bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of Intra-Venous Homoharringtonine (HHT) in the Treatment of Myelodysplastic Syndrome (MDS).
Authors: Borthakur Gautam , Kantarjian Hagop , Estey Elihu , Verstovsek Srdan , Garcia-Manero Guillermo , Cortes Jorge 
Published: April 2020

Abstract
Homoharringtonine (HHT) is a plant alkaloid that inhibits protein synthesis, induces differentiation and apoptosis of myeloid cells. We initiated a phase II study of intra-venous HHT in patients (pts) diagnosed with MDS by WHO criteria to assess safety and efficacy of HHT in this setting. Responses were recorded according to the MDS response criteria defined by NCI working group. Pts received HHT 2.5 mg/m2 by continuous 24-hour intravenous infusion daily for 7 days every 4 weeks until a) a complete remission (CR) was achieved, or b) failure to achieve a CR after 3 courses of therapy or c) unacceptable toxicities developed. The dose was increased to 3.0 mg/m2 for pts with no response after the 1st course. Nine pts have been enrolled (6 male and 3 female). Median age was 70 yrs (range 55 to 84 yrs) and 4 pts had secondary MDS. Four pts had refractory anemia with excess blasts-1 (RAEB-1), 3 had RAEB-2, 1 had chronic myelomonocytic leukemia (CMML-1) and 1 had MDS/myeloproliferative disorder (MDS/MPD). IPSS score was intermediate-1 in 1 pt, intermediate-2 in 7 pts and high in 1 pt. Seven pts (78%) received only one cycle of HHT. One (11%) pt had a CR (including cytogenetic CR) that lasted for 67 days, 5 pts discontinued treatment due to lack of response and1 pt with stable disease decided to withdraw from the study. After a median follow-up of 54 days (range, 37 to 145 days) 2 pts have died, one on day 37 due to intracranial bleed secondary to thrombocytopenia and one on day 39 due to invasive fungal infection. Grade 2 toxicities included fatigue (4 pts), diarrhea (3 pts) and nausea (3 pts). Grade 3 cytopenias were seen in all pts and grade 3 nausea in 1 pt. Three pts had neutropenic fever. Treatment during first course was interrupted after 5 days of infusion in 1 pt due to grade 3 congestive heart failure (CHF). This pt received his second course of treatment without recurrence of CHF. In conclusion, HHT has modest activity in intermediate to high risk MDS. After first interim analysis, the study meets criteria for continued accrual.
Reversal of Myelofibrosis in a Patient with Low Risk Myelodysplastic Syndrome on Revlimid Therapy.
Authors: Besa Emmanuel C. , Swami Vanlila , Roda Paul , Laudadio Mary Ann , Knight Robert , Zeldis Jerome 
Published: April 2020

Abstract
The observation of increasing myelofibrosis has been interpreted as a sign of progression in the course of low risk patients with myelodysplastic syndrome (MDS). We report here a 64 year old, Caucasian woman who was diagnosed to have refractory anemia in 5/19/03 with a bone marrow findings showing hypercellularity of 95%, erythroid dysplastic changes with 1% myeloblasts with no ringed sideroblasts. Her cytogenetic study show normal chromosomes and she had an IPSS score of 0. However, she began to require red cell transfusions with no response to EPO and G-CSF therapy for 5 months when she was entered into an open label, multi-center clinical trial using Revlimid at 10 mg/day given orally in tablet form. Her growth factors were discontinued 4 weeks before entry and a baseline bone marrow study on 10/7/04 show a 90% cellular marrow with same abnormalities. In addition, she now has developed a grade III/IV diffuse reticulin fibers as shown by silver stains indicating increased myelofibrosis. She tolerated the treatment well with very little side effects and by second month of therapy, she had her last red cell transfusion and her hemoglobin level started to increase from 8.3 to 9.7 g/dl. Other than a mild neutropenia with ANC between 800 to 900/μL, she tolerated treatment well. She attained a normal hemoglobin of 12 g/dl at the 4th month. Repeat BM done at this time shows a normal cellularity of 50% but erythroid cells show persistence of dysplasia but overall fibrosis has reversed to Grade I/IV. She currently remains in remission 21 months on Revlimid treatment. Demonstration of reversal of myelofibrosis in MDS indicate that this drug may be effective in primary myelofibrosis and agnogenic myeloid metaplasia.
Phase I/II Trial of Bortezomib + CHOP-Rituximab in Diffuse Large B Cell (DLBCL) and Mantle Cell Lymphoma (MCL): Phase I Results.
Authors: Leonard John P. , Furman Richard R. , Cheung Ying-Kuen K. , Feldman Eric J. , Cho Hearn J. , Vose Julie M. , Nichols Gwen , Glynn Patricia W. , Joyce Maureen A. , Ketas Jamie , Ruan Jia , Carew John , Niesvizky Ruben , LaCasce Ann , Chadburn Amy , Cesarman Ethel , Coleman Morton 
Published: April 2020

Abstract
BACKGROUND: Bortezomib (PS-341, VelcadeR) is a proteasome inhibitor with anti-tumor activity in B cell malignancies including MCL. These effects, which in part may be mediated via NF-kappaB pathways, could sensitize tumor cells to standard chemotherapy-based treatment regimens and enhance efficacy. We report phase I findings from a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL and MCL patients.
METHODS: Thirty-five patients have been enrolled and initiated treatment, with the first 20 subjects comprising the phase I group. Patients received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n= 9) or 1.3 mg/m2 (Arm 2, n=7 in phase I, then all subsequent patients in phase II) on days 1,4 of each cycle. Phase 1 dose assignments were conducted according to the continual reassessment method as patients entered the study.
RESULTS: Phase I included 16 DLBCL and 4 MCL patients. Median age was 65 years (range 29–84) and all patients were treatment-naïve except for 1 MCL subject who had received prior local radiotherapy. Fourteen subjects (70%) had stage IV disease at study entry, and 11 (55%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 7 subjects (35%) and 3 or 4 in 10 subjects (50%). Median followup of the phase I cohort is 9 months (range 5 – 18 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 15 subjects (75%), with 65% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity (platelets and/or white blood cells) was observed in 7 subjects (35%). Three subjects did not complete therapy (1 withdrawal by patient request with subsequent death, 1 due to dose-limiting pulmonary toxicity and 1 with concurrent lyme meningitis). Intent to treat overall response rate (n=20) is 95% with 80% CR/CRu and 80% of subjects currently alive without progression.
CONCLUSIONS: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Further safety and efficacy analyses, as well as molecular correlative studies, are ongoing with both the phase I and II cohorts. Preliminary findings with the combination regimen in this adverse prognosis group of patients are encouraging.
Down Regulation of hTERT Is an Important Mechanism in Apoptosis of MUTZ-l Cells Induced by As2O3.
Authors: Jin Jie , Xu Weilai , Qian Wenbin 
Published: April 2020

Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myeloid leukemia (AML). In this study, MDS cell line MUTZ-1 cells were treated with As2O3 to demonstrate the effects of As2O3 on MDS. We found As2O3 inhibited the proliferation of MUTZ-1 cells in a dose- and time-dependent manner. As2O3 induced apoptosis in MUTZ-1 cells via activation of caspase8, 3 and subsequent cleavage of the DNA repair enzyme pol(ADP-ribose) polymerase(PARP). Subsequently, reduction of NF-kB activity was another important mechanism of As2O3 induced apoptosis in MUTZ-1 cells. Our results also showed that the expression of hTERT mRNA of MUTZ-1 cells was down-regulated by As2O3. Except NF-κB, activity of other nuclear transcription regulator of hTERT, SP-1 and AP-1 were inhibited meanwhile using gel shift assay. Moreover, we further found that NF-κB inhibitor, PDTC, couldn’t activate capase8 but inhibited growth of MUTZ-1 cells and down-regulated hTERT mRNA expression. In addition, caspase8 inhibitor can’t block the reduction of NF-κB activity by As2O3. We concluded that As2O3 could induce apoptosis in MUTZ-1 cells by two independent ways, one is caspase8,3 and PARP activation, the other is inhibition of NF-κB activity subsequent down-regulation of hTERT. hTERT and NF-κB were two important molecular targets in apoptosis induced by As2O3. As2O3 down-regulated hTERT expression via inhibition of NFκB, SP-1 and AP-1.
The Establishment of Mice Model with Myelodysplastic Syndrome Cell Line MUTZ-1 Cell.
Authors: Lu Jie , Jin Jie , Xu Weilai , Chen Zhimei , Ding Wei 
Published: April 2020

Abstract
Objective
To establish myelodysplastic syndrome cell line MUTZ-1 cell mice model.
Methods
75 SCID mice and 10 BALB/CA-node mice were studied in this experiment. MDS-REBT cell line MUTZ-1 cells were cultured in vitro and 1 x108 /ml cell were subcutancously implanted in 4~6-week-old First-Generation SCID mice and BALB/CA-node mice respectively. The subcutancous tumor cells from First-Generation MDS-REBT cell line MUTZ1 cells mice model were respectively implanted in Second-Generation SCID mice and BALB/CA-node mice. The latent period and the rate of subcutancous tumor formation was observed, and tumor size was measured by the MTD twice a week. The biological characteristics of the subcutancous tumor cells were checked and evaluated by the methods of cell morphology and pathology and histopathology and immunology by flow cytometer, chromosome analysis and immunohistochemistry stain. It has been experimented tentatively that arsenic trioxide (AS2O3) (with 7.5mg/g mouse/d x 3d) was injected into abdominal cavity in 10 SCID mice to observe the drug effect on tumor formation in vivo.
Results
The rate of the subcutancous tumor formation was 98.6% (70/71)in SCID mice and 62.5%(5/8)in BALB/CA-nude micerespectively,(P=0.0027). The latent period of the subcutancous tumor formation were 10~17d (median 12d) in 61 SCID mice without injected arsenic trioxide and were 26~31d (median 29d) in 10 SCID mice with arsenic trioxide (with 7.5mg/g mouse/d x 3d) injected into abdominal cavity respectively. The latent period of the subcutancous tumor formation in the group of SCID mice injected by AS2O3 was significantly longer than that of non-injected by AS2O3(Z=5.339, P&lt;0.001), which showed that AS2O3 has probably a inhibition effect on the subcutancous tumor growth of SCID mice model in vivo. The results showed the subcutancous tumor cells of mice model have the biological characteristics of a Hum-MDS-REBT cell line MUTZ1 cell and were anthropo- source. The metastases in liver were found 8 weeks after implanted. HE staining on paraffin sections showed that the tumor cells were microscopic observed on liver and spleen and kidney and medullary cavity of bone and skin. Immunohistochemistry staining showed the subcutancous tumor cells of the mice model have the overexpression of P53 protein, which cued that these tumor cells has the P53 mutation and showed human tumor propert.
Conclusion
A human myelodysplastic syndromes-REBT cell line MUTZ1 cell-severe combined immunodeficiency (SCID) mice model was successfully established, which could be used for the advanced investigation of drug experiment as an animal model system in vivo.
Cytogenetics in Pediatric MDS - Data of the EWOG-MDS 98 Study.
Authors: Michalova K. , Beverloo H. B. , Michaelsen G. , Schlegelberger B. , Harbott J. , Haas O. A. , Kerndrup G. B. , Sainati L. , Bergstraesser E. , Hasle H. , Starý J. , Trebo M. , Van den Heuvel-Eibrink M. M. , Zecca M. , Noellke P. , Fischer A. , Niemeyer C. M. , Betts D. R. 
Published: April 2020

Abstract
Myelodysplastic syndrome (MDS) represents a heterogeneous group of hematopoietic stem cell disorders. Although the precise pathogenesis of MDS remains to be clarified, cytogenetic abnormalities appear to be involved in the disease mechanism and are considered an important factor in predicting clinical outcome. Here, we report the outcome of conventional cytogenetic analysis performed at diagnosis in 300 children with MDS who were enrolled in the prospective study EWOG-MDS 98. The patients were divided into 3 clinical groups: primary refractory cytopenia (RC) (n=142), primary advanced MDS (aMDS) (n=94), and MDS secondary to chemo- or radiation therapy, bone marrow failure disorders or familial disease (sMDS) (n=64). A full cytogenetic result was obtained in 263 cases (87.7%) including 116 (44.1%) with an abnormal clone. Comparing the 3 diagnostic subgroups, there was a statistically significant difference in the frequency of abnormalities observed. In RC, only 25 of 116 patients with successful analysis had a detectable clone that showed monosomy 7 as sole aberration in the majority of cases (52%). In addition, this subgroup also showed the greatest rate of failure to obtain a karyotypic result. In contrast, 42 (65.6%) of the sMDS cases were cytogenetically abnormal with a broad spectrum of aberrations including 16 patients (25%) with a complex karyotype (≥4 abr.). The presence of karyotypic evolution was also more frequently observed in this group. The overall karyotypic results showed monosomy 7 to be present in 50% of all abnormal cases, a figure that greatly exceeded the prevalence of the other frequent non-random aberrations of −5/del(5q), +8, del(7q), and +21, each of which occurred in 5–10% of abnormal cases. Despite the small numbers of these latter cases, clear trends of karyotypic events occurring in a particular clinical subgroup were demonstrated in the form of +8 with aMDS and −5/del(5q) with sMDS. The clinical and cytogenetic subgroups were further analyzed for correlations with gender and age. Whereas no clinical group showed any correlation between gender and karyotype, in RC and aMDS it was shown that patients with monosomy 7 were significantly younger than those with another karyotypic result (median 3.2 vs. 10.4 yrs and 5.2 vs. 11.0 yrs, respectively). The results demonstrate that while a general karyotypic picture can be defined in childhood MDS, future studies need to clearly differentiate between individual clinical subgroups.
No Evidence for Constitutively Activated FLT3 in Juvenile Myelo-Monocytic Leukemia.
Authors: de Vries Andrica C.H. , Stam Ronald W. , Schneider Pauline , Niemeyer Charlotte M. , van Wering Elisabeth R. , Kratz Christian , Haas Oskar A. , den Boer Monique L. , Pieters Rob , van den Heuvel-Eibrink Marry M. 
Published: April 2020

Abstract
Activating FLT3 mutations have been identified as prognostic factors in multiple myeloid malignancies. Recent studies have demonstrated that ligand-independent activation of FLT3 can also result from overexpression of wild-type FLT3. In addition, ligand-dependent activation has been observed in leukemic cells co-expressing FLT3 ligand (FLT3L), resulting in autocrine FLT3 signaling which is independent of FLT3 mutations. In Juvenile Myelo-Monocytic Leukemia (JMML), FLT3 internal tandem duplications (FLT3/ITDs) mutations affecting the tyrosine kinase domain (TKD) are rare. However, no data are yet available on the frequency of expression levels of FLT3 and FLT3L in JMML. If activated FLT3 occurs in JMML, one could imagine that these patients might benefit from treatment with small molecule FLT3 inhibitors, especially as to date the curative treatment of JMML is limited to allogeneous bone marrow transplantation.
In 36 JMML patients FLT3 and FLT3L mRNA levels were assessed using real-time quantitative PCR (Taqman). Furthermore these samples were screened for the presence of activating FLT3/ITDs and FLT3/TKD mutations. MTT assays were performed to assess the response of JMML cells to the known FLT3 inhibitor PKC412 (Novartis). FLT3 appeared to be expressed only at basal levels and FLT3L expression was very low. In none of the 36 JMML samples FLT3/ITDs or TDK mutations were found, consistent with the observation that PKC412 was not cytotoxic in JMML samples (n=12), in contrast to leukemic cells of children with ALL which carried an activated FLT3. These data suggest that constitutively activated FLT3 does not occur in JMML. Therefore targeting FLT3 by tyrosine kinase inhibitors like PKC412 is unlikely to be effective in JMML.
Revised International Prognostic Index (R-IPI) Is a Better Predictor of Outcome Than the Standard IPI for Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Rituximab and CHOP (R-CHOP).
Authors: Sehn Laurie H. , Chhanabhai Mukesh , Fitzgerald Catherine , Gill Karamjit , Hoskins Paul , Klasa Richard , Savage Kerry , Shenkier Tamara , Sutherland Judy , Wilson Kenneth , Gascoyne Randy D. , Connors Joseph M. 
Published: April 2020

Abstract
Background: The IPI, which was developed prior to the availability of rituximab, remains the primary clinical tool used to predict outcome for patients with DLBCL. Since clinical trials investigating the use of rituximab and chemotherapy in this patient population have been confined to either elderly or young patients exclusively, the utility of the IPI in the era of immuno-chemotherapy remains unknown.
Methods: We performed a retrospective analysis to assess the predictive value of the IPI in an unselected population of patients with DLBCL treated with R-CHOP. Patients were identified using the Lymphoid Cancer Research Database of the British Columbia (BC) Cancer Agency. We included all patients ≥16 years of age who were newly diagnosed with DLBCL prior to Jan 15, 2005, and were treated in BC with an R-CHOP protocol. Patients were excluded if they were HIV positive, had evidence of an active second malignancy or an underlying indolent lymphoma.
Results: 365 patients were identified. Patient characteristics were as follows: median age 61 y (16–90); male, 61%; advanced stage III/IV, 59%; elevated LDH, 54%; PS≥2, 40%; &gt;1 extranodal site, 35%. Central pathology review was performed on 95% of patients; 324 DLBCL, 36 PMBCL, 5 other. All patients received R-CHOP; 9% were treated with R-CHOP x 3 and involved field radiation therapy for limited stage disease, remaining patients received 6–8 cycles of R-CHOP. Median follow-up for living patients is 22 months. Overall, the IPI remains predictive for both progression-free survival (p&lt;0.0001) and overall survival (p&lt;0.0001). However, the IPI no longer permits separation between the two low risk subgroups (low v low-intermediate) or between the two high risk subgroups (high-intermediate v high). (see Table) An alternate grouping of the IPI is proposed (R-IPI) that identifies three distinct prognostic groups. (see Table and Figure)
Conclusions: The IPI remains predictive in the era of immuno-chemotherapy, but the R-IPI provides a simplified and more accurate prediction of outcome. The IPI factors can no longer be used to identify a group with less than a 50% chance of survival.
Overall Survival According to Revised IPI (R-IPI) Overall Survival According to Revised IPI (R-IPI)
Pilot Study of Lovastatin in Patients with Myelodysplastic Syndrome (MDS) Receiving Arsenic Trioxide (Trisenox®) Therapy.
Authors: Stroh Ann , Carter Thomas H. , Hohl Raymond J. , Zehr Pamela , Ritchie Justine M. 
Published: April 2020

Abstract
Statins have been shown to impair processing of RAS proteins, which are signaling molecules mutated in some patients with MDS, and the addition of lovastatin to myeloid cell lines exposed to arsenic trioxide in vitro has suggested enhanced cytotoxicity. To address the hypothesis that statins may modulate the therapeutic effect of arsenic, we are conducting a pilot study for MDS treated by arsenic trioxide combined with lovastatin. Objectives are to estimate the response rate, and secondarily to describe safety. Patients with MDS by FAB diagnostic criteria are treated with arsenic trioxide 0.25 mg/kg IV twice weekly for 16 weeks, after initial dosing for 5 consecutive days in the first week. Lovastatin is given at 20 mg/day for 2 weeks, then 40 mg/day for 2 weeks, and finally 80 mg/day for 12 weeks. Toxicity is monitored continuously and reviewed by a local Data and Safety Monitoring Committee. Stopping rules include serious adverse events (SAE) definitions for evidence of myopathy (symptoms or CPK &gt;2x upper limit of normal) or hepatocellular injury (transaminases &gt;3x upper limit of normal). Nine patients have been enrolled to date, with sufficient follow up to assess efficacy and safety. Five of these 9 patients completed the planned 16-week regimen. One subject was removed from study because of a rapid rise in blast count before treatment, based on marrow exams in a brief interval between screening and enrollment. Three patients had study drugs stopped per the above stringent SAE definitions, for elevations of CPK in 1 and transaminases in 2 subjects -- these abnormalities were asymptomatic and resolved. Toxicities were otherwise tolerable and as expected, including QTc prolongation in 1 patient, which resolved after withholding arsenic trioxide for several days and drug resumption was uneventful, as well as grade &lt;=2 fatigue, nausea and insomnia. Responses are assessed by IWG criteria. One patient had a minor erythroid response with need for packed red blood cell transfusion decreased by 50%. One patient had a minor platelet response documented as a net increase greater than 10,000/mm3 but less than 30,000/mm3. One patient showed progression of disease to AML before completing the trial. Remaining patients showed stable disease; one showed marked but non-sustained improvement in counts and suffered necrotizing faciitis after completing the study as a complication of a bone marrow biopsy. Preliminary findings in an additional patient after 8 weeks of therapy suggest an early response in multiple lineages and freedom from red cell transfusion. Tentative conclusions are that this combination of a statin and arsenic trioxide has activity in MDS, and toxicities are tolerable.
Enhanced HDAC (Histone Deacetylase) Enzyme Activities in Blood CD 34+ Cells in Patients with Agnogenic Myeloid Metaplasia Are Not Related to Jak 2 Mutation.
Authors: Wang Jen-Chin , Boghossian Nubar , Chang Tsong S. , Novetsky Allan D. , Astrow Allan 
Published: April 2020

Abstract
We have previously reported that HDAC enzyme activities were elevated in patients with agnogenic myeloid metaplasia (AMM) as compared with patients with other myeloproliferative disorders including essential thrombocytosis (ET) and polycythemia vera (PV) and normal volunteer controls (Exp hematol33:1052005). Jak 2 mutations were found in 35–50% patients with AMM. The present study was designed to see if the elevated HDAC activities in AMM are related to JAK 2 mutations. 9 patients of AMM, and 17 of other MPD, and 10 normal volunteer controls were studied. Detection of Jak 2 mutation was using Bsa X1 digestion of the PCR product (Lancet365: 1054, 2005). 4 patients with AMM were found to have elevated HDAC enzyme activities (defined as more than 2 SD of controls) and only one patient was found to have an heterozygous mutation of Jak2 mutation.. We conclude that enhanced HDAC activities in AMM are not related to the Jak-2 mutation and enhanced HDAC activities may represent another mechanism than JAK2 mutations in the pathogenesis of AMM.