bluuebunny/crossref_metadata_2025_split huggingface dataset:
Philadelphia Chromosome (Ph’) Negative, MLL-Rearranged AML Arising in a Patient Treated with Imatinib for CML.
Authors: Perl Anna Sechser , Perl Alexander E. , Robinson Blaine W. , Bagg Adam , Porter David , Tomczak Ewa , Nowell Peter C. , Carroll Martin , Felix Carolyn A. 
Published: April 2020

Abstract
Background: Imatinib has become standard front-line therapy for CML. In ~3% of patients treated with imatinib, abnormalities including trisomy 8 and/or monosomy 7 occur in Ph’ negative subclones and dysplasia occasionally is present, but transformation to AML is rare. We describe the first known case of AML with an MLL translocation during an imatinib-induced molecular remission of CML.
Methods: The Ph’ and the t(11;19)(q23;p13.1) were detected and monitored in sequential marrows using cytogenetic and FISH analyses. The BCR-ABL1 fusion transcript was traced by RT-PCR. The MLL translocation was identified and characterized in the AML blasts by Southern blot analysis, panhandle PCR-based methods and conventional PCR.
Clinical History and Results: The patient presented with chronic phase CML at age 53 and was treated with hydroxyurea for 6 weeks, IFN-α for 20 months and imatinib for 32 months. Complete cytogenetic response was achieved at 10 months. Molecular remission, as indicated by absence of the BCR-ABL1 transcript, occurred after 15 months of imatinib (37 months from CML diagnosis). Mild dysgranulopoiesis was noted 6 months after imatinib was started and increased on subsequent studies. After 28 months of imatinib (50 months from CML diagnosis), there was marked trilineage dysplasia and the karyotype showed t(11;19)(q23;p13.1) in cells that were Ph’ negative and negative for the BCR-ABL1 fusion transcript. FAB M5b AML was diagnosed four months later. The patient succumbed to AML despite aggressive management with chemotherapy and allogeneic stem cell transplantation. Southern blot analysis of the AML revealed two MLL bcr rearrangements. The reciprocal breakpoint junctions on the der (11) and der (19) chromosomes indicated a translocation of intron 8 of MLL and intron 1 of the known MLL partner gene ELL, which encodes a transcription elongation factor. The involved region of MLL was more 5′ than the secondary leukemia translocation breakpoint hotspot. The der (11) fusion transcripts joined MLL exon 7 to ELL exon 2, which is consistent with alternative splicing, and the der (19) fusion transcript joined ELL exon 1 to MLL exon 9.
Conclusions: Secondary leukemias with MLL translocations have been associated with topoisomerase II poisons, but not with the agents administered to this patient. The entity that we describe is distinct from blast crisis, in which Ph’ positive subclones evolve to acquire additional alterations. This case establishes that persistent clonal abnormalities and/or dysplasia in Ph’ negative cells following imatinib therapy may not be benign and may herald AML transformation. With effective and selective molecular eradication of the Ph’ positive clone, the emergence of leukemia with independent abnormalities may become more common. This is a highly concerning clinical complication to consider with BCR-ABL targeted agents.
Treatment of Imatinib-Sensitive and -Resistant Chronic Myelogenous Leukemia Cells with a Combination of Imatinib and Farnesyltransferase Inhibitors.
Authors: Radujkovic Aleksandar , Topaly Julian , Zeller W. Jens , Ho Anthony D. , Fruehauf Stefan 
Published: April 2020

Abstract
Farnesyl protein transferase inhibitors (FTIs) represent a new class of anticancer agents. We were interested whether the farnesyltransferase inhibitors L-744,832 and LB42918 alone and in combination with imatinib are active in imatinib-sensitive and -resistant CML cells. LB42918 was more potent with ED50 = 4 ± 1 μM (mean ± S.D., n = 3) in the BCR-ABL+ imatinib-sensitive cell line EM-3 vs. ED50 = 25 ± 2 μM for L-744,832 after 48 hrs of treatment and assessment by MTT assay. The growth of imatinib-sensitive K562 and LAMA84 cells was not measurably inhibited by L-744,832 doses up to 25 μM. Similarly, the growth of K562 was not affected by 25 μM of LB42918. However, for LB42918 in LAMA84 cells an ED50 value of 30 ± 11 μM could be determined. In the imatinib-sensitive cell line EM-3, combination index values (CI) obtained using the method of Chou and Talalay indicated synergistic effects following simultaneous treatment with imatinib and FTI (CI = 0.5 ± 0.2 and 0.7 ± 0.2 at ED75 for imatinib + L-744,832 and imatinib + LB42918 respectively). In the cell imatinib-sensitive and -resistant lines K562 and LAMA84 a trend to lower ED50 values of imatinib was determined when up to 16 μM of L-744,832 or LB42918 were added, indicating potentiation of imatinib activity. Annexin V / propidium showed a strong increase of the apoptotic cell fraction in all imatinib-sensitive and an increase in the imatinib-resistant cells treated for 48 hrs by the combination imatinib + L-744,832 or imatinib + LB42918 as compared to treatment with each drug alone. Growth inhibition of CFU-GM colonies of primary imatinib-sensitive CML cells obtained from 4 patients is stronger after treatment with different concentrations of the combination of both drugs than after monotherapy with either imatinib or L-744,832. On the basis of the observed potentiation effects FTIs may find their place as supplement for CML patients on imatinib treatment.
Additional Cytogenetic Changes and Prior Genotoxic Exposure Predict Unfavorable Prognosis in Myelodysplastic Syndromes and Acute Myeloid Leukemia with der(1;7)(q10;p10).
Authors: Ohyashiki Kazuma , Hsiao Hui-Hua , Sashida Goro , Ito Yoshikazu , Ohyashiki Junko H. 
Published: April 2020

Abstract
We analyzed 23 patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) showing der(1;7)(q10;p10) (hereafter der(1;7)), to identify the exact predictive factor of this cytogenetic change. Eight (34.8%) patients, including 6 MDS and 2 AML patients, had a prior history of genotoxic exposure, especially radiation and/or antimetabolites. Patients with der(1;7) consisted of three groups; one-third of patients had a prior history of genotoxic agents, one-third had additional cytogenetic changes at the time of MDS/AML diagnosis without prior exposure history, and the remaining one-third had neither prior exposure history nor additional cytogenetic changes. The current study demonstrated that the poor outcome of MDS/AML with der(1;7) is due to the high frequency of associated risk factors, i.e., prior history of genotoxic exposure, the presence of additional cytogenetic changes, or both. Identification of prognostic disadvantage might be required for appropriate strategy in managing MDS/AML patients with rare der(1;7) abnormality.
Myelodysplastic Syndromes with Myelofibrosis May Be a Target for the JAK2 V617F Tyrosine Kinase Mutation.
Authors: Ohyashiki Kazuma , Aota Yasuo , Gotoh Akihiko , Miyazawa Keisuke , Kimura Yukihiko , Ohyashiki Junko H. 
Published: April 2020

Abstract
The JAK V617F tyrosine kinase mutation is responsible for development of the disease in chronic myeloproliferative disorders, including myelofibrosis (MF). Since MF is associated with various hematologic diseases as a terminal hematologic condition and is an important issue in managing patients, we searched for the V617F mutation in primary and secondary MF in various hematologic diseases using the sequence-specific primer-single molecule fluorescence detection assay (SSP-SMFD). Of the MF patients associated with acute myeloid leukemia and (n = 3), lymphoma (n = 3), and chronic myeloid leukemia (n = 3), none of them showed the mutation at the time of the diagnosis of MF. Approximately 40% of essential thrombocythemia (ET: n = 16) and primary MF (n = 4) showed the JAK2 V617F mutation, whereas 6 of 8 patients with polycythemia vera showed the mutation. Of note is that 2 of 6 patients with myelodysplastic syndromes (MDS) terminating in MF showed the mutation, while no MDS patient without MF (MDS: n = 3) had the JAK2 V617F mutation. Our study clearly demonstrated that MF in MDS patients is sometimes associated with JAK2 V617F mutation, while other underlying diseases developing MF may involve other pathways. Moreover, it permits speculation that clonal evolution in some MDS patients with the JAK2 V617F tyrosine kinase mutation may be responsible for secondary MF.
Phase II Study of Bortezomib in Waldenstrom’s Macroglobulinemia: Results of WMCTG Trial 03-248.
Authors: Treon Steven , Hunter Zachary R. , Matous Jeffrey , Badros A. , Joyce Robin M. , Mannion Brian , Advani Ranjana , Cook D. , Songer J. , Hill John , Kaden Bruce R. , Sharon D. , Steiss R. , Branagan Andrew R. , Patterson Christopher J. 
Published: April 2020

Abstract
In this multi-center phase II study, 27 patients with the consensus panel definition of Waldenstrom’s macroglobulinemia received bortezomib as a single agent. All but one patient had relapsed/or refractory disease, and the median number of prior therapies was 2 (range 0–3). Intended therapy consisted of 8 cycles of bortezomib at 1.3 mg/m2 on days 1,4,8,11. Twenty-six patients have completed therapy and are eligible for evaluation. The median age for this group was 62 (44–79 years) and baseline laboratories were as follows: serum IgM: 4,565 (1,067–9,330 mg/dl); bone marrow (BM) involvement 30% (1–95%); and hematocrit 34.9% (25.6–45.3%). Following a median of 6 cycles of therapy, serum IgM levels decreased in 25/26 patients to a median of 2,685 (125–5,650 mg/dl), while hematocrit rose in 20/26 patients to a median of 37.2% (30.9–46.3%). The overall response rate was 84.6%, with 11 and 11 patients achieving a minor (&lt;25% decrease in IgM) and partial (&lt;50% decrease in IgM) response, respectively, using consensus panel criteria. Post therapy bone marrow biopsies were not required for response determination, but were available for 8 patients who demonstrated a median decrease in bone marrow involvement from 37.5%(range 20–55%) to 17.5% (range 5–48%). However, in 3 of 8 patients discordance between serum IgM levels, bone marrow involvement and/or adenopathy was demonstrated including in one patient who demonstrated a decrease in serum IgM levels from 2,291 to 618 mg/dL whilst bone marrow involvement rose from 25% to 48%. With a median follow-up of 8 months, 10 patients have demonstrated progressive disease. In general, therapy was well tolerated with grade III/IV toxicities as follows: neutropenia (15%); sensory neuropathies (12%); thrombocytopenia (8%); pleural effusion (4%); neuropathic pain (4%); diarrhea (4%); infection (8%); anorexia (8%); and fatigue (4%). The results of these studies demonstrate that bortezomib is an active agent in the salvage setting for patients with WM, and may independent of direct tumor cell killing inhibit secretion of IgM in some patients. Moreover, BM biopsies and CT scans (if baseline adenopathy or splenomegaly were present) should be considered to assess response in WM patients receiving bortezomib. In view of these results, a phase II study of bortezomib in combination with dexamethasone and rituximab has been initiated in patients with WM.
A Case of Fulminant Myelodysplastic Syndrome Versus Acute Erythroleukemia Variant.
Authors: Mazzella Fermina M. 
Published: April 2020

Abstract
Case: A 73 year old male with no significant past medical history presented with chronic fatigue. A routine CBC revealed an H/H of 6.8/19, MCV 103, WBC 4,100 and platelet count 92,000. Reticulocyte count was 0.6%. Serum iron, B12 and red cell folate studies were within normal limits. A bone marrow aspiration and biopsy were performed.
Bone Marrow Findings: The bone marrow aspirate showed an M:E ratio of 1.8:1, with 33% erythrocytic elements. There was markedly left shifted erythropoiesis, with 57% of erythrocytic precursors being pronormoblasts. 1.2% blasts were present. Moderate erythrocytic dysplasia was present, with mild granulocytic and megakaryocytic changes. Vacuolated pronormoblasts were readily identified. No ringed sideroblasts were present. A diagnosis of MDS, NOS was rendered. No cytogenetics were obtained.
Follow-up: The patient was transfused 4 units of packed red cells. Due to the patient’s rapidly deteriorating condition, comfort measures only were provided. The patient died 2.5 weeks after the bone marrow procedure. No autopsy was performed. The cause of death was listed as MDS.
Discussion: This case is an extremely rare instance of left shifted erythropoiesis in the absence of the requisite number of erythrocytic elements for consideration of acute erythroleukemia (50%). By current definitions, this is an example of a fulminant MDS. However, this case does beg the question of whether or not pronormoblasts should be included in the assessment of malignant disorders of bone marrow.
Deletion of Tumor Suppressor Genes (TSGS) in Patients with Myelodysplastic Syndrome (MDS).
Authors: Galanopoulos Athanasios G. , Papadhimitriou Stephanos , Tsourveloudis Ioannis , Michalis Evridiki , Marinakis Theodoros , Tsakiridou Anastasia , Savvidou Ioanna , Xanthopoulos Vasilios , Theodoropoulos George , Gortzolidis George , Zomas Athanasios , Georgiakaki Maria , Anagnostopoulos Nikolaos I. 
Published: April 2020

Abstract
Background: The deletion of genomic sites harboring TSGs is known to be a powerful prognostic indicator in various chronic hematologic malignancies. However, the clinical significance of TSGs loss in MDS has not been thoroughly investigated.
Aims: To summarize our experience on the incidence and essential clinical correlates of TSGs deletions in MDS, providing preliminary results from the study of 27 patients.
Methods: The study included 17 men and 10 women (median age 74; range 38–84 years) with a documented diagnosis of MDS. The distribution of FAB subtypes was RA in 13, RARS in 3, RAEB in 6, RAEB-T in 4 and CMML in 1 case. According to the IPSS stratification, 5 patients were characterized as “low-risk”, 16 as “intermediate-risk” (11 as INT-1 and 5 as INT-2) and 6 as “high-risk” patients. The diagnostic bone marrow smears were studied with fluorescence in-situ hybridization (FISH) for deletions of chromosome regions 9p21 (p16/p14 and p15 genes), 9q34, 12p13 (TEL gene), 13q14 (RB1 gene D13S319 locus) and 17p13 (p53 gene).
Results: A deletion in at least one of the chromosome regions or loci studied was detected in 10 patients (37%). In 6 of them, more than one region locus was lost, making up a total of 20 deletions. The commonest finding was loss of the 17p13 region (5 cases; two of them homozygous), followed by 9p21 loss (5 cases; one of them homozygous). Overall, the presence of TSGs deletions was associated with complex karyotype, high IPSS score and risk of death (regardless of leukemic progression). Interestingly, deletion in at least one of the TSGs studied was found in 5 of the 17 patients presenting with normal karyotype. In 3 of these patients, the MDS progressed to acute leukemia. Two of the 5 patients died at one and six months from diagnosis of the MDS, without leukemic conversion.
Summary/Conclusions: Deletions of TSGs are not uncommon in MDS. Interestingly, we have found that certain TSGs, such as the p16/p14 and p15 genes at 9p21, the loss of which is mostly involved in the initiation or progression of lymploid neoplasms, are also frequently deleted in MDS. Overall, TSGs deletion in this small group of patients is apparently associated with other adverse biological and clinical features and poor outcome. Therefore, these preliminary observations justify the expansion of the study in a larger patient cohort, in order to clarify if the loss of certain TSGs is an independent prognostic factor in MDS and, thus, may be of help in the initial diagnostic approach and risk stratification of the patients.
Sideroblastic Changes Can Be Recognized in the Erythrogram.
Authors: Rovó Alicia , Passweg Jakob R. , Favre Geneviève , Heim Dominik , Meyer-Monard Sandrine , Tsakiris Dimitrios , Gratwohl Alois , Tichelli André 
Published: April 2020

Abstract
The scatter plots of red blood cells (RBC), called erythrogram produced by the ADVIA® 2120 cell counter gives a visual representation of RBC characteristics. Using a pair of threshold gates on each axis, nine areas are defined according to the cell volume and the hemoglobin (Hb) content. Normal RBC are distributed in the central quadrant. In diseases such as iron deficiency and thalassemia the erythrogram shows a characteristic pattern commonly used for diagnostic approach. We observed in patients, mainly with myeloid diseases with ringed sideroblasts (RS) in the bone marrow a particular erythrogram pattern with a broad distribution of the RBC and a marked variation in RBC size and hemoglobinization. From the central quadrant an abnormal RBC population shifts on an imaginary axis to the lower-left quadrant representing a tail advancing into the microcytic and hypochromic quadrants (Fig1). To confirm whether this particular erythrogram was predictive for bone marrow sideroblastic changes; we compared retrospectively the erythrogram of patients with RS to a group of myeloid diseases without RS. Between January 2004 and August 2005, 33 of 1973 cases with more than 15% of RS in the marrow were identified, 21/33 patients were evaluable (AML=2, MDS=13, MPS=1, MDS/MPS=3, non neoplasia=2). These patients were compared to 30 consecutive cases with myeloid diseases without RS (No RS) (AML=16, MDS=11, MPS=2, MDS/MPS=1). In addition to the erythrogram pattern, Hb, RBC indices, and bone marrow iron staining were analyzed in both groups. We defined two types of erythrogram pattern in respect of sideroblastic changes: a) typical (fig1) b) non typical: any other pattern (i.e. macrocytosis, fig 2). The erythrogram was typical in 17/21 patients with RS and in 0/30 patients with No RS (p&lt;0.0001). The positive predictive value for sideroblastic changes was 100% and the negative predictive value was 88%. Despite the RBC indices comparison showed statistical significance in some variables, they were not specific enough to identify sideroblastic changes. In the group with RS, mean cell Hb was lower (median 30.8 versus 33.6pg), RBC distribution width was higher (19.3 versus 16.5%), the % of hypochromic RBC was higher (5.3 versus 0.9%) and Hb content of reticulocyte was lower (33 versus 37 pg) compared to No RS patients (p&lt;0.05). This last index was particularly useful to rule out iron deficiency in RS group as a cause of hypochromic RBC changes, since in contrast to iron deficiency it was not decreased. In conclusion: sideroblastic changes can be recognized in the erythrogram. Indeed, despite myeloid diseases with RS are a heterogeneous group of diseases they have a common pattern of RBC distribution that can be considered as a kind of fingerprinting for sideroblastic changes with a high predictive value allowing a straightforward diagnostic approach in clinical practice.
Figure 1 Figure 1. Figure 2 Figure 2.
MtDNA Sequence of MDS Patients Treated with CoQ10.
Authors: Sechman Eric V. , Galili Naomi , Einstein Eric , Raza Batool , Ferrante Kimberly , Raza Azra 
Published: April 2020

Abstract
We conducted a pilot study to test the efficacy of coQ10 in improving the cytopenias of MDS patients with low to intermediate risk MDS. Almost every patient experienced a reduction in fatigue and improvement in life quality. Among 25 evaluable patients, 7 responded according to the International Working Group (IWG) criteria. Responses included two trilineage and 1 monolineage response, two cytogenetic responses, and two patients showed a change in FAB type from CMMoL to RA and RARS. CoQ10 is an important coenzyme that has been shown to be involved in protection against oxidative stress, inhibition of apoptosis, and generation of ATP. Mutations in mitochondrial DNA have previously been found in MDS patients. We hypothesized that acquired mutations in the mitochondrial genome may relate to the efficacy of coQ10 treatment. We therefore sequenced the mitochondrial genome (mtDNA) of 9 patients, including 4 responders and 5 nonresponders, and 2 normal samples to determine if differences in the frequency or location of mtDNA mutations could be correlated to response. Whole genomic DNA was isolated from bone marrow monocytes and the mtDNA was PCR amplified in 40 overlapping segments. The PCR products were then sequenced and compared to a mitochondrial genome database (www.mitomap.org) to identify mutations. This technique will not detect mutations present in only a small subset of DNA copies. However, mutations present in a majority of mtDNA that may directly contribute to the expansion of the MDS clone will be identified. Interestingly, although mutations were observed, no differences were found that distinguished responders from nonresponders. We conclude from this analysis that the clinical benefit to MDS patients is not related to specific mutations in the mitochondrial genome. Clinical response may instead be related to other pleiotropic effects of coQ10, such as inhibition of apoptosis.
Research of Subset and Function of Th Cells in Bone Marrow of Myelodysplastic Syndrome Patients.
Authors: Wang Xiuli , Wu De Pei , He Guangsheng , Miao Miao , Sun Aining 
Published: April 2020

Abstract
Objective
To study the quantity and ratio of Th1, Th2 cells in the bone marrow of patients with MDS;The tumor burden that Th1 cells bear in the patients with MDS. Evaluation of the correlation between the ratio of the blast cells and the number of the Th1 cells in the bone marrow in the patients with MDS.
Methods
By FACS, the quantity and ratio of IFN-γ producing CD4+ T cell (Th1) and IL-4 producing CD4+ T cell (Th2) cells in the bone marrow were detected in 21 patients with MDS,18 normal controls and 13 patients with SAA respectively;The karyotypes of 18 patients with MDS and 15 normal controls were detected, The burden,(the number of the cells with anormal karyotypes /the number of all the detected cells) that Th1 cells bear in the patients with MDS and that in normal controls were analyzed;The correlation between the ratio of the blast cells in the bone marrow and the number of the Th1 cells in the patients with MDS was also analyzed.
Results
The percentages of Th1 cells and Th2 cells and ratio of Th1/Th2 in the bone marrow of normal controls were: (0.48±0.10)%,(0.24±0.19)%,2.31±0.76 respectively, while those of the patients with MDS were (0.36±0.11)%,(0.76±0.35)% and 0.51±0.13. The percentage of Th1 cells of patients with MDS was reduced and the ratio of Th1/Th2 of them was significantly lower than that of normal controls(p&lt;0.01); Those of the patients with SAA were: (4.75±0.49)%,(0.40±0.28)%,26.5±8.79 respectively, their Th1 cells and ratio of Th1/Th2 were markedly higher than those of normal controls (P&lt;0.01); In all of the 15 normal controls the karyotypes were normal, and tumor cell burden was zero, While in the group of MDS, tumor cell burden, (the number of the cells with anormal karyotype /the number of all detected cells) was (50.00±0.10)%. The MDS patients’ ratio of tumor cell burden / Th1 cells (1.72±1.23) was much higher than that of normal controls whose burden was zero;The lower ratio of the Th1 cells in the bone marrow of the patients with MDS and the AML which converts from MDS, the higher percentage of the blast cells, they were negatively correlated (r=−0.563, p&lt;0.01).
Conclusion
The immune function of T lymphocytes in MDS is abnormal: the balance between Th1 and Th2 cells is broken. Th1 cell, the most important element for antitumorigenesis, is decreased. Comparing with the burden of the malignant clone, the number of Th1 cells of the patients with MDS is overwhelmingly scarce. With descending of the number of Th1 cells in the bone marrow of the patients with MDS, the number of the blast cells contrarily grows. MDS is a heterogeneous group of neoplastic disease accompanied with hypofunction of the T lymphocytes mediating immune surveillance.
All these hint that during the treat of clearing the malignant clone of MDS, enhancement of the T cell fuction should been done.