bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis on Characteristics of Dysplasia in 345 Patients with Myelodysplastic Syndrome
Authors: Xu Xiaoping , Ji Meirong , Chen Bobin , Lin Guowei 
Published: April 2020

Abstract
Objective To investigate the characteristics of dysplasia in myelodysplastic syndrome (MDS).
Methods Collect 716 samples of adult patients with abnormal blood routine but unclear cause between July 04, 2003 and March 14, 2007. Based on the gold standard of WHO MDS classification, all cases were detected on cytomorphological observation, cytochemical stain, bone marrow pathological study, cytogenetics, flow cytometry, and ect. The bone marrow cytological study on some abnormal hematopoietic cells has a diagnostic value to determine clonal or non-clonal diseases and assess sensitivity and specificity.
Results In the complicated various dysplasia of hematopoietic cells, the following characteristics can be the main basis of cytomorphological diagnosis:
One of granular Auer bodies, micronucleus (MN), or nuclear budding; Erythroid nuclear budding; Megakaryocytes presented in peripheral blood; Myeloblast or prorubricyte exhibited in peripheral blood; ringed sideroblasts&gt;1%.
The subordinate basis of cytomorphological diagnosis was as follows:
Granular pseudo Pelger-H≥et anomaly, hard nucleus segmentation, unsynchronous development of nuclei, ring-shaped nuclei, and aggregation of nuclear chromatin. Erythroid multi-nuclei, odd nucleus, mother-daughter nucleus, nuclear fragmentation, vacuole, and anisocytosis; micromegakaryocytes.
Conclusion Cytomorphologic is the base for the diagnosis of MDS, however, it presents certain limit, especially cytomorphological change does not possess specificity for early MDS, hereby, it requires to combine other detection methods.
The Multiple Myeloma Genomics Portal
Authors: Liefeld Ted , Gao Qing , Chapman Michael A , Tonon Giovanni , Auclair Daniel , Reich Michael , Golub Todd R. 
Published: April 2020

Abstract
Current integrative genomics projects are enabling new discoveries in cancer research through the ability to combine multiple modalities of data, e.g. gene expression, copy number, RNAi, exon resequencing, and epigenetics. However, the tools to access and analyze this data have traditionally been out of the reach of clinicians and research biologists, due to the widely distributed nature of the available data and the significant learning curve required to use the analytical tools. This problem is particularly relevant to the multiple myeloma research community because of the heterogeneity of genomic aberrations underlying this disease and lack of a central repository of multi-modal multiple myeloma data. To address these problems, the Broad Institute has created a pilot Multiple Myeloma Genomics Portal, http://www.broad.mit.edu/mmgp, which serves as an interface between biologists (and clinical investigators), analytical tools, and multiple myeloma datasets. The Portal provides access to a number of advanced gene expression, gene set enrichment, and copy number analyses and visualizations within an easy to use Web interface. These analyses can be performed on the datasets hosted on the Portal, which include previously published curated, high quality genomic multiple myeloma datasets as well as a new reference collection of multiple myeloma samples. The Portal is continuously updated with new datasets, data types, and analytical capabilities as they become available. The Portal’s accessibility allows it to serve as a significant venue for investigators from other fields, engaging a broader range of investigators in exploring these data, and its design is readily adaptable to integrative genomics studies of other cancer types.
Flow Cytometric Detection of Minimal Residual Disease in Multiple Myeloma Patients
Authors: Kovarova Lucie , Buresova Ivana , Pour Ludek , Michalek Jaroslav , Hajek Roman 
Published: April 2020

Abstract
Background: Multiple myeloma (MM) is a hematological malignancy characterized by expansion of neoplastic plasma cells (PCs). Despite of advances in treatment, achieved in past ten years, many patients relapse due to minimal residual disease (MRD) existence.
Aim: Monitoring of number and phenotype of plasma cells in transplanted MM patients by multiparametric flow cytometry.
Patients and Methods: Bone marrow of 24 MM patients (13 male, 11 female) after autologous stem cells transplantation was used. Analyses were done in 1st month and 1st year after transplantation. Relapsed patients were analyzed earlier. Plasma cells were identified as CD138+CD38+ cells, CD19 and CD56 markers were used for discrimination of normal polyclonal (N-PCs) and abnormal monoclonal (A-PCs) plasma cells, respectively.
Results: Median number of PCs in whole group of patients in 1st month after transplantation was 0.1% (range 0.0–2.5%), median number of CD19+ N-PC 39.6% (5.0–79.2%), CD56+ A-PC 31.7% (3.5–90.9%) and N-PC/A-PC ratio was 1.1 (0.1–22.6). There were identified 8 relapsed patients during 1st year from transplantation, all with detectable monoclonal immunoglobulin, and with median number of PCs 10.6% (range 0.1–76.6%), N-PC 0.2% (0.0–56.2%), A-PC 60.1% (0.8–99.9%) and N-PC/A-PC ratio 0.0 (0.0–3.0). In a group of non-relapsed patients in 1st year after transplantation was median number of PCs 0.2% (range 0.0–1.9%), N-PC 64.2% (6.3–90.0%), A-PC 21.7% (3.0–93.2%) and N-PC/A-PC ratio 3.4 (0.1–25.0). There is an evidence that relapse is relate to loss of CD19 expression on PCs and to higher number of CD56+ PC.
Conclusion: Flow cytometric analysis of PCs phenotype profile is relatively quick and sufficiently sensitive method that can be used for monitoring of MRD. Detailed analysis of higher number of patients and comparison of their data with other parameters (immunofixation etc.) are necessary for verification of this method and for its application in routine diagnostics.
Anti-Heparanase Therapy in Combination with Conventional Chemotherapy Potently Inhibits Multiple Myeloma Growth in Vivo
Authors: Ritchie Joseph P. , Naggi Annamaria , Torri Giangiacomo , Casu Benito , Pisano Claudio , Carminati Paolo , Vlodavsky Israel , Sanderson Ralph D. , Yang Yang 
Published: April 2020

Abstract
Targeted agents directed at specific intracellular signaling pathways and the tumor microenvironment have improved the management of many cancers, including multiple myeloma. Work by our lab has demonstrated that heparanase, an endo-β-D-glucuronidase which cleaves the glycosidic bond of heparan sulfate chains at only a few sites, is expressed by a subpopulation of myeloma cells. Expression of heparanase promotes myeloma growth and spontaneous metastasis to bone, correlates with increased microvessel density and is an indicator of poor patient prognosis. This makes heparanase a viable target for myeloma therapy. Current approaches for treating multiple myeloma are ineffective, with relapse occurring frequently. Recently, a modified non-anticoagulant species of heparin, designated SST0001, was identified as a specific inhibitor of heparanase. SST0001, when tested in multiple in vivo models of myeloma, potently inhibited both angiogenesis and tumor growth in a dose dependent manner. However, in vitro, it did not have direct tumor cell cytotoxicity. Therefore, because SST0001 apparently targets the tumor microenvironment and conventional chemotherapy directly targets the tumor cell, we hypothesized that combination therapy would synergistically decrease tumor burden and provide an alternative biological approach to treating myeloma. In this study, using a syngeneic subcutaneous model of myeloma, we screened three potential novel combinations; SST0001 + dexamethasone, SST0001 + doxorubicin, and SST0001 + bortezomib. While all three combinations were effective in blocking tumor growth, SST0001 + dexamethasone was identified as being the most potent and was chosen for further testing. In two separate SCID-subcutaneous models using the CAG and MM1.R dexamethasone resistant human myeloma cell lines, SST0001 + dexamethasone also proved to be a potent inhibitor of tumor growth in vivo. These results identify an effective combination therapy, which is not cell line specific, for further development and translation into clinical trials.
PKC412 Shows Strong Anti-myeloma effects in in-Vitro-Studies
Authors: Elmaagacli Ahmet H , Koldehoff Michael , Steckel Nina K , Beelen Dietrich 
Published: April 2020

Abstract
Background. The protein kinase C (PKC) inhibitor PKC412 (N-benzylstaurosporine) is a derivate of the naturally occurring alkaloid staurosproine and has been shown to inhibit the conventional isoforms of PKC (alfa, beta1, beta2 and gamma). PKC412 has been shown to have an antitumor effect on non-small cell lung cancer and acute leukemia with FLT3 mutations, but little is known about its effect on multiple myeloma up to date.
Methods. Since PKC is also an inhibitor of a tyrosin kinase which is associated with VEGF, and inhibits the release of Interleukin-6, TNF alfa, and that of growth factor dependent C-FOS, we postulated that PKC412 might have also strong anti-myeloma features. Here we evaluated the anti-myeloma effect of PKC412 in the multiple myeloma cell lines INA-6, OPM-2 and RPMI 8226 by measuring its effect on their proliferation rate, the apoptosis rate and the Interleukin-6 mRNA expression.
Results. PKC412 showed strong anti-myeloma effects in all three celllines. 50nM of PKC412 was enough to drop the proliferation rate in all three cell lines under 10% compared to untreated cells(p&lt;0.01). The apoptosis rate increased in INA cell line up to 2,5 times and in RPMI cell line up to 3 times (p&lt;0.05), whereas only a moderate increase was observed in the OPM2 cell line with 500nM of PKC412. As expected, the IL-6 mRNA expression decreased after PKC412 treatment in all three cell lines more than 50%. The addition of Bevacizumab to PKC412 in RPMI and OPM-2 cell lines did not increased the apoptosis rate significantly, whereas the addition of short-interference RNA (RNAi) against VEGF increased the apoptosis rate in RPMI 8226 cells about 20% (p&lt;0.05) and in OPM-2 cells up to 30% (p&lt;0.01) compared to PKC412 alone, which was also associated concordantly with a further reduction of the proliferation rate in RPMI and OPM-2 cells up to 30%.
Conclusions. PKC412 shows strong anti-myeloma effects and might be effective also in the treatment of patients with multiple myeloma. These in-vitro studies might encourage to initiate clinical trials with PKC412 in patients with multiple myeloma.
Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy Followed by Thalidomide and Dexamethasone (TD) as a Salvage Treatment for Relapsed Multiple Myeloma (MM): Analysis of Efficacy and Safety
Authors: Lee Jae Hoon , Suh Cheolwon , Lee Sung Sook 
Published: April 2020

Abstract
Introduction: PAD was reported to be highly effective regimen as an induction therapy before high dose therapy. TD is an another effective regimen with no cross resistance. We conducted a phase II study with PAD followed by TD in relapsed MM to test effectiveness of this combination.
Method: Patients were planned to receive 6 cycles of PAD, (bortezomib 1.3 mg/m2 days 1, 4, 8 and 11, doxorubicin 4.5 mg/m2 days 1–4, dexamethasone 40 mg days 1–4, every 21 days). Responders following 6 cylces of PAD received 12 cycles of TD (thalidomide 100 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days). In patients with progression during PAD therapy, regimen was changed to 12 cycles of thalidomide 200 mg days 1–28 and dexamethasone 40 mg days 1–4, every 28 days. Response was assessed by EBMT criteria, with additional categories of nCR and VGPR. Adverse events were graded by the NCI-CTC, Version 3.0.
Result: This study aimed to enroll 40 patients till Oct 2007 and we are reporting the result with 40 patients. Efficacy could be assessed in 34 patients. After two cycles of PAD, 34 patients showed response with 6 CR. Overall response rate to 6 cylces of PAD was 90.9% with 36.4% CR. Seven of total 24 patients with TD showed further improvement of response status with 7 additional CR. Overall response to PAD followed by TD was 94%: CR 57.6%, nCR 15.2%, VGPR 6%, PR 15.2%, SD 3%, PD 3%. There was no prognostic factor for CR+nCR achieving in the univariate analysis. The median follow-up was 16.2 months with 2 year OS 54.5%. The median PFS time from study treatment was 18 mon (95% CI, 11.0~24.9 mon), median OS was not reached. The median OS time from first diagnosis was 112.9 mon (95% CI, 24.6~201.1 mon). One hundred seventy-eight PAD cycles (median 6, range 1–6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3/4 in 39.5%. Grade 3/4 neutropenia was observed in 10.5%. Sensory neuropathy occurred with grade 2 in 26.3% and grade 3 in 13.2%. The median dose intensity was 1.35 mg/m2/week for bortezomib and 5.21 mg/m2/week for doxorubicin, which correspond 78% and 86.8% of the planned dose intensities, respectively. A total of 185 TD treatment cycles (median 2, range 0–12 cycles) was administered. One patient die by the pneumonia.
Conclusion: PAD followed by TD in patients with relapsed multiple myeloma is very active and tolerable.
Ritonavir Sensitizes Multiple Myeloma Cells to Bortezomib-Induced Apoptosis
Authors: Shibata Robert , Bassermann Florian , Chandra Pranil , Resemann Henrike , Mazumder Amitabha , Pagano Michele , Ibrahim Sherif 
Published: April 2020

Abstract
The ubiquitin-proteasome system plays a central role in the regulation of cell growth and cell proliferation by controlling the abundance of key cell cycle proteins. Increasing evidence indicates that unscheduled proteolysis of many cell cycle regulators contributes significantly to tumourigenesis and is indeed found in many types of human cancers, including colon and renal cell cancer, non hodgkin lymphomas, and multiple myelomas. Protein degradation pathways are also targets for cancer therapy, as shown by the successful introduction of bortezomib (B), an inhibitor of the 26S proteasome, for the therapy of multiple myeloma. Recently, protease inhibitors conventional in HIV therapy (e.g., ritonavir (R)) have been found to exert an antiproliferative effect on different tumor types, including multiple myeloma cells. More recently, ritonavir has been shown to induce endoplasmic reticulum stress and to sensitize sarcoma cells towards bortezomib induced apoptosis.
In this study, we show that the combination of therapeutic concentrations of bortezomib and ritonavir acts synergistically on cultured multiple myeloma cell lines (U266, RPMI 8226, ARH-77 (2 variants-One is more resistant)). Cell proliferation was significantly reduced in an overadditive fashion as compared to individual treatments (proliferation as % of DMSO control after 48hrs: CRL-1621 (ARH-77): B: 40%, R: 50%, R&B: 7%, CCL-155 (RPMI 8226): B: 37%, R: 50%, B+R: 6%; n=3). Moreover, we found proteasome inhibition by bortezomib to be associated with low levels of expression of Skp2 and consequent stabilization of its target p27Kip1, a negative cell cycle regulator at the G1/S cell cycle transition. Accordingly, bortezomib induced cell cycle arrest at the G1/S transition followed by caspase dependent apoptosis. In contrast, only mild induction of apoptosis and no activation of Caspase 3 were observed in myeloma cells treated with ritonavir, although growth arrest was present. Interestingly, growth arrest in ritonavir-treated cells was associated with an accumulation in G2 phase.
In a limited clinical study, we treated two patients with stage III relapsed and refractory myeloma with a combination of bortezomib at standard doses and ritonavir at 600 mg twice a day. Both patients had MR or greater lasting for more than 2 months. Only grade 2 GI toxicity was seen.
Taken together, our findings suggest different mechanisms of action for bortezomib and ritonavir on myeloma cells and suggest that the combination of the two drugs may be a valid therapeutic strategy.
Identification of Key Factors That Are Associated with the Clinical Anti-Tumor Effect of Zoledronic Acid in Multiple Myeloma
Authors: Teoh Gerrard , Koh Liang Piu 
Published: April 2020

Abstract
Despite compelling preclinical data, only anecdotal reports have shown that zoledronic acid (ZOMETA, Zol) exerts an anti-multiple myeloma (MM) effect in humans. We postulate that this could be related to the dose-intensity of Zol, since anti-MM effects were clearly observed in mice given a dose equivalent of 8.0 mg (8.0 EQmg) weekly; but not in humans who received only 4.0 mg monthly. We describe 3 patients, who were treated with 2- to 3-fold higher dose-intensity of Zol; who demonstrated brisk clinical improvements. When the equivalent dose of Zol was normalized to the patient’s body surface area, the maximum EQmg rate of Zol administered was between 11.4 EQmgmax and 12.0 EQmgmax per 28 days. Since the potency of Zol is measured by the degree of inhibition of differentiation of osteoclast precursors (pOC) (i.e. monocytes) to osteoclasts (OC) in vitro, we next investigated whether high-dose rate Zol had an in vivo inhibitory effect on this renewable pOC pool. We demonstrate that there was a linear relationship between the absolute monocyte count (AMCO) and the stage of MM at presentation. Specifically, patients with International Staging System (ISS) stage I disease had the lowest AMCO levels, whereas ISS stage III patients had the highest. We also show that treatment with Zol resulted in progressive decreases in AMCO levels, and these changes correlated with response to therapy. By contrast, AMCO levels increased in patients who either failed to respond to treatment or who had progressive disease. Finally, since Zol is known to induce the gamma delta T cells in vitro, we studied the recovery patterns of various T cell subsets following treatment using a high dose-intensity Zol-based regimen called “dtZ”. To our surprise, there was no difference in gamma delta T cell numbers, but instead bone marrow CD4+ CD25+ regulatory T cells were significantly decreased in patients who achieved CR, as compared to those that did not. These data suggest that high dose-intensity Zol has a very desirable anti-tumor profile in MM that could be related to inhibition of both myelomagenic processes as well as the immunosuppressive elements of host anti-tumor defense.
Analysis of JAK2V617F and MPLW515L/K Mutation in 30 Patients with Early Stage Myeloproliferative Disease
Authors: Zhang Ri , Fan Zhen , Zhang Xuhui , Fei Hairong 
Published: April 2020

Abstract
The classic Bcr-Abl negative myeloproliferative disorders (MPDs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). They are considered clonal stem cell disorders. Recently two acquired somatic mutations JAK2V617F and MPLW515L/K have been identified to play an important role in pathogenisis of MPDs. JAK2V617F was detected in almost all PV and nearly 50% in ET and IMF, and the MPLW515L/K mutation occured in only 1% and 4% in ET and IMF respectively. However it is interesting that there are some patients with slightly increased blood cells did not meet the criteria of PV and ET clinically. These early prefibrotic stages of MPDs are overlooked by both the Polycythemia Vera Study Group (PVSG) and the 2001 WHO criteria for the diagnosis of PV, ET and IMF. In order to investigate the prevalence of JAK2V617F and MPLW515L/K mutation in patients with early MPDs without a secondary cause, genomic DNA from bone marrow or blood mononuclear cells of 30 patients with early MPDs was screened by allele specific polymerase chain reaction (AS-PCR) for JAK2V617F and MPLW515L/K mutations and the history of thrombosis was assessed retrospectively by using patient files. Results showed that 14 out of 30 patients (46.7%) were positive for the JAK2V617F mutation, and none of them had the MPLW515L/K. Of the 14 patients with JAK2V617F mutation, a history of thrombosis was comfirmed in 5 patients(35.7%), while none of 16 patients with WT JAK2 had the thrombosis history. The average age of patients with the JAK2V617F mutation exceeded the patients with wild type JAK2(P&lt;0.05), whereas there is no statistical significance on sexual Athe counts of white cell and the occurance of complications (thrombosis) between the patients with and without the JAK2V617F mutation. All the patients have been followed up since onset and 22 patients have available results. Among them, 12 patients with the burden of JAK2V617F turned out to be MPDs, however only 1 out of 10 patients without this mutation also evolved to MPDs. Our results suggest that JAK2V617F mutation can occur in a certain percentage of these early stage of MPDs patients and has help to diagnose early MPDs. Because these patients might have a high rate of complications, proper treatment of the MPD including aspirin and/or cytoreductive therapy is recommended in latent MPDs patients associated with the JAK2V617F mutation.
The Clinical and Histological Characterization of Malignant Lymphoma, Kikuchi-Fujimoto Disease and L-Forms Acid-Fast Bacillus Infection
Authors: He Jie , Li Rui-ping , Wang Jian-hua , Chen Bao-An 
Published: April 2020

Abstract
Objective: Malignant lymphoma (ML), Kikuchi-Fuljimoto disease (KFD) and L-forms Acid-fast bacillus infection (L-forms TB) usually affect the cervical lymph nodes. KFD and L-form TB are often confused with ML and take misdiagnosis and inappropriate treatment. The diagnosed of these diseases is on basis of an excision biopsy of affected lymph nodes.
Methods: We analyzed 63 patients (including case diagnosed in our hospital) by clinical characteristic, laboratory, pathological morphology, histochemistry and immunohistochemistry.
Results: Of 63 cases, 43 were ML, 17 were KFD and 3 were L-forms TB. In ML disease, 46% were male and 54% were female, mean age was 54 (11–82). 9% cases have persistent fever and associated with hepatosplenomegaly. In KFD, 47% were male and 53% were female, mean age was 26 (17–45). 59% cases with cervical hymphadenopath and no fever, 41% had painful, accompanied by fever. hepathosplenomegaly, occasionally leucopenia and lypadenopathy especially involving cervical region not responsive to antibiotic treatment. 29% lymph tissues were morphologically, and characterized by a necrosis in the cortical or paracortical areas of enlarged lymph node around the necrotic area. T lymphocytes were found and absence of granulocytes. 30% cases were mistaken to ML. L-forms TB disease, there were fever, clinical and histological were similar KFD and ML. 3 cases were misdiagnosis to ML or KFD. Laboratory analyses: PAM and PAS were positive, and anti acid test to found L-forms bacterium in tissues.
Conclusions: Kikuchi-Fujimoto disease and L-forms Acid-Fast bacillus infection are easily confused histological and clinically with malignant lymphoma. Clinicians and pathologists must be aware of this condition. Although Malignant lymphoma, Kikuchi-Fujimoto disease and L-forms Acid-fast bacillus infection can be found any age, but should be considered for malignant lymphoma in older patients. Kikuchi-Fujimoto disease is predominantly a self-limiting disease of the young and most cases with fever, nodal biopsy showing fragmentation necrosis and karyorrhexis, not responsive to antibiotic treatment. In the L-forms Acid-fast bacillus infection, the PAM and PAS are positive, and have an effective antibiotic treatment.