITAF involved in the IL-6 response. hnRNP A1 may serve as a new therapeutic target in myeloma.