bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of Light-Chain Monoclonal Gammopathy of Undetermined Significance (LC-MGUS) among Olmsted County, Minnesota Residents Aged 50 Years or Greater.
Authors: Rajkumar S. Vincent , Kyle Robert , Plevak Matthew , Clark Raynell , Larson Dirk , Therneau Terry , Bradwell Arthur , Dispenzieri Angela , Melton L. Joseph , Katzmann Jerry 
Published: April 2020

Abstract
Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that carries a 1% per year risk of progression to multiple myeloma (MM) or related malignancy. The prevalence and natural history of MGUS, in which by definition intact immunoglobulin heavy chain (IgH) is expressed, has been well described. However, up to 20% of myeloma (MM) is characterized by complete lack of IgH expression (Light-chain MM); the prevalence of a corresponding precursor entity, light chain MGUS (LC-MGUS) has not been determined. We report the first prevalence estimates of LC-MGUS in the general population from a large, well-defined geographic population using modern laboratory techniques.
Methods: The cohort for this study was derived from one previously assembled by us to estimate the prevalence of MGUS (N Engl J Med2006;354:1362-9). The original cohort used to estimate the prevalence of MGUS consisted of 21,463 of the 28,038 enumerated residents aged 50 or over of Olmsted County Minnesota as of January 1, 1995. The sensitive serum free light chain (FLC) assay (The Binding Site Limited, Birmingham, U.K.) was performed on stored serum samples from these 21,463 persons. IgH expression was determined by immunofixation on all FLC results that had an abnormal kappa/lambda ratio (&lt;0.26 or &gt;1.65). LC-MGUS was defined as the presence of an abnormal FLC ratio and a negative immunofixation for IgH expression.
Results: Adequate stored serum samples were available in 20,733 (97%) of the 21,463 persons. To date, the FLC assay has been performed and results were available for analysis on samples from 16,637 persons. An abnormal FLC ratio was observed in 572 persons. IgH expression was detected in 255 of these cases on immunofixation; these persons are considered as having MGUS, and were excluded from the estimation of LC-MGUS prevalence. This resulted in 317 persons out of 16,637 who had an abnormal FLC ratio without evidence of IgH expression, resulting in an estimated prevalence of LC- MGUS of 2%. Of the 317 cases of LC-MGUS identified in this study, 217 were kappa and 100 were lambda; in 35 cases the presence of the corresponding monoclonal light chain was apparent on immunofixation. The median age of the cohort of LC-MGUS was 62 years; males=151, females =166. The involved FLC level ranged from 0.118–270.0 mg/dL. The FLC ratio ranged from 0.014–0.253 (lambda) and 1.67–511.01 (kappa). So far, progression to multiple myeloma has occurred in 4 patients, a rate much higher than what is expected based on the prevalence of myeloma in the general population. Two additional patients have developed CLL.
Conclusions: LC-MGUS is prevalent in 2% of the general population aged 50 years of age or older. The natural history of this disorder needs to be determined.
Impact of Whole-Body Magnetic Resonance Imaging on Staging in Patients with Newly Diagnosed Plasma Cell Disease.
Authors: Zoz Martin , Baldauf Andreas , Schipp Anne , Hillengass Jens , Ho Anthony D. , Goldschmidt Harmut , Hansmann Jochen , Moehler Thomas 
Published: April 2020

Abstract
INTRODUCTION: MRI has a high sensitivity in determining changes in bone marrow induced by metastatic disease or primary neoplasms of the bone marrow. Whole-Body Magnetic Resonance Imaging (WB-MRI) is a novel imaging technique that displays nearly the complete skeletal system in one exam. We investigated the differences between conventional skeletal survey and WB-MRI and their impact on staging of patients with newly diagnosed plasma cell disease.
METHOD AND MATERIALS: In 41 consecutive patients with newly diagnosed MGUS (n=5), Multiple Myeloma (n=34) or AL-Amyloidosis (n=2) conventional radiographs and WB-MRI (coronar T1 tse and T2 tirm sequences and sagittal T2 star sequences, 1,5 T MRI with parallel imaging, Siemens Avanto®) were performed. Radiographs and scans were evaluated for diffuse and focal bone marrow involvement in consent by two experienced radiologists blinded for patient name and study time. Staging was performed including clinical data according to the Salmon/Durie classification system and the Durie/Salmon PLUS classification system with inclusion of WB-MRI.
RESULTS: In 24 (59%) patients there were no lesions in conventional radiography or MRI. In 17 (41 %) patients results of MRI and conventional radiography were discrepant. 4 (10%) patients had lesions only in MRI, 3 (7%) only in conventional radiography and 10 (24%) in both techniques but in different localization. In 16 (38%) patients with radiological signs of osteopenia there was no diffuse infiltration in MRI or vice versa. We systematically analysed the consequences of WB-MRI on staging of patients based on the newly proposed staging system Durie/Salmon PLUS. Replacing conventional radiographs by WB-MRI resulted in reclassification of 12 patients. 3 patients were reclassified from MGUS or stage I into stage II or III. 9 patients were downstaged from stage III or II into stage I or MGUS.
CONCLUSION: WB-MRI is a valuable technique for the initial work-up of patients with Multiple Myeloma. In comparison with conventional skeletal survey there are often differing results with impact on clinical staging and influence on therapy decision. WB-MRI can give additional information in patients with unclear staging situation before onset of therapy. Further evaluation of WB-MRI within prospective studies is warranted in particular with respect to prognostic impact regarding overall prognosis as well as regarding local complications. Until then WB-MRI should be used complementary to conventional radiography or CT-techniques that provide accurate imaging of the bone.
Differential Effects of Hsp70 Inhibition within the Tumor and Microenvironment in Multiple Myeloma.
Authors: Braunstein Marc J. , Liu Na , Klueppelberg Uwe , Scott Craig , Behrman Shannon , Tamucin Can , Walter Peter , Wipf Peter , Brodsky Jeffrey , Batuman Olcay 
Published: April 2020

Abstract
Multiple myeloma (MM) remains fatal despite prolonged survival by recent advances in treatment, including the use of proteasome inhibitors. It has been proposed that proteasome inhibitors target MM by modulating the NF-κB pathway. Alternatively, proteasome inhibitors may target MM cells because the proteasome helps alleviate the unfolded protein response (UPR) that results from the accumulation of aberrant proteins in the endoplasmic reticulum (ER), which in turn may trigger apoptosis. Indeed, the UPR is induced in neoplastic plasma cells, possibly because of increased immunoglobulin (IG) synthesis that exceeds the protein folding capacity of the ER. Consequently, the degree to which inhibition of the proteasome induces apoptosis may be related to the concentration of unfolded light chains within the ER in MM. We therefore examined whether inhibition of a protein-folding mediator, the Hsp70 molecular chaperone, results in synergistic induction of MM cell apoptosis when combined with a proteasome inhibitor. To this end, the effects of MAL3-101, a novel inhibitor of Hsp70 function, both alone and in combination with a proteasome inhibitor (MG132) on three MM cell lines as well as primary patient MM cells were examined. Dose-response and time course studies in MM cell lines U266, RPMI-8226, and NCI-H929 showed increasing apoptosis and inhibition of proliferation after 16 hours of exposure to MAL3-101 (IC50: 0.9 μM) or to MG132 (IC50: 7 μM). Strikingly, when sub-effective concentrations of MG132 and MAL3-101 were combined, a strong, synergistic apoptotic response was observed in the NCI cell line after 16 hours, and synergistic effects were observed in all cell lines after 36 hours of exposure to the two drugs. Next, we studied MM cells and endothelial progenitor cells (EPCs) derived from the bone marrow of five untreated patients. These two cell populations, which were shown to bear clonotypic similarities, also showed sensitivity to dual targeting. However, these effects occurred at drug concentrations different than those found to be most potent in the cell lines. Moreover, semi-quantitative RT-PCR studies indicated that RPMI cells but not U266 cells exhibited a strong UPR induction after 16 hours of exposure to 7 μM MG132. These data correlated with the greater degree of IG secretion observed in RPMI cells compared to U266 cells as assessed by pulse-chase analysis. Taken together, these results suggest that the apoptotic response of MM cells via targeting the UPR and ER stress pathways may be dependent on basal protein production, including IG synthesis. Studies relating the secretion “index” to UPR induction and sensitivity to Hsp70 and proteasome inhibition in primary tumor cells as well as in microvascular cells from MM patients are ongoing.
Single Institution Study of Abnormalities Involving Chromosomes 13 and 17 Detected by Classical Cytogenetics and Fluorescent In Situ Hybridization in Myeloma and Their Relationship to Survival in Patients Undergoing Autologous Stem Cell Transplant.
Authors: Rajan Arun , Stein Constance , Gentile Teresa , Shah Chirag 
Published: April 2020

Abstract
Multiple myeloma is associated with a variety of chromosomal anomalies each of which may affect survival to varying degrees. Recent data indicate that patients with chromosome 13 and 17 anomalies have a poor prognosis. In the current single institution study we analyzed the presence of anomalies involving chromosomes 13 and 17 detected by classical cytogenetics (karyotype analysis) (CC) and interphase fluorescent in situ hybridization (FISH) in patients who underwent autologous stem cell transplantation for multiple myeloma and correlated this with mean survival. Our patients had undergone autologous stem cell transplantation between April 1998 and March 2006. Of the 79 patients studied, data on CC and FISH was available on 43 patients and 29 patients respectively. 34 of 43 patients had normal CC and 11 of 29 patients had normal FISH. The mean survival of patients with normal cytogenetics was 45.36 months and for those with a normal FISH result it was 50 months. 9 of 43 patients had an abnormal CC result and 18 of 29 patients had an abnormal FISH result. Mean survival with an abnormal CC result was 30.40 months compared to 40.83 months with an abnormal FISH result. Anomalies of chromosomes 13 and/or 17 were seen in 6 of 9 patients by CC and 15 of 18 patients by FISH. Mean survival in these two groups was 30.25 months and 42.80 months respectively. These results indicate that normal cytogenetics and fluorescent in situ hybridization results at the time of diagnosis are associated with favorable outcome. The presence of abnormalities detected by conventional cytogenetics is associated with poorer outcome, particularly for deletion 13q and deletion 17p. Patients with interphase FISH abnormalities for chromosomes 13 and 17 have better survival than those with abnormalities for these chromosomes detected by conventional cytogenetics. Abnormalities in conventional cytogenetics may suggest actively proliferating disease. Thus interphase FISH should not substitute for conventional cytogenetic analysis in the diagnosis of myeloma.
Bortezomib Therapy Response Is Independent of Cytogenetic Abnormalities in Relapsed/Refractory Multiple Myeloma.
Authors: Chang Hong , Trieu Young , Qi Xiaoying , Xu Wei , Stewart Keith , Reece Donna 
Published: April 2020

Abstract
Myeloma patients with unfavorable molecular cytogenetics have a poor prognosis irrespective of treatment with conventional chemotherapy or autologous stem cell transplant. To investigate whether bortezomib, a new proteasome inhibitor, is active in relapsed/refractory myeloma patients with genetic risk factors, we evaluated the outcome of 65 patients and correlated the clinical response with 13q deletion, translocations t(11;14) and t(4;14) and CKS1B amplification as detected by interphase cytoplasmic fluorescence in situ hybridization (cIg-FISH). Thirty-seven of 61 (61%) evaluable patients had an objective response to bortezomib with median progression free (PFS) and overall survivals (OS) of 9.5 and 15.1 months, respectively. Of 43 cases with evaluable bone marrows, cIg-FISH determination of del(13q), t(4;14), t(11;14) and CKS1B amplification was done on 40, 41, 41 and 37 cases and the frequency of their detection was 35%, 15%, 15%, and 32% respectively. Two different abnormalities coexisted in 12 patients: 13q deletion with CKS1B amplification in 7, t(11;14) with CKS1B amplification in 2, t(4;14) with CKS1B amplification in 1, 13q deletion with t(11;14) in 1 and 13q deletion with t(4;14) in 1 patient. There was no statistically significant difference in response to bortezomib for patients with or without 13q deletion (77% vs. 50%), t(4;14) (67% vs. 56%), t(11;4) (33% vs. 62%), or CKS1B amplification (67% vs. 57%). Furthermore, there was no statistically significant difference in PFS or OS following bortezomib therapy between patients with or without these molecular cytogenetic abnormalities. Our data suggest that, in this pilot study, bortezomib is an effective salvage therapy for refractory/relapsed myeloma, irrespective of genetic risk factors.
Radiation Recall Dermatitis after Bortezomib Therapy.
Authors: Amin Alpesh J. , Maroules Michael 
Published: April 2020

Abstract
Introduction: Radiation recall dermatitis (RRD) is an inflammatory skin reaction at a site of previous radiation therapy after the administration of a medication, usually a chemotherapeutic agent. A radiation recall reaction has not been previously reported with bortezomib.
Case Report: A seventy-year-old man with stage III IgD multiple myeloma was treated with bortezomib after previous treatments with pulse decadron and cyclophosphamide. The patient was treated ten years earlier for a chest wall sarcoma with a local resection and radiation therapy to the tumor bed. After receiving bortezomib therapy for multiple myeloma, the patient developed erythema, desquamation, and ulceration only at the site of radiation therapy ten years prior. The patient received a dose reduced second infusion, causing a similar reaction.
Discussion: RRD is an inflammatory skin reaction that develops in a previously irradiated area after administration of certain promoting agents, most often with chemotherapy. Unlike radiation enhancement, there may be a long interval between the eruption and the administration of the causative agent. A number of drugs have been associated with this phenomenon, particularly the anthracyclines. Bortezomib has not been previously described as a causative agent for RRD. Erythema is the most common sign, which may be painful. Vesiculation, desquamation, and ulceration have also been reported. Histologically, the involved areas reveal epidermal dysplasia, necrotic keratinocytes, mixed inflammatory reaction, and sometimes psoriasiform dermatitis. Dose reduction, and the use of corticosteroids have been used to prevent recurrence of RRD, although rechallenge with the same agent may not lead to RRD again. The pathogenesis of this local phenomenon is not well understood, although an idiosyncratic drug hypersensitivity reaction has been proposed.
Uptake of New Therapeutics in the Treatment of Multiple Myeloma (MM) in Germany (GER) - Results from a Representative Multicentre Treatment Survey 2006.
Authors: Angermund Ralf , Knauf W. , Freund M. , Nowrousian M. , Einsele H. , Goldschmidt H. , Berdel W. , Poenisch W. , Straka C. , Kellermann L. , Pliskat H. 
Published: April 2020

Abstract
Background: Over the past decade new treatment options and drugs significantly altered the treatment paradigm and treatment guidelines for patients with MM. We reported in 2005 initial results from a treatment survey in GER (Freund ASH2005# 5158; Angermund, ASH2005, #5156). Bortezomib (Velcade®, Vel) at that time (6 months (m) after approval) was the 2nd most frequently (freq) used drug after dexamethasone (dex) in the approved indication (3rd line) and played a minor role in 2nd line therapy. The survey performed in 1st quarter 2006 (1.5 years (y) after the initial survey), used identical methods and questionnaires. These results allow for monitoring of changes in treatment patterns.
Methods: The method of this representative analysis was provided elsewhere (Freund ASH2005# 5158). The data presented here are a subset analysis based on 66 sites and 428 patients.
Results: 230 male and 195 female patients, 43% at the time of analysis for decision on primary therapy, 27% for secondary treatment and 30% for further treatment were included in this analysis. The centers participating were 11% university hospitals (UH), 38% non-university hospitals with specialized (SH) and 20% without specialized (NSH) haematology department, and 32% office-based haematologists (OBH). The main treatment in primary therapy did not change (table) whereas Vel gets more commonly used. The increase in Vel in all treatment lines is mainly due to SH (64 (2006) vs. 52 % (2004); OBH: 32 (2006) vs. 32% (2004); NSH: 0 (2006) vs. 2 % (2004); UH 4 (2006) vs 14% (2004)). In 2nd line Vel was the 2nd most prescribed drug (31%) (1st dex 41%; 2004: Vel 8% ranked 10th) mainly in UH/SH in patients below 60 y and after primary high dose chemotherapy (HDCT) (35% Vel vs. 28 % all) and with longer remission period (median 9 m Vel, median 7 m all). Within treatment ≥ 3rd line, Vel was the most freq used drug followed by dex (42% and 38% respectively). For patients currently in 1st remission Vel was most freq planned as next therapy (45%) followed by lenalidomide (len) (19%) and dex (12%). Vel was mostly used by SH following melphalan or VAD/VID treatment (multivariate analysis). Len and thalidomide (thal) (both drugs not approved in GER at that time) are rarely used in MM therapy (0% len vs. 10% thal in ≥ 2nd line).
Conclusion: New approved treatment options like Vel are quickly integrated into treatment behaviour in GER, mainly used in SH within approved indication, whereas not approved drugs like len or thal play only a minor role. 9 m after approval for 2nd line therapy, Vel increased uptake within ≥ 2nd line indicating this drug’s possibility to become a future treatment standard in pretreated patients. In order to detect the dynamic of change of treatment of MM, further follow up is planned.
Renal Recovery Following Light Chain Removal by Extended Haemodialysis in a Patient with Cast Nephropathy.
Authors: Hutchison Colin A. , Cook Mark , Bradwell Arthur R. , Cockwell Paul 
Published: April 2020

Abstract
Cast nephropathy is the main cause of renal impairment in patients with multiple myeloma (MM). Serum free light chain (sFLC) removal by extended hemodialysis on a protein leaking membrane may aid renal recovery. A patient presenting with MM, high serum FLC concentrations and dialysis dependent acute renal failure was studied. A renal biopsy showed monoclonal kappa FLC cast nephropathy. He was dialysed for 2–8h on daily / alternate days using the Gambro HCO 1100 dialyser. sFLC were measured at frequent intervals in the serum and dialysate fluids. Albumin and urea concentrations were measure pre- and post-dialysis. Over 22 days the patient underwent 14 dialysis sessions with an average sFLC reduction of 38% (15.2–61.8%). A total of 16.5g of kappa was removed in the dialysate fluid with an average concentration of 18.3mg/L (3.3–27.3). Figure 1 demonstrates serum reductions in kappa concentrations pre- and post-dialysis and timing of chemotherapy. The average serum reductions were: albumin 2.1g/L, urea 56% and creatinine 44%. By day 22 the patient was independent of dialysis. Four months later renal function is stable with an eGFR of 35ml/min (Cockcroft-Gault). Further studies are needed to determine whether this method would benefit many patients with acute renal failure and light chain cast nephropathy.
Figure Figure
Identification and Characterization of Cancer Stem Cells in Multiple Myeloma.
Authors: Sze Daniel , Loh Yen S. , Mo Suilin , Kaplan Warren , Brown Ross D. , Ho Phoebe Joy , Gibson John , Joshua Douglas E. 
Published: April 2020

Abstract
There is increasing evidence that the Cancer Stem Cell (CSC), a small percentage of cancer cells that have the characteristic to self-renew, proliferate, differentiate and replenish the bulk of the tumor, may be the leading cause of cancer relapse after chemotherapy. A distinct subpopulation within cancer cells known as the side population (SP), distinguished via Hoechst 33342 staining, has been repeatedly reported to be enriched with cells possessing CSC characteristics. In this study, we first examine if SP can be identified in four established myeloma cell lines. Hoechst-33342 stained cells were analyzed through FACS LSRII using a blue and red dual-wavelength analysis after UV excitation to detect the important red-blue differential dye emission feature of the SP cells. An average of 26.5% of SP cells was found in RPMI8226, 21.4% in KMS-11, 5.4% in U266 and 10.1% in OPM-2 within the viable cells compartment in four separate experiments. In addition, 4.9% of SP cells were also identified in the plasma cell leukemia cell line ARH77.
SP and non-SP cells of RPMI8226 and KMS-11 were then sorted and respective RNAs were extracted, amplified and labeled for subsequent Affymetrix microarray scanning. The gene-expression profiles of SP and non-SP cells from RPMI8226 and KMS-11 were compared before selecting statistically significant genes of interest. Two genes were found to be highly upregulated in SP cells. The first one was the Receptor for Hyaluronan-Mediated Motility (RHAMM) gene of 29.0 and 3.9 fold increase in RPMI8226 and KMS-11 respectively. Increased expression of RHAMM has been previously reported to correlate with human B cell malignancies. The second upregulated gene was the human inhibitor of apoptosis protein-family gene, Apollon, of 4.4 and 3.2 fold increase in RPMI8226 and KMS-11 respectively. Another gene - interferon gamma receptor 1 (IFNGR1) gene was found to be down-regulated in SP cells, of 4.3 and 1.2 fold decrease in RPMI8226 and KMS-11 that may provide an explanation of their escape from immune response via T cells.
We then examine if SP cells that represent putative CSC exist in primary myeloma cells. Seven myeloma patients’ bone marrow samples were investigated and 0.1 to 5.2 %, of an average of 1.4% of SP cells were identified in the CD38++ plasma cells compartments in 6 out of 7 bone marrow samples. This study reports the existence of SP in both myeloma cell lines and primary myeloma cases. Further studies will be required to confirm the protein expression of selected genes selected from the gene-expression profiles of SP versus non-SP from myeloma cells for the insights into the characteristic and tumorigenicity of CSC in myeloma.