bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blast Cell Reduction in Elderly Patients with Acute Myeloid Leukemia Secondary to Myelodysplastic Syndrome Treated with Methylprednisolone.
Authors: Suzuki Kei , Sekine Takao , Ohishi Kohshi , Katayama Naoyuki 
Published: April 2020

Abstract
Treatment of elderly patients with acute myeloid leukemia (AML) is challenging, because they are often resistant to chemotherapy and not eligible for standard myelosuppressive chemotherapy. Here we report three elderly patients (above 70 years of age) with AML secondary to myelodysplastic syndrome and a poor performance status (PS 4), in whom methylprednisolone (mPSL; 125 mg/body) resulted in a decrease in blast cells in the peripheral blood (PB). Although this reduction was transient, the blast counts could be controlled by intermittent or daily treatment with mPSL, without significant adverse effects. We examined the effects of mPSL on leukemic blasts (CD34+CD33+CD13+CD4+) in detail in one patient and found that the blast count in the peripheral blood rapidly decreased from 14.2 × 109/l to 0.3 × 109/l for 18 hours after mPSL administration. The neutrophil counts gradually increased. Annexin V assays revealed that the percentage of annexin V+PI−cells among the blast cells increased from 4% to 20% at 9 hours after mPSL treatment, indicating that mPSL decreased the number of blasts in part through induction of apoptosis. In in vitro liquid cultures, mPSL inhibited the survival of blast cells from the patient in a dose-dependent manner. Furthermore, mPSL suppressed the growth of leukemic progenitors in semisolid cultures. Although our experience is limited to these three patients, our findings suggest that mPSL may offer therapeutic benefits for a subset of elderly patients with AML evolved from myelodysplastic syndrome.
The Extrinsic Apoptotic Pathway Is Implicated in Myelodysplastic Syndromes through the Fas/Fas-L/FADD System.
Authors: Ribeiro Patricia , Pereira Herminia , Costa Isabel , Sousa Maria H. , Conduto Antonio , Pocas Isabel , Viegas Paula , Costa Maria M. , Goncalves Cidalia , Rodrigues Antonio S. , Sousa Aida B. 
Published: April 2020

Abstract
The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, peripheral blood cytopenias, increased apoptosis and possible transformation into acute myeloblastic leukemia (AML). MDS are considered “clonal” stem cell disorders but the precise mechanism is yet unknown. Lately there has been some evidence implicating the extrinsic apoptosis pathway in the pathogenesis of these diseases. The present study included 30 cases (2001/03) classified according to WHO: 6 RA, 1 RARS, 7 RAEB type I, 3 RAEB type II, 2 RCMD, 2 MDS/MDP, and 2 aplastic anemias, 3 AML secondary to MDS and 4 control cases with normal histology. We assessed the expression of TNF-related-apoptosis-inducing ligand (TRAIL) and its receptors, of Fas, Fas-L, Fas-associated-death-domain (FADD), caspase-8, caspase-3 and DNA fragmentation factor (DFFP) by RT-PCR and by immunohistochemical staining. Results were correlated with the expression of CD34, HLA-DR15, CD15, CD20, CD68 and CD117. Patients were stratified according to the international prognostic scoring system (IPSS). Fas, Fas-L and FADD were overexpressed in low risk IPSS categories and in RA and RARS, but gradually lost their expression in more advanced stages and were not expressed in RAEB II and AML cases. This expression was inversely correlated with the expression of caspase-8 and DFFP. We observed that CD34+ and HLA-DR15+ samples were positively correlated with the expression of FADD, caspase-8 and DFFP. TRAIL was positive in normal histology and AML cases but its expression was diminished in all other samples. Our data suggest that the extrinsic apoptotic pathway may be implicated in MDS through Fas, Fas-L and FADD. RAEB II may be grouped with AML, as it shows a lesser degree of apoptosis than lower risk MDS categories. A better understanding of these diseases will allow for a better and more individualized management. This work was supported by a grant from the Terry-Fox Foundation.
A Pilot Study To Test the Efficacy of a Combination of Gleevec with Thalidomide in Patients with Idiopathic Primary Myelofibrosis, Myelofibrosis with Myeloid Metaplasia and Myelodysplastic Syndromes Who Present with Myelofibrosis.
Authors: Batus Marta , Shammo Jamile M. , Venugopal Parameswaran , Gregory Stephanie A. , Raza Azra 
Published: April 2020

Abstract
Purpose: Prompted by the finding that Gleevec can reduce marrow fibrosis in patients with CML who present with myelofibrosis, we sought to evaluate the safety and efficacy of a novel combination of thalidomide and imatinib mesylate (Gleevec®) for treatment of patients with myelofibrosis with myeloid metaplasia and myelodysplastic syndrome who presented with Grade 3/4 myelofibrosis. The rationale for this combination is that the anti-angiogenic and anti-TNF effects of thalidomide may be potentiated by the anti-TGF-b, anti-PDGF effects of Gleevec to reduce marrow fibrosis in this group of patients.
Methods: We enrolled and treated 19 patients with MDS, (RA: 9, RAEB: 9, CMMoL:1) with IPSS score (Low: 3, Int-1: 11, Int-2: 4, High: 1) fulfilling the inclusion criteria. 7 patients had a normal karyotype, 2 patients with del 5q alone, 3 patients with del 5 q with other abnormalities, 2 patients with complex karyotype, and 5 with others. In this study we treated patients with Thalidomide starting at a dose of 100 mg per day escalating to 400 mg per day and Gleevec at 600 mg per day. Treatment was continued for one year or until disease progression. Response to treatment was assessed at 16 weeks of treatment according to the International Working Group (IWG) criteria, and dose modifications were employed according to set criteria per protocol.
Results: Three of nineteen patients responded, with overall response rate of 15.8%. Two patients (10.5%) had complete response. One patient (RAEB-I, del 5q and trisomy 8) achieved CR at 16 weeks and continued to be in CR for 9 months with a follow up bone marrow biopsy showing no overt evidence of the previously diagnosed myelodysplastic syndrome by morphology or flow cytometry. The second patient (RAEB-II, normal karyotype) achieved CR at 1 year of treatment, however developed grade 3 peripheral neuropathy and subsequently, Thalidomide was held; this patient continues to be in CR todate while on Gleevec monotherapy. Finally, one patient (5.3%) had a partial response at 16 weeks for 5 months. Four patients died during treatment due to progressive disease; all other patients did not respond. Most patients tolerated that treatment well, three patients developed grade 3 neutropenia, one patient developed grade 3 pulmonary toxicity, and one patient developed grade 3 peripheral neuropathy, these adverse events were managed by dose reduction/interruption.
Conclusion: Thalidomide and Gleevec is a relatively well-tolerated regimen that can be considered for treatment of a small subset of patients with myelofibrosis and MDS. The finding that the combination led to reduction of bone marrow fibrosis in responding patients is intriguing and warrants further investigation.
HLA-DRB1 Allele Frequency and TNF Polymorphism in Patients with Myelodysplastic Syndromes (MDS).
Authors: Chang C.K. , Gooley T. , Petersdorf E.W. , Scott B.L. , Hansen J.A. , Joachim H. 
Published: April 2020

Abstract
MDS, a heterogeneous group of hematopoietic stem cell disorders, are associated with dysregulated cytokine profiles in marrow and blood plasma, including upregulation of tumor necrosis factor alpha (TNF-alpha). Other data suggest that patients with MDS who carry the human leukocyte antigen (HLA)-DRB1*1501 allele are more likely to respond to immunosuppressive therapy. The genes for HLA-DR and TNF are in close linkage on human chromosome 6. Preliminary data had shown a higher than expected frequency of single nucleotide polymorphism (SNP) at position -238 of the TNF gene. We wanted to determine, therefore, the strength of linkage disequilibrium between a given TNF polymorphism and HLA-DR alleles. We analyzed HLA-DR allele frequencies in 1,040 patients with MDS, in comparison to 2,474 patients with chronic myeloid leukemia (CML); 1,422 and 160 of these patients, respectively, had TNF polymorphism data (AA vs. AC vs. CC alleles) for SNP 308 and 863 available. Significant differences in frequency were observed for HLA-DRB1*0401 (9.1% vs. 6.9%; p=0.03), *0701 (3.8% vs. 1.3%; p&lt;0.0001), *1302 (2.7% vs. 4.3%; p=0.03), and *1501 (13.6% vs. 9.9%; p=0.0009). When determining the association of a given TNF SNP with the presence of two, one, or no copy of a given HLA-DR allele, TNF SNP 863 showed a significant association with HLA-DRB1*0101 (p=0.003), *0301 (p&lt;0.0001), *0401 (p=0.0002), and *1101 (p=0.02); HLA-DRB1*0301 was also associated with TNF SNP 308 (p&lt;0.0001). There was no significant correlation of either one of these two TNF SNPs with diagnosis. However, when only MDS patients were considered, there was a suggestion of a correlation of SNP 308 and HLA-DR*1501 (p=0.11); among patients with the TNF genotype AA or AC only 3 of 24 (12%) carried at least one DRB1*1501 allele, compared to 20 of 56 (36%) among those with the CC genotype. While TNF SNPs remain to be typed in a large proportion of MDS patients, results suggest a higher frequency of some HLA-DR alleles, in particular *0701 and *1501, in patients with MDS than seen in CML, and a correlation of TNF SNPs, in particular, TNF 308 CC with HLA-DRB1*1501. Thus, these data are consistent with an association of DRB1 *1501 and TNF alleles, and it will be of interest to identify the pattern of TNF polymorphism in HLA-DRB1*1501 negative patients, Additional studies are needed to further determine potential haplotypes that are associated with MDS and possible correlations with disease course and treatment responses.
Frequency of the JAK2 Mutation and Its Usefulness as a Marker for Treatment Response and Disease Progression in Korean Patients with Chronic Myeloproliferative Disorders.
Authors: Shin Myung-Geun , Kim Hyeoung Joon , Kim Hye-Ran , Lee Sun-Young , Lee Il-Kwon , Shin Jong-Hee , Suh Soon-Pal , Ryang Dong-Wook 
Published: April 2020

Abstract
Background: The recent discovery of a single point mutation in the JAK2 gene (V617F) is a major advance in our understanding of the pathogenesis of BCR/ABL-negative chronic myeloproliferative disorders (CMPD). The frequency of the JAK2 V617F mutation in CMPD differs according to methods and research groups. We investigated the frequency of JAK2 mutations in Korean CMPD patients and demonstrated their usefulness as a new molecular marker for treatment response and disease progression in BCR/ABL-negative CMPD using quantitative real time PCR and pyrosequencing.
Methods: Seventy-eight patients with BCR/ABL-negative CMPD comprising 42 cases of essential thrombocythemia (ET), 26 of polycythemia vera (PV), 7 with idiopathic myelofibrosis (MF), and 3 unclassifiable (UC) CMPD were enrolled in this study. A 364-bp PCR product containing the JAK2 V617F mutation was sequenced in both directions from total bone marrow cells. Restriction enzyme-based assessment with BsaXI was also used to search for JAK2 mutations. A quantitative real-time PCR-based allelic discrimination assay and pyrosequencing (Pyrosequencer PSQ96) were used to quantify the JAK2 V617F mutation status.
Results: A single JAK2 V617F point mutation was identified in 20 (77%) of 26 patients with PV, 12 (26%) of 42 with ET, 7 (100%) of 7 with MF, and 2 (67%) of 3 with UC. The V617F mutation was present in over half of Korean patients with BCR/ABL-negative CMPD, giving an overall frequency of 53%. The proportion of mutant alleles ranged from 36 to 100% in the real-time PCR and pyrosequencing analysis. Patients with MF had a higher percentage of JAK2 mutant alleles than patients with ET (MF&gt;PV&gt;ET). PV patients (n=8) with a good response (phlebotomy only) had a relatively low proportion (58.9±20.1%) of the JAK2 mutant, while patients (n=9) showing a poor response (additional chemotherapy) initially had a higher proportion (76.6±19.0%; p=0.04185).
Conclusion: The frequency of the JAK2 V617F mutation in Korean patients with PV was lower than that in reports from Western countries, although the overall frequency in Korean patients with BCR/ABL-negative CMPD was similar to previous reports. The results also suggest that the JAK2 mutation (quantification of JAK2 mutant alleles) can be used as a new marker for treatment response and disease progression in BCR/ABL-negative CMPD using quantitative real-time PCR or pyrosequencing.
Dose-Modified Oral Chemotherapy for AIDS-Related Non-Hodgkin’s Lymphoma (AR-NHL) in East Africa.
Authors: Orem Jackson , Mwanda O.W. , Fu P. , Banura C. , Kakembo J. , Ness A. , Johnson J. , Subbiah V. , Bako J. , Black J. , Katongole-Mbidde E. , Remick S.C. 
Published: April 2020

Abstract
Background: Dose-modified chemotherapy for AR-NHL in the pre-HAART era has been shown to be equally efficacious and less myelotoxic [N Engl J Med1997;336:1641 (mBACOD); J Clin Oncol2001;19:2171 (mCHOP)]. In resource-constrained settings, intravenous chemotherapy and supportive care of the AIDS / cancer patient are challenging (J Natl Cancer Inst2002;94:718).
Methods: We embarked on a pilot feasibility trial of dose-modified oral chemotherapy [lomustine 50 mg/m2 D1 (C#1 only); VP-16 100 mg/m2 D1–3; and cyclophosphamide / procarbazine 50 mg/m2 each D22–26 at 6-week intervals (1 cycle) for 2 cycles] in HIV-infected patients with biopsy-proven AR-NHL in East Africa.
Results: A total of 49 pts (21 Uganda; 28 Kenya) were treated on study. The majority of pts were female (59%) with median age 39 yrs (range 18–64); poor PS (2 or 3) − 63%; high grade lymphoma (69%); advanced stage (III or IV) − 69%; and B symptoms (79%). At study entry median CD4 count was 200/μL and HIV-1 viral load 97,973 copies/ml. Eighteen pts (36%) had access to ARV. A total of 78 cycles of therapy were administered to 49 pts (median 2; range 0.5–2). The regimen was well tolerated. There were 4 episodes of febrile neutropenia and 3 treatment-related deaths (6% mortality rate). Overall objective response rate is 77% (CR/uCR 56%); median survival 12.3 months; and 18 patients remain alive as of 7/11/06.
Conclusions: Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the US in pre-HAART era, an acceptable safety profile, and is pragmatic in the resource-limited setting. Further investigation of the oral regimen vs. mCHOP is warranted.
Denileukin Diftitox (Ontak™) Therapy for Patients with Systemic Mastocytosis.
Authors: Quintas-Cardama Alfonso , Kantarjian Hagop , Giles Francis , Cortes Jorge , Verstovsek Srdan 
Published: April 2020

Abstract
Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells in various tissues. Patients (pts) with SM are empirically treated with recombinant interferon-alpha (IFN-α) or cladribine when cytoreduction is required. However, treatment with these agents has been associated with poor response rates, poor tolerance, and/or short response duration, and the prognosis of pts with SM is unchanged. This underscores the urgent need of new therapeutic approaches. Atypical expression of CD25 (the alpha-subunit of the interleukin-2 [IL-2] receptor), on the membrane of neoplastic mast cells represents an attractive therapeutic target. Denileukin diftitox (Ontak™) is an engineered fusion protein containing the active domain of the diphtheria toxin and the full-length sequence of IL-2, thus targeting IL-2 receptor-expressing cells. Upon internalization, protein synthesis is inhibited and cytotoxicity ensues. We designed a pilot trial for SM pts that either had aggressive form, or indolent form with uncontrolled symptoms despite supportive care measures, in which Ontak™ was initially administered at 9 ∝g/kg/day intravenously on days 1 through 5 every 21 days. This dose was increased after 3 cycles to 18 ∝g/kg/day in pts with no response and no significant toxicity. Therapy was discontinued in pts who showed no response after 6 cycles. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). Thus far, a total of 7 symptomatic pts have been treated, 5 with aggressive and 2 with indolent SM. Median age was 58 years (range, 41 to 65), time from diagnosis to Ontak™ therapy 64 mo (range, 1 to 158), Hb 11.8 gr/dL (range, 9.2 to 13), WBC 7.9 ×109/L, (range, 2.5 to 16.9), platelet count 275 ×109/L (range, 54 to 759), eosinophil 2.3% (range, 0% to 6.1%). Five patients were previously treated with imatinib mesylate and one with cladribine; one pt had not received any prior therapies. One pt, who had undergone splenectomy, had hepatomegaly and 1 other had splenomegaly prior to start of Ontak™ therapy. In all patients malignant mast cells expressed CD25. A total of 33 cycles were administered. The median number of cycles was 5.5 (range 3 to 6). No significant responses have been observed among 7 pts treated. No significant difference was found between pre- and post- Ontak™ therapy in the percentage of bone marrow mast cells, and only one patient had decreased serum tryptase level at the end of the therapy (by 33%). No responses in C-findings were noted in patients with aggressive disease. However, symptoms related to SM improved in 3 patients and were eliminated in one. Therapy with Ontak™ was well tolerated with all toxicities being grade 1–2, without any grade 3–4. In summary, therapy with Ontak™ is very well tolerated but has no appreciable activity in pts with SM at the dose and schedule used in this study.
The Novel Tyrosine Kinase Inhibitor (TKI) Exel-0862 Potently Induces Apoptosis in Human FIP1L1-PDGFR-α-Expressing Cells through Caspase-Dependent Cleavage of MCL-1.
Authors: Pan Jingpan , Quintas-Cardama Alfonso , Kantarjian Hagop , Lamb Peter , Tefferi Ayalew , Cortes Jorge , Giles Francis , Verstovsek Srdan 
Published: April 2020

Abstract
The FIP1L1-PDGFR-α fusion kinase induces hypereosinophilic syndrome (HES) in a subset of patients (pts). Imatinib is a potent inhibitor of PDGFR-α and has been associated with durable hematologic responses in pts with HES. However, development of kinase domain mutations may hamper TKI activity, underscoring the need for novel agents to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-α-expressing cells. In 72-hour MTS assay, EXEL-0862 inhibited EOL-1 cell proliferation with an IC50 of 1.0 nM and markedly decreased phosphorylation of STAT3 and Erk1/2, suggesting inhibition of downstream targets of PDGFR-α. More important, EXEL-0862 induced dose-dependent inhibition of PDGFR-α phosphorylation in peripheral blood mononuclear cells from a pt with HES. Exposure of EOL-1 cells to EXEL-0862 10 nM for 24 hours caused apoptosis as evidenced by flow cytometry (annexin-V/PI staining) and transmission electron microscopy. This was coupled with time-dependent cleavage of caspases-3, caspase-9, and PARP and with mitochondrial damage as reflected by cytochrome c translocation into the cytosol, and a diminished mitochondrial transmembrane potential. Of note, apoptotic features were not evident after 16 hours of EXEL-0862 exposure. Immunoblots showed marked downregulation of Mcl-1, but not of Bcl-2, Bcl-XL, or Bax. To elucidate the mechanism of Mcl-1 cleavage, EOL-1 cells were exposed to 10 nM EXEL-0862 for 6 hours followed by cycloheximide (5 μg/ml), a potent translation inhibitor, which resulted in marked Mcl-1 turnover. Treatment with the proteasome inhibitor MG-132 failed to abrogate EXEL-0862-induced Mcl-1 cleavage, suggesting proteasome-independent degradation. Rather, a decrease of pro-form Mcl-1 (p42) and increase of the cleaved Mcl-1 peptide form of Mcl-1 (p28) coincided with caspase-3 activation. Pretreatment with 20 μM pan-caspase inhibitor Z-VAD abolished EXEL-0862-induced Mcl-1 cleavage, pointing to a caspase--dependent mechanism. Collectively, our results establish EXEL-0862 as a solid candidate for the targeted treatment of pts with FIP1L1-PDGFR-α-positive HES.
Effect of Tyrosine Kinase Inhibitor INNO-406 on Human Mast Cells Bearing Mutated c-KIT Tyrosine Kinase.
Authors: Pan Jingxuan , Kantarjian Hagop , Cortes Jorge , Giles Francis , Verstovsek Srdan 
Published: April 2020

Abstract
Systemic mastocytosis (SM) is characterized by a clonal accumulation of mast cells (MC) in bone marrow and other tissues. Malignant MC have abnormal spindle shape, express aberrant surface markers, and carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V). This mutation results in a constitutively activated c-kit receptor associated tyrosine kinase and is responsible for disease progression. Agents that affect mutated c-kit may have clinical benefit in SM, but there is none clinically available. INNO-406 is a novel multi-targeted tyrosine kinase inhibitor, previously shown to inhibit the growth of cells expressing c-kit by inhibiting its phosphorylation (Kimura, Blood, 106:3948–54, 2005). We investigated the effects of INNO-406 on mast cells with mutated c-KIT, and compared it to that of imatinib mesylate, tyrosine kinase inhibitor effective against selected c-KIT mutants. HMC-1560 cells carrying juxtamembrane domain c-KIT mutation in codon 560, and HMC-1560, 816 cells carrying both codon 560 mutation and tyrosine kinase domain c-KIT mutation in codon 816, were exposed to increasing concentrations (0.02 to 5 μM) of INNO-406 or imatinib in 72-hour cell proliferation assay. Both INNO-406 and imatinib effectively inhibited the growth of HMC-1560 cells, with IC50 of 45 and 75nM, respectively. Neither drug was effective against HMC-1560, 816 cells at the doses tested. INNO-406 effectively induced apoptosis in HMC-1560, but not in HMC-1560, 816 cells, as judged by the Annexin V flow cytometry test and by PARP specific cleavage seen on western blotting. In addition, INNO-406 was effective in inhibiting phosphorylation of c-kit in HMC-1560 cells in nM range. Our results suggest similar potency of INNO-406 and imatinib in mast cells with mutated codon 560 (found in gastrointestinal stromal tumor), but no activity against cells with mutated codon 816 c-KIT (found in SM).