bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Chromosome 13 Deletion and Plasma Cell Load on Long-Term Survival of Patients with Multiple Myeloma Undergoing Autologous Transplantation
Authors: Paul Esbjörn , Sutlu Tolga , Alici Evren , Gahrton Goesta , Nahi Hareth 
Published: April 2020

Abstract
High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common treatment for patients under 60–65 years of age with multiple myeloma (MM). In this study, we present a retrospective analysis of the prognostic impact of different factors in patients who have received this treatment as first line therapy in our centre. Abnormalities in chromosome 13 were identified by fluorescence in situ hybridization at the time of diagnosis. The median OS and PFS from transplantation time in the whole group of 193 patients were 90 and 48 months respectively. The median follow-up was 65 months (range: 6–186 months). The complete remission (CR) rate in patients with and without del(13) was 31% and 40% respectively whereas the median OS in patients with del(13) was 58 months but not reached in patients without del(13) (p=0.006). The PFS was 26 months in patients with del(13) and 84 months in those without del(13) (p=0.001). The transplantation related mortality was 2.5% both in the absence and presence of del(13). Patients who achieved CR following ASCT had longer OS and PFS when compared to those who only achieved partial remission. Thus, this study confirms the role of del(13) as a marker of poor prognosis. Multivariate analysis showed that the existence of del(13) was the only single independent factor effecting survival (p=0.001). In patients without del(13), the prognostic impact was even stronger when combined with the plasma cell load in the bone marrow (p=0.020), whereas the plasma cell load had no effect on survival of patients with del(13). Overall, the absence of del(13) in combination with low plasma cell infiltration at diagnosis predicts the best survival.
NF-Kb Localization in Multiple Myeloma Plasmacells and Mesenchimal Cells
Authors: Conticello Concetta , Giuffrida Raffaella , Adamo Luana , Anastasi Gabriele , Iannolo Gioacchin , Salomone Edvige , Memeo Lorenzo , Amato Gabriella , Gorgone Ausilia , Romano Alessandra , de Maria Ruggero , Gulisano Massimo , Giustolisi Rosario , Di Raimondo Francesco 
Published: April 2020

Abstract
Several reports have clearly demonstrated that the activation of Nuclear factor-kappa B (NF-kB) is essential for the pathogenesis of MM because it regulates the expression of many proteins involved in cell survival, proliferation, and resistance to chemotherapeutic drugs. We therefore analyzed by immunohistochemistry, immunofluorescence and western blot analysis the nuclear localization of NF-κB in MM cells derived from 60 different patients with MM at presentation and in relapse, as well as in three myeloma cell lines (XG1, RPMI 8226, KMS-18). Surprisingly, nuclear localization (the active form) of NF-κB was detected in only one MM sample from a refractory MM patient and in two samples from relapsed patients, while all the other samples, including the MM cell lines, exclusively express the cytoplasmic (inactive) form of NF-κB. We next analyzed the NF-κB status in mesenchymal cells from MM patients and we found that NF-κB was clearly present in the nucleus. We have also analyzed the sensitivity of MM primary cells to different doses of the proteasome inhibitor Bortezomib, which is described to antagonize NF-κB activity. We found a consistent dose- and time-dependent antitumor activity against both chemoresistant and chemosensitive myeloma cells in all the samples analyzed, independently of NF-κB localization. In conclusion, contrary to the current dogma that indicates a constitutive activation of NF-kB in MM cells, we demonstrated that in a steady state, especially in patients at diagnosis, NF-kB resides in the cytoplasm (the inactive form) but the cells maintain the sensitivity to Bortezomib, thus indicating that block of IkB degradation is not the only mechanism responsible for proteasome inhibitor induced-apoptosis.
Decreased Expression Levels of CD54 Associated with Decreased Activity of CXCL12 in Primary Myeloma Cells
Authors: Kawano Michio M. , Iqbal Mohd S. , Otsuyama Ken-ichiro , Shamsasenjan Karim , Amin Jakia , Islam Abul , Abroun Saeid 
Published: April 2020

Abstract
In order to evaluate NF-kB activity in the primary myeloma cells, we examined the expressionlevels of CD54 by a flow cytometer. First, we confirmed that the expression levels of CD54 showed good correlation with the levels of DNA binding activity for NF-kB in human myeloma cell lines. Primary myeloma cells unexpectedly revealed lower expression levels of CD54 compared to normal BM plasma cells, while plasma cells from MGUS had high expression levels of CD54 as same as normal BM plasma cells. Furthermore, the expression levels of CD54 on these plasma cells showed the significantly positive correlation with the plasma levels of CXCL12 (SDF-1α) in their BM aspirates, and the expression levels of CXCR4, the receptor for CXCL12, decreased on primary myeloma cells compared to normal BM plasma cells. It was also confirmed that addition of CXCL12 in the in vitro culture significantly induced up-regulation of CD54 expressions in primary myeloma cells. Furthermore, myeloma cells with lower expressions of CD54 were unstable in the in vitro culture, resulting in the marked reduction of viable cell number; this was also the case where cell lines with lower or no expression of CD54 were sensitive to H2O2 treatment. Therefore, these data suggest that primary myeloma cells have lower expression levels of CD54, possibly lower NF-kB activities and different stability of in vitro survival from normal BM plasma cells, depending on expression levels of CD54.
Long-Term Arsenic Trioxide (ATO) Treatment Changes Multiple Myeloma (MM) Cells Micro-RNA and RNA Expression Profiles
Authors: Wen Jianguo , Feng Yongdong , Ballon Douglas J , Chang Chung-Che 
Published: April 2020

Abstract
Although the preliminary results of treating refractory and relapsed multiple myeloma patents with ATO are promising, the data suggest that the resistance to ATO treatment frequently occurs (57 to 79%). We treated MM cells RPMI8226 with long-term low dosage ATO (0.5 μM) and harvested the ATO resistant cells. ATO resistant cells IC50 is 4 times higher and ATO resistant cells formed 2 times more colonies with 0.75 μM ATO treatment than parental RPMI8226. P-p38 MAPK, Bcl-2, XIAP and survivin were elevated to a relatively high level in ATO resistant cells under continuous ATO stress. We have established a custom designed miRNA microarray printed with a comprehensive panel of miRNAs in miRBase version 9.0 (238 mmu-mirs) and miRNA predictions including 2617 MED-MIR predictions, 321 ‘Cand” predictions discovered through a strategy based on pylogenetice-shadowing, 129 ‘MIR” predictions discovered through a search for miRNA targets in 3′ UTR sequences. We used this miRNA array to probe the miRNA expression profiles of RPMI8226 and resistant cells and observed differences in miRNA expression between the two lines. We also performed oligonucleotide microarray analysis using HG-U133 plus 2.0 array to screen the differential gene expression. Results showed that ATO resistant cells repressed the expression of has-miR-181a, has-miR-181b, has-let-7i, has-miR-19b, has-miR-18a, has-miR-20a and has-miR222. On the other hand, LMAN1, NPGPx, HSP73 and EIF1 genes expression were up-regulated. These data revealed the preliminary mechanism how MM cells adapt to ATO and provide potential targets to overcome the ATO in MM therapy.
Solitary Plasmacytoma. Presentation of 22 Cases of Two Centres from Buenos Aires, Argentina
Authors: Dragosky Marta , Alcaraz Susana , Anetta Isabel , Corzo Ariel , Devotto Laura , Deza Ernesto Gil , Luchetta Patricia , Marquez Marisa 
Published: April 2020

Abstract
Solitary plasmacytoma is a rare plasmatic cell tumor. Plasma cell neoplasia usually are generalized disease, in a small number of cases, less than 5 %, presents as a single bone lesion: solitary bone plasmacytoma (SBP) or develops outside the bone: extramedullary plasmacytoma (EMP).
Diagnostic criteria are: single bone tumor or single extramedullary mass of clonal plasma cells, normal bone marrow, no evidence of disseminated disease on skeletal survey, no anemia, hypercalcaemia or impairment of renal function, absent or low serum or urinary monoclonal immunoglobulin.
Material and Methods We present 22 patients treated at the Departament of Hematology of Marie Curie Hospital and Henry Moore Institute, 13 with SBP and 9 with EMP diagnosis. All were studied with the criteria of multiple myeloma. Prevalence of male 3.4/1 in both. Ages: SBP: 27–68 range, medium 47.23, EMP: 29–74 range, medium 55.
Locations of SBP: 5 in rachis (D3, D5, D7, D7, D8), 2 in clavícula, 2 in humerus, 1 in femur, sternum, etmoides, frontoparietal. The EMP: 7 in the head and neck: 3 in sinuses, 2 oropharynx, 1 uvula, maxillary mass (in area irradiated by NHL 7 years before), 1 lung + amyloid, 1 inguinal mass. Presence of a monoclonal paraprotein in serum/urine, was founded in 6 SBP (46%): 2 IgG kappa, 2 IgG lambda, 2 IgA lambda and in 2 EMP (22%): 1IgG lambda, 1 light chain lambda.
Results Treatment: SBP: in 10 RT + QT (VAD, Tal/Dex), 2 RT, 1 QT. Surgery was used to stabilize spine and/or long bones. EMP: 4 surgery + RT, 3 QT (VAD, Tal/Dex), 1 surgery + QT, 1 QT + RT. 8 patients underwent autologous bone marrow transplantation, 7 with SBP and 1 EMP, 5 of them aged under 36 years SBP: 3 patients achieved CR (10, 39, 77 months), 1 had local bone relapse, 2 without follow up, 3 of 7 transplanted patients relapsed, with evolution to multiple myeloma, 8 months, 23 months and 7 years later; the other 4 remain in CR, 27 to 82 months, media 36. EMP: 8 of 9 remain in CR, 2 to 120 months, media 35. One patient had a ileocecal relapse (initial site: oropharyngeal).
Conclusions Our series present male predominance, as reported by other studies. SBP prevail in axial skeleton and long bones in 61.5 %. Presents a worst development and prognosis, even though after ABMT. EMT was most frequently localized in head and neck (77,7%), in upper airways and oral cavity. The evolution was favorable, with only a single relapse. Diverse therapeutic methods happen to be useful. Low monoclonal paraprotein was present in 46 % of BPS and 22 % EMP.
A Clinical Study of Bortezomib in Combination with Dexamethasone and/or Doxorubibcin for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma
Authors: Jin Jie , Qian Jiejing , Meng Haitao , Qian Wenbin , Tong Hongyan , Tong Yin , Mao Liping 
Published: April 2020

Abstract
Purpose: This study assessed the safety, tolerability, and response rate of bortezomib in combination with dexamethasone and/or doxorubibcin in patients with relapsed or refractory multiple myeloma.
Methods: Botezomib was administered 1.3mg/m2 on days 1, 4, 8, 11 of a 28-day cycle. Intravenous dexamethasone was administered 20–40mg/d on day 1–2, 4–5, 8–9,11–12, and 5 patients were also given 20mg/d doxorubibcin on day 1–4.
Results: Thirty relapsed or refractory myeloma patients (table 1) were enrolled; two patients could not be evaluated because they were lost to follow-up. Of the remaining patients 19 are male, 9 are female. Median age of the patients were 61(49–78). Median number of prior therapies was 4 (1–11). 22 of 28 patients who had been evaluated were assessable for response according to the EBMT criteria (European Group for Blood and Marrow Transplantation criteria). One CR(3.6%), twelve immunofixation-positive CRs[nCR] (42.9%), six PRs(21.4%), and three MR (10.7%) were observed. All patients who had an objective response were alive as of this analysis. Nine patients died during follow-up. Mean response time (time to best response)for the 28 patients was 25 days. Most common Grade ≥3 toxicities (table 2) were peripheral neuropathy(3/28), thrombocytopenia (3/28), rash(one in 28 patients). Six patients(21.4%) suffered herpes after one or two cycles.
Table 1. Patents and Disease Characteristics (N=28)
No. % Abbreviations: Ig, immunoglobulin; Parameter 61 49–78 Age, years Median Range 19 Sex Male Female 9 Paraprotein type IgG IgA Light-chain only 18 β2..Cmicroglubulin, 3 64.3 10.7 Range 7 25.0 Prior treatments 1262–8691 Median 4 Range 1–11
Table 2. Treatment-emergent adverse events
Total No. of patients with event(%) Adverse event 0 Hematologic Neutropenia No. with 3(10.7) grade ≥3 event Thrombocytopenia No. 0 with grade ≥3 event Anemia No. with 6(21.4) grade ≥3 event 5(17.8) Nonhematologic herpes Diarrhea 10(35.7) Fatigue Rash No. with 1(3.6) grade ≥3 event Tachycardia Peripheral 1(3.6) neuropathy Total No. No. 16(57.1) with grade ≥ 3 event 3(10.7)
Conclusion: Bortezomib plus dexamethasone given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for multiple myeloma patients.
Toxicity of Bortezomib: Is There An Influence of Application Rates of Doxorubicin and Dexamethason Administration?a Clinical Monitoring
Authors: Steinborn Wolfram , Stein Wolfgang , Klebe Sandra , Kiehl Michael 
Published: April 2020

Abstract
Background: Bortezomib has shown significant anti-tumor activity in multiple myeloma. There are varied protocols including bortezomib, doxorubicin and dexamethason with different application rates. We observed in a retrospective analysis a wide range of toxicity, so that we have to modified our standard approach. The purpose of our analysis was to assess the frequency of toxicity and their alteration after changing the protocol.
Patients and methods: Eleven patients were treated for two 28-day cycles using our standard protocol. Bortezomib was given at 1.3 mg/m2 (days 1,4,8,11) and dexamethason at 40 mg (days 1–4, 9–12, 17–20) as well as doxorubicin at 9 mg/m2 (days 1–4). Seven patients received a third modified cycle composed of Bortezomib at 1.3 mg/m2 (days 1,4,8,11), dexamethason at 40 mg days 1–4 and doxorubicin at 20 mg/m2 days 1 and 4.
Results: One patient had unergone prior autologous transplantation, the other ten patients (90%) were newly diagnosed. All patients reported moderate peripheral neuropathic pain during the first two cycles. Eight patients (72%) developed severe adverse effects, twenty-five percent during the first cycle and seventy-five percent after the second one. The age of the affected patients range from 65 to 77 years (average age 70.5 years), the mean age of the unaffected is 64.7 years (54 to 72 years). Grade 3–4 toxic effects included infections (100%), neutropenia (25%), acute renal insufficiency (25%) and pulmonary edema (1 patient). Within the group of infections a pneumonia were diagnosed in six patients (75%), herpes zoster in two patients (25%) and an erysipelas in one patient. Two patients (25%) with pneumonia are died from a septic-toxic shock. The seven patients receiving the modiefied third cycle were without any grade 3–4 toxicity.
Conclusions: The age seems to have an influence on adverse effects (p=0.19) but there is a high significant benefit concerning the toxicity of bortezomib depending on application rates of doxorubicin and dexamethason.
No Evidence for Increased Prevalence of JAK2 V617F in Women with a History of Recurrent Miscarriage
Authors: Dahabreh Issa J. , Jones Amy V. , Voulgarelis Michael , Alafakis-Tzannatos Christina , Giannouli Stavroula , Varla-Leftherioti Marighoula , Keramitsoglou Theodora , Zoi Christine , Loukopoulos Dimitris , Fotiou Stelios , Cross Nicholas C.P. , Zoi Katerina 
Published: April 2020

Abstract
Myeloproliferative neoplasms (MPN) have been associated with increased rates of pregnancy complications. Women with essential thrombocythemia (ET), and, much less frequently, polycythemia vera (PV) present at a childbearing age and it has been reported that up to a third of MPN pregnancies may fail as first trimester miscarriages. A recent study has demonstrated that the JAK2 V617F mutation, seen in nearly all PV cases and half of those with ET, was significantly more common in women with a first unexplained pregnancy loss compared to controls, although the overall incidence was low (1.06% of women with a first unexplained pregnancy loss versus 0.2% in controls, p&lt;0.001). We hypothesized that JAK2 V617F may be further enriched in women who had multiple miscarriages. We studied peripheral blood leukocyte DNA from 389 women who had suffered at least three consecutive spontaneous early miscarriages (&lt;10 weeks gestation) or at least one late pregnancy loss (&gt;10 weeks) by a tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) assay with a sensitivity of detection of 1% JAK2 V617F. 92% of women had a history of early miscarriage and 14.1% of late miscarriage. Detailed clinical information was available for 230 (59%) cases: the mean age was 35.9 years (standard deviation=5.4; range: 20–50) and the median number of miscarriages was 3 (range: 3–7). Factors known to be associated with recurrent miscarriages were excluded. The JAK2 V617F mutation was not detected in any case, yielding a 95% confidence interval for the prevalence of the mutation ranging from 0 to 0.009 and excluding a 1% prevalence of JAK2 V617F in this population (p=0.038 for the overall population; p=0.057 for early miscarriages only; 2-tailed Clopper-Pearson exact test). Our study therefore demonstrates no enrichment of JAK2 V617F among unselected women with a history of recurrent miscarriages. Although we cannot exclude the possibility of a small, significant excess of V617F over background levels, our findings indicate that a latent maternal JAK2 V617F-positive MPN is an unlikely cause of miscarriage.
Flow Cytometry Analysis of Peripheral Blood CD34+ Cells in Patients with Primary Myelofibrosis
Authors: Agarwal Archana M , Samuelson Scott James , Preobrazhensky Sergey , Parker Charles J. , Hickman Kimberly , Perkins Sherrie L. , Prchal Josef T. , Bahler David W. 
Published: April 2020

Abstract
Primary myelofibrosis (PMF) is a clonal chronic myeloproliferative disorder characterized by the accumulation of megakaryocytes in the bone marrow (BM), variable degrees of BM fibrosis, tear-drop erythrocytes, increased numbers of CD34+ hematopoietic progenitors in the peripheral blood (PB), and extramedullary hematopoiesis. Since the antigenic properties of the circulating CD34 cells may yield clues to disease pathogenesis and have not been extensively studied, we used five-color flow cytometry to examine these cells from 20 well characterized patients with PMF and 10 normal controls. Bone marrow biopsies, molecular and cytogenetic studies were also reviewed. As expected, the percentages of peripheral-blood CD34 cells were significantly higher in the PMF patients (mean 1.4%, range, range 0.065–7.15) compared to the controls (mean 0.05%, range 0.01–0.57). The mean fluorescence intensity (MFI) values related to HLA-DR expression were increased (more than 3 fold) on the CD34+ cells in 12/20 (60%) PMF patients relative to normal control levels, while increased levels of CD13 were seen in 5/20 (25%) of PMF patients. CD33 and CD117 expression were similar on the CD34+ cells in both groups. Aberrant expression of lymphoid antigens was observed in 6/20 (30%) with CD7, 6/20 (30%) with CD4, and 3/20 (15%) with CD56 on CD34 positive cells in PMF. In the18 cases also studied with antibodies against CD45RA and CD123, the majority of CD34+ CD38 + cells phenotypically resembled megakaryocyte-erythroid precursors (CD45RA−, CD123−) in 5 cases, common myeloid progenitors (CD45RA−, CD123+) in 12 cases, and granulocyte-macrophage progenitors (CD45RA+, CD123 +) in 1 case. JAK2-V617F mutations were detected in 9 of 20 cases, but were present in only 1 of 5 cases showing predominately megakaryocyte-erythroid precursors. The percentage of CD34+ cells also expressing CXCR4 (CD184) appears to be increased in some patients relative to normal controls in contrast to other reported studies. In conclusion, the peripheral blood CD34+, progenitor cells in PMF patients are heterogeneous phenotypically resembling megakaryocyte-erythroid precursors in approximately 30% of cases, and common myeloid progenitors in approximately 70% of cases. In addition, these cells often show phenotypic abnormalities (increased intensity of HLA-DR and CD13 expression) that can be detected with flow cytometry relative to normal peripheral blood CD34+ cells. Patterns of antigen expression in PMF also appear to differ from those reported for CD34 positive cells in other myeloproliferative disorders which may help in early diagnosis and/or monitoring treatment responses.
Enhancment of SCA1 Positive Hematopoietic Progenitors in Polycythemic Mice Inhibits Leukemogenesis
Authors: Ben-David Yaacov , Usenko Tatiana , Haeri Mehran , Vecchiarelli-Federico Laura , Prchal Josef T. 
Published: April 2020

Abstract
PV is a myeloproliferative disease, displaying a pronounced increase in the number of erythroid cells. Despite this increase, PV patients exhibit a lower incidence of acute leukemia and in particular erythroleukemia compared to its related disorder CML. In this study we induced erythroleukemia in a mouse model of familiar polycythemia, carrying a truncated form of the human erythropoietin-receptor (Epo-R). Previous studies have shown that these mice develop a disease similar to patients with familiar polycythemia, from whom this gain-of-function receptor was isolated and introduced as transgene. We show that the progression of erythroleukemia induced by Friend virus is significantly delayed in this genetic mouse model of polycythemia. These mice exhibit a massive enrichment of Sca1+/cKit− progenitors and mature immune cells compared to normal mice. Co-transplantation experiments revealed that Sca1+/cKit− progenitors inhibit the robust tumorigenic potential of Sca1−/cKit+ erythroleukemic cells.
In order to determine the mechanism of erythroleukemia inhibition, we established cell lines from Sca1+/cKit− cell populations and demonstrated a similar anti-leukemic inhibition in vivo. These cells also express cell surface markers for early B-cells (B220) and macrophages (Mac1), and are able to undergo differentiation into macrophages and dendritic cells following treatment with GM-CSF and IL4. We have shown that these cells also secrete factors that inhibit proliferation of erythroleukemic cells in culture, such as Nitric Oxide (NO). Accordingly, an NO inhibitor can suppress the inhibitory effect of the Sca-1+/cKit−/B220+/Mac1+ cells. To further demonstrate the importance of these leukemic inhibitory cells, we induced a polycythemia in normal mice through administration of Epo. Epo administration delayed the development of Friend virus-induced erythroleukemia and significantly increased the number of leukemic inhibitory Sca1+ cells. Our study also demonstrates a significant increase in the number of leukemic inhibitory cells with anti-proliferative effects in response to Epo and granulocyte macrophage-colony stimulating factor (GM-CSF) stimulation. We therefore propose that administration of Epo and GM-CSF in combination with NO agonistic drugs, as well as the identification of novel drugs that can induce the inhibitory Sca-1+/cKit−/B220+/Mac1+ cells, may lead to improved therapies for the treatment of myelodysplastic syndrome. Together, our results identify Sca-1+/cKit−/B220+/Mac1+ cells as potent cellular inhibitors of leukemia and unravel a potentially novel therapeutic approach.