bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of IMiDs (Immunomodulating Agents) Induced “Flare Reaction” in Patients with Chronic Lymphocytic Leukemia (CLL) and Correlation with Changes in Serum Cytokine Levels.
Authors: DiMiceli Laurie , Miller Kena C. , Rickert Michael , Wallace Paul , Marshall Patricia , DePaolo Dawn , Padmanabhan Swaminathan , Landrigan Beverly , Chanan-Khan Asher A. 
Published: April 2020

Abstract
Introduction: Several cytokines (including TNF-alpha, IL-6 and VEGF) are reported to play a critical role in the pathogenesis of CLL cells. Targeting the tumor microenvironment through modulation of the cytokine milieu thus is a potential way to treat CLL. In 2 separate clinical studies we investigated the role of IMiDs (thalidomide and lenalidomide) either in combination with standard chemotherapy (thalidomide + fludarabine, FT) or single agent (lenalidomide, L) in pts with previously untreated or relapsed/refractory CLL, respectively. In these studies we observed tumor flare reaction not previously reported. In this report we describe the clinical characteristics of this side effect, its management and correlation with changes in serum cytokine levels. Flare Reaction (FR): CLL pts treated with IMiDs were noted to have tender increase in lymph nodes size starting within 24–48 hours of initiating therapy with or without erythema and rash. Some patients also increased their total white cell as well as absolute lymphocyte count (ALC).
Results: A total of 48 pts (20 on FT and 28 on lenalidomide) are collectively treated on 2 clinical trials. Median age was------, -----had limited stage (0-II) and ----- has advance Rai stage (III, IV). ------(%) on the FT and 22 (78.5%) on the L developed a FR, which was noted as early as 24 hours after initiation of therapy (median 48 hours). Most pts resolved FR by day 14. A comparison of serum cytokine level at day 0 and 7 was done in 10 pts (9 with FR) treated with L. An increase in TNF-a (n=4), MIG (n=6), IP-10 (n=8), IL-8 (n=7) and IL-10 (n=6) was noted at day 7.
Management: FR was treated with ibuprofen 400 mg q 6 hr with addition of oral morphine (or agents of equivalent potency) for improved pain control.
Conclusion: FR is a new side effect noted in CLL pts treated with IMiDs that is fairly well managed by anti-inflammatory agent along with aggressive pain control. Higher incidence is noted with L. There seems to be no correlation of FR with clinical response to therapy. Identification of the FR is important to avoid confusion with disease progression. An increase in levels of inflammatory cytokine was noted in all pts treated with L which may explain the underlying mechanism of this phenomenon.
Multiple Myeloma Presenting as a Clivus and Brain Stem Plasmacytoma.
Authors: Rezazadeh Arash , Kloecker Goetz H. , Laber Damian A. 
Published: April 2020

Abstract
Multiple myeloma is the most common hematological malignancy. MM can affect many organ systems; therefore, it may mimic different clinical syndromes at presentation. We report an extremely rare presentation of MM.
CASE REPORT: A 62-year-old man presented with progressive cervical pain for 2 months and double vision for 2 weeks. Physical exam demonstrated a cranial nerve 6 palsy, nuchal rigidity and no other abnormalities. A magnetic resonance image (MRI) of the brain revealed a 5 cm enhancing mass in the clivus which extended into the brain stem, left internal auditory and carotid canal, nasopharynx, sphenoid and cavernous sinuses, without midline shift or hydrocephalus. MRI of the spine showed 2 small enhancing lesions in thoracic vertebrae 4 and 11. Computer tomography of the chest abdomen and pelvis demonstrated a lesion in the sternum and no other abnormalities. Technetium-99 bone scan showed uptake in the skull base mass only. Complete blood count and metabolic profile were normal except for an albumin of 3.2 g/dL. Serum protein electrophoresis with immunofixation revealed hypogammaglobulinemia without a monoclonal protein. 24 hour urine collection demonstrated monoclonal free kappa light chains. Transsphenoidal stereotactic biopsy of the mass showed an atypical plasma cell proliferation with multi-nucleation and mitotic activity, positive for kappa light chain. Bone marrow aspirate revealed 17% of the nucleated cell to be abnormal plasma cells, some with plasmablastic morphology. He improved rapidly with dexamethasone and was referred for radiotherapy.
DISCUSSION: The most common neurologic complications of MM are spinal cord compression due to epidural plasmacytomas or vertebral fractures, and peripheral polyneuropathy due to the presence of antibodies directed against myelin structures or due to amyloid deposits. Brain involvement in MM is uncommon. Furthermore, neurologic symptoms due to plasmacytomas located either in the clivus and brain stem are extremely rare. A MEDLINE search from 1950 until July 2005 revealed only 9 cases of MM or plasmacytoma involving the brain stem. Since there is no published autopsy series on MM patients describing the percentage of patients with brain involvement at death, the denominator is difficult to assess. Clinically, extramedullary involvement from MM bears a poor prognosis, and has been described in cases of plasma cell leukemia. We speculate that the aggressive behavior of the MM in our patient might be consistent with the atypical phenotype of the plasma cells.
CONCLUSION: The unusual presentation of this patient adds to the medical knowledge about the clinical spectrum of multiple myeloma.
Bone Marrow Microcirculation Parameter Amplitude A of Contrast-Enhanced Dynamic MRI Is a Prognostic Factor for Progressive Multiple Myeloma for Patients with Low Beta2-Microglobulin.
Authors: Hillengass Jens , Wasser Klaus , Benner Axel , Delorme Stefan , Zechmann Christian , Ho Anthony D. , Goldschmidt Hartmut , Moehler Thomas 
Published: April 2020

Abstract
Introduction: We have previously shown that contrast-enhanced dynamic magnetic resonance imaging (dMRI) microcirculation parameters Amplitude A and distribution rate constant kep are significantly increased in patients with multiple myeloma (MM) compared to healthy controls and correlate with osteolytic bone involvement. Furthermore an elevated Amplitude A is associated with a high plasmacell-infiltration and increased microvessel density in bone marrow. We now evaluated the prognostic value of changes in microcirculation of bone marrow as detected by dMRI for overall (OAS) and event free survival (EFS) in patients with MM.
Methods: Between 1999 and 2001 62 patients with progressive MM requiring chemotherapy according to international standards (6 newly diagnosed patients, 56 patients with relapse or refractory disease) were investigated with dMRI of the lumbar spine. OAS and EFS were updated for all patients in February 2005. The estimated median follow up was 4.5 years. All patients underwent standardized dMRI with high temporal resolution (T1w-turboFLASH) before start of therapy. The contrast uptake was quantified using a two compartment model with the output parameters Amplitude A and distribution constant rate kep reflecting bone marrow microcirculation. To examine the prognostic value of the findings of dMRI we used the Proportional Hazards model as proposed by Cox.
Results: We recorded a correlation with borderline significance (p-value 0.1) between Amplitude A and EFS. We did not find a correlation of dMRI parameters with OAS. The multivariable analysis of Beta2-Microglobulin, age, Lactat Dehydrogenase (LDH) and Albumin revealed Beta2-Microglobulin as the only statistically significant prognostic factor for EFS in this group of patients. When patients were classified according to high or low Beta2-Microglobulin, Amplitude A was able to provide significant additional information characterizing EFS. Patients with low Beta2-Microglobulin and increased Amplitude A had significant shorter EFS than patients with low Beta2-Microglobulin and low Amplitude A.
Conclusion: Our investigations indicate that dMRI parameter Amplitude A which reflects the increased bone marrow microcirculation and angiogenesis is a novel prognostic factor for progressive multiple myeloma in patients with low Beta2-Microglobulin. So a more precise differentiation of patients may be possible through dMRI. The prognostic impact of dMRI for newly diagnosed myeloma patients and patients with monoclonal gammopathie with undetermined signifikance will now be evaluated in a prospective study.
Modification of Cytokine Levels and CD34+ Stem Cell Adhesion Molecules during Mobilization in Multiple Myeloma (MM) Patients.
Authors: Zappasodi Patrizia , Corso Alessandro , Rusconi Chiara , De Amici Mara , Consensi Erica , Pascutto Cristiana , Varettoni Marzia , Mangiacavalli Silvia , Pica Gianmatteo , Lazzarino Mario 
Published: April 2020

Abstract
The mechanisms underlying the mobilization of peripheral blood stem cells (PBSC) are still unknown, even though studies on healthy donors and on cancer patients have hypothesised a central role for CD34+ stem cells adhesion molecules and for chemokines serum levels. The type of mobilizing regimen and the pathologic condition can exert different effects on cytokine levels and adhesion molecules expression. To evaluate the modification of these parameters during mobilization we studied 10 MM patients treated with DCEP chemotherapy (Decadron, Cyclophosphamide, Etoposide, cis-Platin) followed by G-CSF (5 mg/kg/day starting 48 hours after chemotherapy until PBSC collection).
The expression of four CD34+ cell adhesion molecules (Thy1, L-selectin, VLA4, CXCR4) was measured in the bone marrow before mobilization therapy and in the leukapheresis product. Serum levels of five cytokines (TGF-β, IL-8, HGF, VEGF-A, sVCAM-1) were assessed, through specific ELISA kits, before therapy, 5 days after the G-CSF stimulation and at stem cells collection. Each parameter was correlated with the number of CD34+ cells collected.
Thy1 significantly decreased (p=0.007) and L-selectin significantly increased (p=0.038) in nearly all cases. By contrast, no statistically significant differences were observed for VLA4 and CXCR4 due to a consistent variability. Serum levels of IL-8 showed an increase at day 5, then a significant decrease at the time of the harvest (p=0.013); VEGF-A constantly increased (p&lt;0.001) and TGF-β decreased (p=0.001). The modifications registered for sVCAM-1 and HGF did not reach statistical significance. The expression of CD34+ adhesion molecules did not correlate with the number of PBSC collected, while among cytokines, high baseline levels of TGF-β and VEGF-A significantly correlated with high number of CD34+ stem cells yielded (p=0.016, p=0.042 respectively).
In conclusion, this study shows that during stem cells mobilization in MM Thy-1 expression significantly decreases while L-selectin increases; the behaviour of VLA-4 and CXCR4 is extremely variable. As regards cytokines, we found a statistically significant increase of VEGF-A level, while TGF-β, which induces the stem cell homing, decreases during the mobilization allowing stem cells to migrate in the peripheral blood. High baseline levels of TGF-β and VEGF-A predict a good stem cells harvest.
Gene Expression Profiling in Multiple Myeloma Cells Treated with the Novel Anti-Myeloma Agents Zoledronate and Fluvastatin.
Authors: Molloy Timothy J. , Cindy Baulch-Brown , Deng Yi-Mo , Spencer Andrew , Ma David F. 
Published: April 2020

Abstract
We have shown in vitro that multiple myeloma (MM) cells can be destroyed by treating them with the mevalonate pathway inhibitors zoledronate and fluvastatin. While the efficacy of these compounds singly and combination have been demonstrated, their exact modes of action remain largely unknown. The present study aimed to use microarray and quantitative real-time PCR (QRT-PCR) techniques to analyse gene expression in treated myeloma cells to identify novel genes and pathways involved in the anti-myeloma action of these compounds. The human MM cell line NCI-H929 was treated with zoledronate and fluvastatin singly and in combination, and RNA was extracted and used to interrogate oligonucleotide microarrays consisting of 19,000 features representing known and unknown genes. Quantitative real-time PCR was subsequently used to confirm the expression of several genes of interest. Flow cytometry with Annexin V FITC staining was used to detect apoptosis. It was observed that genes related to apoptosis (caspases and p53-related genes), cell cycle control (cyclins), GTPase signalling (Rabs), and growth and proliferation (growth factors) were particularly affected by zoledronate and fluvastatin, and some of these genetic effects were synergistic when a combination of zoledronate and fluvastatin was used. QRT-PCR confirmed the effects on the caspase- and p53-related apoptotic pathways, and these effects were correlated with increased apoptosis in the myeloma cells. The mevalonate pathway inhibitors fluvastatin and zoledronate are highly efficient at killing MM cells, and their effects appear to be synergistic. Our microarray and QT-PCR analyses demonstrated that the expression of specific groups of genes important to the survival and proliferation of myeloma cells are affected by these compounds. p53 and caspase-dependent pathways appear to be the key apoptotic cascades stimulated. Insights into the mechanisms of these novel therapeutics are important as they might help to define their roles in the treatment of multiple myeloma.
Cytogenetic Abnormalities in Histologically Confirmed Multiple Myeloma.
Authors: Mohamed Anwar N. , Bentley Gail , Bonnett Michelle L. , Palutke Margareta , Al-Katib Ayad M. 
Published: April 2020

Abstract
In multiple myeloma, conventional cytogenetics is limited by low proliferation activity of plasma cells in culture. Despite that, nonrandom chromosomal abnormalities have been reported in one third of cases. Recently, the karyotype has emerged as an important prognostic factor in multiple myeloma. In this study, we identified 104 histologically confirmed multiple myeloma cases with satisfactory cytogenetic evaluation and abnormal karyotype. FISH analysis was used to evaluate certain chromosome abnormalities or to monitor treatment response. Hyperdiploid karyotype was found in 67 cases (64%), hypodiploid in 25 cases (24%), and the remaining 12 cases (12%) had a pseudodiploid karyotype. The most common numerical abnormalities were gains of chromosomes 9, 15, 3 followed by chromosomes 19, 21, 11, 7, and 5. Whole chromosome losses were also frequent involving primarily chromosomes 13, 8, 14, 22, and 16. In the hypodiploid cases, loss of chromosome 13 was more evident, seen in 19/25 (76%) cases. Most cases showed also structural rearrangements leading to del(1p), dup(1q), del(6q), del(9p), del(13q), del(17p), del(8p), 3p/3q abnormalities, and 11p/11q abnormalities. Translocations affecting 14q32/IGH region was the most frequent seen 36 times in 34/104 (33%) cases; t(11;14)(q13;q32) in 13 cases, t(1;14), t(6;14), and t(8;14) in 2 cases each, and the remaining cases had various t(V;14) partners or of an undetermined origin. The 14q32/IGH translocations were less frequent in the hyperdiploid karyotypes than the hypodiploid and pseudodiploid karyotypes (18% vs 60%). Nine cases showed break at 8q24/CMYC site; six of those had Burkitt’s-type translocations. Other non-random translocation was t(1;16) seen in three cases. Coventional cytogenetic remains an important tool in elucidating the complex and diverse genetic anomalies of multiple myeloma. Acccordingly well defined cytogenetic subgroups can be identified. At the present time, FISH and other molecular genetic techniques are important adjuncts, but should not be a substitute for conventional karyotyping. The clinical and hematological correlates of the karyotype in our series is being evaluated.
Prognostic Relevance of CD56 Expression in Patients with Multiple Myeloma Treated with High-Dose Melphalan-Based Chemotherapy and Autologous Stem Cell Transplant.
Authors: Yeung Joanna , Samiee Sara , Yi Qi Long , Pantalony Dominic , Chang Hong 
Published: April 2020

Abstract
CD56 is a neural adhesion molecule and expressed in 70–80% cases of multiple myeloma (MM). Lack of CD56 expression has shown to be a poor prognosis in MM patients treated with conventional chemotherapy, but its prognostic relevance in MM treated with high dose chemotherapy and autologous stem cell transplant (ASCT) is not known. CD56 expression was evaluated by immunohistochemistry on bone marrow paraffin embed specimens from 107 MM cases undergoing Melphalan-based high dose therapy and ASCT. The 66 men and 41 women had a median age of 54 years. 53 patients had an IgG paraprotein, 30 IgA, 4 IgD, 15 light chain disease and 5 were nonsecretory. The median post-transplant follow-up was 20 months. Of 107 MM patients, 76 (71%) were CD56 positive and 31 negative. 27 died during the follow-up period including 7(23%) in CD56 negative and 20 (26%) in CD56 positive group; 50 were in relapse including 11 (35%) in CD56-negative, and 39 (51%) in CD56 positive group. The median overall survival for the CD56 positive patients was 48.1 months and for the CD56 negative patients, 44.8 months (p=0.67). The median progression free survival of the CD56 positive patients was 25.8 months and for the CD56 negative patients, 33.1 months (p=0.28). CD56 negative myeloma was associated with bone lesions (69% for CD56 positive vs 90% for CD56 negative group, p=0.032). However, CD56 was not associated with other biological factors including age, sex, hemoglobin, calcium, albumin, c-reactive protein, beta-2 microglobulin, immunoglobulin isotype, stage of the disease or bone marrow plasmacytosis. Furthermore, there was no correlation between CD56 expression and genetic aberrations including deletions of 13q14, 17p13.1 (p53), translocations t(11;14) or t(4;14) as evaluated by fluorescence in situ hybridization (FISH). In contrast to reports of CD56 in myeloma treated with conventional chemotherapy, we found CD56 negativity does not confer a poor prognosis in our patients, suggesting Melphalan-based high-dose chemotherapy and ASCT may overcome the adverse influence of CD56 negative myeloma.
Differential Expression of Genes in Multiple Myeloma (MM) and Identification of Candidates to Targeted Therapy.
Authors: Felix Roberta S. , Vettore André L. , Yamamoto Mihoko , Almeida Manuella S.S. , Silva Wilson A. , Zago Marco A. , Colleoni Gisele W.B. 
Published: April 2020

Abstract
Considering the heterogeneity of genetic aspects related with MM pathogenesis, recent studies have been focused on prognostic factors that could define the best therapeutic approach for each case or to contribute for the development of new therapies. In this way, gene expression profiling analysis can be very helpful to define such prognostic factors. Serial analysis of gene expression (SAGE) allows not only the identification of genes expressed in a given tissue, but also their expression levels. Until now, there was no data of gene expression in normal or neoplastic plasmacytes in public SAGE databases.
Purpose: The aim of this study is to create two SAGE libraries using normal and neoplastic plasmacytes and to identify genes differentially expressed in MM.
Methods: Normal plasmacytes were obtained from palatine tonsils of children who underwent tonsillectomy. MM library was obtained from bone marrow plasmacytes of two IgGk newly diagnosed MM patients. Purified normal and neoplastic plasmacytes were obtained after magnetic sorting of CD-138-positive cells (MACS - Magnetic Cell Sorting of Human Cells, Miltenyi Biotec). Both SAGE libraries were obtained using the kit I-SAGE (Invitrogen), according to manufacture’s instructions.
Results: We generated 4,000 clones from each library and, after automatic sequencing, we got 29,918 tags from normal and 10,340 tags from tumoral libraries (corresponding to 8,241 and 2,359 unique tags, respectively). After comparison of unique tags expression levels, we selected 15 overexpressed (at least 10 times) genes in the MM library (ZFHX1B, XBP1, PIM2, LGALS1, RANBP2, HSPC132, PRDM2, DDX5, ARMCX3, LSM5, JUND, MAPKAPK2, SP140, KLF2 and NTN1). Once these genes are related with transcription, signaling, cell proliferation and/or apoptosis, they can have important role in the tumorigenesis process and may be possible therapeutic targets for MM control
Dual Roles of T/NK Immunomodulatory and Anti-Tumor Properties for Selected Herbal Medicines in Multiple Myeloma Therapy.
Authors: Fan Kei , Li George Q. , Yang Shihong , An Xin , Ma Guoyi , Roufogalis Basil D. , Joshua Douglas E. , Sze Daniel 
Published: April 2020

Abstract
Thalidomide is one of the current therapies for multiple myeloma (MM) which has multiple mechanisms on myeloma cells, bone marrow microenvironment, T cells and NK cells. Chinese herbal medicines have been used in the treatment of cancer and also have multiple pharmacological activities; however, there is a strong need for evidence-based scientific data to understand their anti-cancer mechanisms. The aim of this study is to integrate thalidomide and Chinese herbs to enhance the beneficial effects and minimize the side-effects of thalidomide. The melanins from an anti-cancer Chinese herb Ligustrum lucidum were extracted and tested. The dual roles of the herbal extracts on T/NK immunomodulatory and anti-tumor properties were investigated in the following three aspects:
Proliferation measured by both [3H] thymidine assays and CFSE assays; Cell survival measured by propidium iodide exclusion and trypan blue staining; and NK cytotoxicity using myeloma cell line 8226 as target cell labeled with CalceinAM, and peripheral blood mononuclear cells (PBMC) from healthy subjects as the source of effector cells.
It was found that in the [3H] thymidine assays, Ligustrum lucidum melanin (LLM) extracts exhibited both stimulatory effect on PBMC proliferation and inhibitory effects on myeloma cell line 8226 proliferation at the concentration of 0.02 to 20 μg/ml. The stimulatory effect on PBMC was also observed with CFSE assays when PBMC was incubated with LLM (20 μg/ml) for 2 days with a proliferated population of 33%, compared with thalidomide (5 μg/ml) 57%, and control, 12%. In the cell survival assay tumor cell line NK92-MI was completely inhibited by LLM (20 μg/ml). NK cytotoxicity assay showed the LLM (0.02 to 20 μg/ml) showed dose response increase of cytotoxic effects of NK cells from 50% to 70%, higher than 42% achieved by thalidomide (5 μg/ml). These results indicate that herbal medicine Ligustrum lucidum posses both T cell / NK cell immunomodulatory effects and anti-tumor effects to myeloma cells. Further works will be to determine the structure of the plant constituent and to assess the synergistic combinations of the active extracts and constituents with thalidomide in the cellular assays.