bluuebunny/crossref_metadata_2025_split huggingface dataset:
Striking Coincidence of IgD M-Protein and Translocation t(11;14) in Hungarian Myeloma Patients.
Authors: Mikala Gabor , Adam Emma , Kozma Andras , Kapas Balazs , Nahajevszky Sarolta , Masszi Tamas 
Published: April 2020

Abstract
Multiple myeloma exhibiting production of IgD M-protein is a rare subset (appr. 1 %) of all patients. Translocation t(11;14) is, on the other hand, the most common primary translocation in myeloma that involves the IgH locus and cyclin D1, approximately 16–22% of all patients harbor this genetic rearrangement. This cytogenetic abnormality has been previously associated with nonsecretory behavior and also with production of IgE M-protein. Out of 317 myeloma patients treated in our department in 2004–2006, five patients had IgD M-protein (four belonged to IgD-lambda and one to IgD kappa subtype). Cytogenetic analysis by interphase fluorescent in situ hybridization (FISH) revealed the presence of the IgH/Cyclin D1 abnormality in all five of them (100%), while the prevalence of this translocation was 17% in the entire myeloma population seen by our ward and tested by FISH (132 patients). One IgD patient had a complex IgH/MYC/CyclinD1 translocation, also confirmed by conventional cytogenetic analysis of metaphases, while two of five patients had additional copies of IgH and Cyclin D1 genes, possibly indicating atypical translocations and/or hyperdiploidy. Although the number of patients with this rare disease in our report is low (5), we find the uniform presence of translocation t(11;14) a striking occurrence that may explain some of the unusual biological properties of this myeloma subtype.
Ex Vivo Anti-Tumor Activity of Rosiglitazone on Multiple Myeloma Cells.
Authors: Huang Haiwen , Wu De Pei , Leung Anskar Y.H. , Liang Raymond , Lie Albert K.W. 
Published: April 2020

Abstract
Peroxisome proliferation activated receptor-g (PPAR-g) belongs to the family of nuclear hormone receptors (NHRs), it is normally expressed in adipocytes, adrenal gland, spleen and liver. Recently it was reported that PPAR-g can also be found in tumor tissues. Activation of PPAR-g by its ligands has potential anti-neoplastic effects in a variety of human malignancies, including leukemia through inhibition of cell proliferation, induction of apoptosis and terminal differentiation. The ligands of PPAR-g may represent a promising, novel therapeutic approach for certain human malignancies.
The thiazolidinedione (TZD) class drug rosiglitazone (RGZ), one of synthetic ligands of PPAR-g, is currently used for the treatment of type 2 diabetes. In this study, we cultured myeloma cell line U266 with different concentration of rosiglitazone, as well as combined with dexamethasone. Cell proliferation was measured by [3H] thymidine incorporation after 48h incubation. Rosiglitazone was found to generate inhibition of cell proliferation on U266 cells in a dose-dependent manner. Cell cycle analysis by flow cytometry showed that rosiglitazone can arrested U266 cells in G0/G1 phase and the G2/M phase cells were significantly decreased compared to controls. We also studied the effect of rosiglitazone on expression of different anti-apoptosis protein FLIP and survivin by RT-PCR, the result revealed that rosiglitazone can also decrease the FLIP and survivin expression. Furthermore, exposure to rosiglitazone can induce the decreased caspase-3 activity in U266 cells, which was associated with apoptosis induction. When rosiglitazone was combined with dexamethasone, the data demonstrated that cell growth inhibition and apoptosis they exerted was much greater than they were used alone, the decreased expression of FLIP and survivin and decreased caspase-3 activity were also greater than when rosiglitazone was used alone. Based on these findings, we suppose that rosiglitazone alone and in combination with dexamethasone holds promise as novel therapy for myeloma.
Monoclonal Gammopathy as a Determinant of Adverse Outcomes in Patients with Chronic Kidney Disease.
Authors: Hutchison Colin A. , Townend John , Mead Graham P. , Chandler Katie , Harper Jo , Bradwell Arthur R. , Zakeri Rosetta , Cockwell Paul 
Published: April 2020

Abstract
Elevated serum free light chain (sFLC) concentrations are associated with glomerular and tubulointerstitial disease. We have analyzed a cohort of patients with chronic kidney disease (CKD) to determine the relationship between sFLC and clinical outcomes. 369 patients from the renal clinics at the Queen Elizabeth hospital in Birmingham were followed for a period of 8 years. We reviewed renal outcomes and all cause mortality over this period. sFLC levels were measured on baseline serum samples using a nephelometric immunoassay (The Binding Site Ltd.). The CKD patients had mean sFLC concentrations significantly higher than the normal population (kappa: 77 vs. 8.4mg/L p&lt;0.0001; lambda: 94.7 vs. 13.4mg/L p&lt;0.03). 65 patients (18%) had abnormal sFLC ratios suggesting clonal production of sFLC. There were 270 endpoints during follow-up (106 deaths and 164 end stage renal failures). By Kaplan Meier survival analysis an abnormal sFLC ratio is significantly associated with a worse composite outcome (p&lt;0.02), with the dominant factor being the progression of renal impairment to end stage disease. This is the first study to assess if an abnormal sFLC ratio is predictive of outcomes in patients with CKD. These findings provide the basis for further work to evaluate whether monoclonal FLCs are prognostic of a worse outcome in patients with CKD.
Incidence, Clinical Presentation and Outcome of Secondary Multiple Extramedullary Plasmacytomas: Experience at Roswell Park Cancer Institute.
Authors: Manochakian Rami , Miller Kena C. , Coignet Jean-Gabriel , Padmanabhan Swami , Musial Laurie , DePaolo Dawn , Chanan-Khan Asher Alban 
Published: April 2020

Abstract
Introduction: Extramedullary plasmacytomas are malignant plasma cell tumors that arise outside of the bone marrow. They occur either as solitary tumors with a cure rate of over 95% with radiation therapy alone; or they may present as manifestations of advanced metastatic multiple myeloma, referred to as secondary extramedullary plasmacytomas (SEP). SEP usually present as multiple tumors, primarily in the head and neck area and often after multiple relapses in MM patient. Although the etiology of multiple SEP remains unknown, they are reflective of clinically advanced disease that no longer relies on the bone marrow microenvironment. The incidence, clinical outcome and natural history of SEP are not clearly delineated in the literature. With the recent use of novel therapies (thalidomide, lenalidomide, bortezomib) resulting in prolonged survival we have noticed an increase incidence of patients relapsing with SEP at our institute. This observation prompted us to formally evaluate SEP to characterize the clinical pattern of presentation, clinical course and correlation with use of novel therapies of SEP.
Methods: This is a single institute retrospective review. All patients seen at our institute with the diagnosis of MM were evaluable. Data was queried since 1990, which included a total of 343 patients.
Results: To date 100 patients have been reviewed and among these, 20 patients (20%) were noted to have SEP. Characteristics of these patients are outlined in details in table (1). 14 patients (70%) remain alive. However, none achieved a complete remission after the diagnosis of SEP.
Conclusion: In this study, the overall incidence of SEP was 20% on the patients so far evaluated. Majority of SEP patients have received prior novel agents. Systemic treatments seem to be effective in controlling progression of SEP though achievement of CR status has not been possible with current therapeutic interventions. Our finding are intriguing as the incidence of SEM seems to be increasing, which may reflect either unveiling of the natural history of the disease through improved survival from the use of novel agents, or this may be reflective of a change in the biology of MM.
We intend to present the complete analysis of all cases at the meeting.
Characteristics of patients with secondary plasmacytoma Characteristics Sex 8 (40%) and 12 (60%) F Age Median: 66, Range(46–86) Stage 16(80%) stage III and 4(20%) &lt; stage III Type 9(45%) IgG,6(30%) IgA, 4(20%) Free Light Chains and 1 (5%) nonsecretory Prior treatments 19(95%) had prior Thalidomide or Bortezomib,17(85%) had prior Thalidomide and12(60%) had prior Bortezomib Locations of Plasmacytomas 5(25%) Head&Neck,7(35%) Paraspinal, 2(10%) Abdomen,4(20%) Thorax and 2(10%) at other locations
Bone Marrow Fibrosis Is a Negative Predictor for Osteolytic Lesions in Patients with Myeloma.
Authors: Paneesha Shankaranarayana , Pol Raj , Chachlani N. , Pratt Guy , Rose Peter , Borg Anton 
Published: April 2020

Abstract
Multiple myeloma is a clonal lymphoproliferative disorder characterised by proliferation of plasma cells in marrow and is associated with an unbalanced bone remodelling leading to osteolytic lesions. Bone marrow interstitial fibrosis is common in myeloma. Correlation of marrow fibrosis with clinical parameters and survival in patients with myeloma is conflicting. We have analysed the impact of marrow fibrosis at presentation in 83 (F: 45; M: 38) patients with median age 67 yrs on osteolytic lesions and survival. Reticulin silver impregnation is employed as standard matrix stain. H & E slides were reviewed for degree and pattern of plasma cell infiltration. Marrow reticulin was quantified from Grade 0–4. 50 had IgG myeloma, 15 had Ig A myeloma, 13 had LC myeloma, 2 had Ig D myeloma and PCL and one had Ig M myeloma. Median marrow plasma cell count was 60%. 42% had increased marrow reticulin (&gt; grade2). 33 received VAD, 16 melphalan and prednisolone, 7 dexamethasone, 6 cyclophosphamide, thalidomide, dexamethasone, 6 cyclophosphamide, 4 thalidomide, 1 dexamethasone and thalidomide combination and 10 only bisphosphonates as initial therapy.
Haemoglobin &lt; 10 gms/dl was in 47% patients. 67% were positive for BJP. 33% had hypercalcaemia. 51% had &gt;2 osteolytic lesions at diagnosis. 55% had β2-microglobulin &gt;4mg/L and 22% had renal failure at diagnosis. 47% needed more than one line of therapy. Marrow reticulin was a negative predictor for osteolytic lesions (Fisher’s Exact test; p: 0.001). Marrow reticulin didn’t correlate with other laboratory parameters. Marrow reticulin, sex, BJP & number of osteolytic lesions at diagnosis did not impact on OS (Log Rank test p values: 0.6, 0.07, 0.6 & 0.4 respectively). Known poor prognostic markers Hb &lt;10gm/dl, hypercalcaemia, renal failure and elevated β2-microglobulin were associated with poor OS (Log Rank test p values: 0.02, 0.04, 0.004 & 0.002 respectively) with median follow-up 27 months. Number of osteolytic lesions and anaemia at diagnosis had impact on progression free survival (Log Rank test; p values: 0.01 & 0.02 respectively) where as raised β2-microglobulin, marrow reticulin, hypercalcaemia and renal failure (Log Rank test; p values: 0.07, 0.7, 0.9 & 0.35 respectively) had no impact. Marrow reticulin also had no effect on requirement for more than one line of therapy (p value: 0.17).
Marrow reticulin is a negative predictor for osteolytic lesions, even though it does not appear to impact on survival in patients with myeloma. Our study also confirms the poor prognostic role of anaemia, hypercalcaemia, renal failure and raised β2-microglobulin in patients with myeloma. Further study of the hepatocyte growth factor/c-Met interaction may identify the negative correlation between marrow fibrosis and osteolytic lesions. This may enhance understanding of skeletal prophylaxis in patients with myeloma.
Combination of the Proteasome Inhibitor Bortezomib and a Histone Deacetylase Inhibitor PXD101 Results in Synergistic Inhibition of Osteoclastogenesis and Significantly Stronger Inhibition of Multiple Myeloma Growth In Vitro and In Vivo.
Authors: Feng Rentian , Oton Ana B. , Patrene Kenneth , Anderson Gulsum , Mapara Markus Y. , Belani Chandra , Roodman David , Lentzsch Suzanne 
Published: April 2020

Abstract
Bortezomib, a proteasome inhibitor, has been known to have in vitro and in vivo activity against multiple myeloma (MM). PXD101, a novel, low molecular weight histone deacetylase (HDAC) inhibitor recently has been recognized to induce growth arrest and apoptosis in MM cells. We hypothesized that these two agents, with different molecular targets, can be combined with a high probability of additive or synergistic effects without exerting cross-resistance.
In this study, we investigated the activity of the combination of PXD101 and bortezomib against osteoclast generation and MM cell growth. To evaluate the effects of bortezomib and PXD101 on the formation of osteoclasts from mononuclear hematopoietic precursors, we generated osteoclasts cultured from human bone marrow cells from healthy donors and MM patients using in vitro RANKL/M-CSF stimulation. Proliferation of MM cell lines treated with PXD101, bortezomib, or their combination was determined by measuring 3H-Thymidine incorporation. Annexin V-FITC/PI staining was used to determine the degree of apoptosis, and trypan blue was used to assess cell viability. We utilized a xenograft murine model to test the in vivo synergistic activity of the two agents against MM tumor formation.
We found that even though either drug alone significantly inhibited osteoclast formation at concentrations of PXD101 at 25 nM or bortezomib at 1 nM, the combination resulted in synergistic inhibition in osteoclast assays. Treatment of MM cells lines (MM.1S, RPMI-8226, OPM2) with serial dilutions (10–100 nM) of the combination also led to significantly stronger inhibition of proliferation, apoptosis and cell death than single drug treatment. In addition, the combination demonstrated synergistic induction of cell death in primary human CD138+ myeloma cells isolated from patient samples. In vivo, the combination of PXD101 and bortezomib resulted in significantly higher xenograft tumor inhibition compared to either drug treatment alone and was not more toxic.
The current study provides the rationale for clinical evaluation of this novel PXD101-bortezomib combination for patients with MM. The data generated here support the hypothesis that simultaneous targeting of different proliferative and anti-apoptotic pathways both in tumor cells and activated osteoclasts avoids cross-resistance and constitutes a dynamic approach to treat MM.
Physical and Functional Association of the MRN Complex with Human Telomerase in Multiple Myeloma.
Authors: Driscoll James J. , Bertheau Robert C. , Shammas Masood A. , Prabhala Rao H. , Anderson Kenneth C. , Munshi Nikhil C. 
Published: April 2020

Abstract
Telomerase is a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon malignant transformation. There is abundant evidence that the regulation of telomerase is multifactorial in mammalian cells, involving telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Initial experiments indicated that the catalytic subunit(s) of human telomerase (hTERT) is highly elevated in Multiple Myeloma (MM) cell lines and MM patient samples relative to normal donor plasma cells. We then exploited this highly detectable level of hTERT to address the potential role of proteins that may physically associate with the telomerase complex in MM. To this end, we investigated whether the MRN complex, a trimeric structure that consists of Mre11, RAD50 and Nbs that is evolutionarily conserved and functions in DNA repair and homologous recombination physically associates with the human telomerase complex. The MRN complex is required in vivo for a 5′ to 3′ exonuclease activity that mediates DNA recombination at double-strand breaks (DSBs). We have observed that each of the three MRN components was associated with the catalytic subunit of human telomerase (hTERT) in MM cell lines as demonstrated by in vivo co-immunoprecipitation with an hTERT monoclonal antibody under non-denaturing conditions. In addition, polyclonal antibodies to each MRN component individually immunoprecipitated the hTERT catalytic subunit. We also detected that the telomerase complex accessory proteins TRF-1 and TRF-2 are also associated with hTERT and the MRN components. TRF-2 may function as bridge coupling hTERT to the MRN complex. The association of the MRN components with hTERT was increased following treatment of myeloma cells with DNA-damaging agents indicating a functional relationship between telomere maintenance and the DNA repair pathway. The functional role of this complex is being addressed by measuring telomerase activity, telomere length and homologous recombination activity. Based upon the data that abolition of exonuclease activity in MRN mutants resulted in shortened telomeric DNA tracts, we hypothesize that this elevated MRN complex expression and its interaction with hTERT in myeloma, provides the ability to maintain telomeres and may be an important therapeutic target in MM.
Osteonecrosis of the Jaw in Multiple Myeloma Patients. Experience of Two Hospitals.
Authors: Garcia-Garay Carmen , Gonzalez-Garcia Consuelo , Majado Maria Juliana , Santos Tomasa , Borrego Domingo 
Published: April 2020

Abstract
Introduction of bisphsophonates (BPs) treatment has changed the history of bone symptoms in multiple myeloma (MM) patients, as well as in metastasic cancers (MC). However, osteonecrosis of the jaw (ONJ) has been recently described in these patients. No clear mechanism is known, although length of BPs treatment, as well as dental procedures, have been argued as possible causes. We reviewed MM patients treated with BPs from two hospitals, in the last 7 years, with the aim of studying the incidence on ONJ and their correlation with: kind of BPs administered, time of treatment and dental procedures. MC patients treated with BPs were also reviewed in order to establish the influence of the disease in ONJ development. Non-parametric Mann-Whitney U-test was used in statistical analysis. From January 1999 to June 2006 a total of 225 MM patients were diagnosed in our two hospitals, 143 of them received BPs: 49 pamidronate (P) only, 64 zoledronic acid (Z) only, and 30 received P and Z (PZ) sequentially. P was administered at a doses of 90 mg every 4 weeks, and Z at a doses of 4 mgr every 4 weeks. 14 MM patients treated with BPs suffered ONJ: one patient (2%) treated with P, six (9,3%) with Z, and seven (23.3%) in the group receiving PZ. In the same period of time 353 MC patients were treated with BPs, two of them (0.6%) developed ONJ. Length of treatment, expressed in months, is shown in the table (in MC patients, only Z group was analyzed).
Months of treatment Diagnosis P Z PZ Total Expressed as median and range. MM without ONJ 22.5 (4–52) 9.5 (1–28) 38 (12–72) 14 (1–52) MM with ONJ 28 12 (7–28) 43.5 (24–59) 28 (7–59) MC 8 (1–41)
The longest administration of treatment was in PZ patients compared with P and Z(p&lt;0.02), followed by P group that was longer than Z group (p&lt;0.01). No difference was found between MC and MM groups in Z treatment length, neither between patients with and without ONJ inside each Z and ZP groups. Five ONJ patients suffered from dental procedures along BPs administration. In our series the incidence of ONJ is higher than that described in literature (4–10%), and it is very surprising the elevated incidence reached in patients treated with both BPs (23%). In our opinion, coincidental with other authors, the lasting of treatment might be one, but not the only, important factor, because in patients receiving P treatment duration was longer than Z but, ONJ incidence was lesser. For this reason we think that more potent BPs might have a role in ONJ development. Since MC patients receiving the same schedule of treatment with Z than MM do not develop ONJ so frequently, so it seems that the disease itself might play a role in ONJ incidence.
Velcade as Retreatment of Multiple Myeloma Patients Previously Responsive to Velcade.
Authors: Petrucci Maria Teresa , Gallucci Cristiano , Federico Vincenzo , Del Bianco Patrizia , Foa Robert 
Published: April 2020

Abstract
Velcade (bortezomib, PS 341) represents a novel class of anti-cancer drugs that, according to the randomized phase 3 trial (APEX) including 669 patients with relapsed multiple myeloma (MM), resulted more effective than high-dose dexamethasone as demonstrated by a significant improvement in response rate (43% vs 18%), median time to progression (6.2 vs 3.4 months) and 1-year survival rate (80% vs 67%, respectively). Its use in addition to dexamethasone in patients who had suboptimal responses to velcade alone has been associated with an improvement in responses without prohibitive toxicity, suggesting that the combination of these two drugs can overcome drug resistance. This agent is highly effective on extramedullary plasmacytomas and usually induces a very rapid response (after 1 or 2 cycles), independently of the previous therapies used. To evaluate the possibility of re-inducing a response in relapsed patients previously treated with velcade, we re-treated 3 patients with the same drug at 1.3 mg/m2 administered on days 1, 4, 8 and 11 of a 21-day treatment cycle for 8 cycles and dexamethasone 20 mg on the day of and on the day after each velcade dose. The patients (2 females and 1 man) previously treated with velcade as single agent after 47, 54 and 93 months, respectively, from diagnosis and after more than two lines of previous therapy, obtained a very good response without a complete disappearance of the monoclonal component. They were thereafter observed and re-treated with the same drug plus dexamethasone for a relapse documented after 7, 13 and 23 months, respectively. Velcade was well tolerated and the toxicity acceptable, without additional adverse events compared to the first administration. No patient experienced a herpes zoster reactivation and all side effects were typically reversible and disappeared upon drug suspension. Response was very rapid with a &gt;50% decrease of the monoclonal component after 3, 4 and 5 cycles, respectively. It can be hypothesized that velcade, which offers great promise to overcome resistance to conventional chemotherapy, may not be susceptible to the most common drug resistance mechanisms. Based on the chronic nature of MM, drugs with documented efficacy, absence of cumulative toxicities and which do not develop resistance following repeated treatment are required. The responses observed in our relapsed MM patients who received velcade for the second time are encouraging. A longer follow-up and a greater number of patients will conclusively confirm the true efficacy of velcade as re-treatment drug. Updated results on a larger number of treated patients will be available at the time of presentation.