bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of Bortezomib Increases Osteoblast Function in Patients with Multiple Myeloma.
Authors: Heider Ulrike , Kaiser Martin , Müller Christian , Schulz Carsten-Oliver , Jakob Christian , Zavrski Ivana , Eucker Jan , Sterz Jan , Kleeberg Lorenz , Possinger Kurt , Sezer Orhan 
Published: April 2020

Abstract
Myeloma bone disease is caused by an enhanced osteoclast activation and impaired osteoblast function. Until now, there is no specific treatment to restore osteoblast activity, and anti-myeloma therapies that lead to a disease remission are usually not associated with an increase of osteoblast markers. Recently, preclinical data suggested that proteasome inhibitors may enhance osteoblast function. Bortezomib (Velcade) represents the first substance from this group which is clinically used in relapsed multiple myeloma. To evaluate whether there is clinical evidence for an osteoblast stimulation under bortezomib treatment, we analyzed serum levels of two specific osteoblast markers, i.e. bone-specific alkaline phosphatase (BAP) and osteocalcin, in 25 multiple myeloma patients treated with bortezomib alone or in combination with dexamethasone. 56 percent of patients achieved a complete or partial remission. In the whole group of patients, mean serum levels of osteocalcin significantly increased from 6.3 μg/l before treatment to 10.8 μg/l after three months of therapy (P=0.024). In parallel, mean levels of BAP increased from 19.7 U/l to 30.2 U/l (P&lt;0.0005). The increase in BAP was irrespective of the combination with dexamethasone and was noted both in responders and in non-responders. This is of special interest, since it implicates that the increase in osteoblast function may be a direct effect of bortezomib on osteoblasts and not an indirect consequence of the reduced myeloma burden. Proteasome inhibition may modulate the Wnt/b-catenin pathway, a major signalling pathway in osteoblasts. Myeloma patients with osteolytic lesions have been shown to overexpress DKK-1, an inhibitor of the Wnt/b-catenin pathway. Recent experiments on mesenchymal cells showed that proteasome inhibitors decreased the DKK-1 production. Moreover, proteasome inhibition elevates cytoplasmatic b-catenin levels by inhibition of its degradation. In addition, animal models gave evidence that proteasome inhibitors stimulate the bone morphogenetic protein (BMP)-2 mediated osteoblast differentiation. Taken together, these preclinical observations suggest that proteasome inhibition may enhance osteoblast activity. Our study gives clinical evidence for a significant improvement of osteoblast function under bortezomib. This is of special interest, since it demonstrates additional effects of proteasome inhibitors and may provide a novel treatment approach in myeloma bone disease.
Open-Label Study of Ibandronate in Elderly Myeloma Patients with Pre-Existing Renal Deterioration.
Authors: Henrich Dirk , Bergner Raoul , Hoffmann Martin , Honecker Andrea , Nagel Dietmar , Uppenkamp Michael 
Published: April 2020

Abstract
Bisphosphonates effectively reduce the number of skeletal-related events and relieve metastatic bone pain, improving quality of life in patients with malignant bone disease. However, clinical studies have highlighted that some, but not all intravenous (i.v.) bisphosphonates are associated with an increased risk of renal toxicity. The renal safety of bisphosphonates is particularly important in patients with multiple myeloma or in the elderly, who often have some degree of underlying renal damage and are at high risk of renal failure. In phase III trials, the renal safety profile of i.v. ibandronate was comparable to placebo. This agent may therefore be suitable for use in patients with impaired renal health. The current open-label study assessed the renal safety of ibandronate in elderly patients with multiple myeloma and varying stages of pre-existing renal impairment. Patients with multiple myeloma (creatinine clearance 8–139mL/min) received i.v. ibandronate (6mg, infused over 30 minutes). For each patient, deterioration in renal function was graded at baseline using creatinine clearance (grade 0: ≥80, 1: 50–79, 2: 30–49, 3: &lt;30mL/min). Urinary markers of tubular damage (α-glutathione-S-transferase [α GST] and β-N-acetyl-glucosaminidase [βNAG]) were measured at baseline and at 24 and 72 hours following ibandronate infusion. Follow-up toxicity data was collected over 6 months for a subset of patients (n=6). A total of 29 patients (15 females and 14 males; mean age 71.1 ± 5 years) were included in this study. At baseline, four patients had a normal renal function (grade 0). The remaining 25 patients had varying degrees of renal insufficiency (grade 1: n=6, grade 2, n=8, grade 3: n=11). Mean proteinuria was 1799 ± 2140mg/24 hours. Serum creatinine and levels of urinary markers (α GST and βNAG) remained stable throughout the study. There was a statistically non-significant decrease in βNAG, and a positive correlation between ibandronate elimination and creatinine clearance. In the subset of six patients receiving six additional monthly infusions, ibandronate had no negative impact on renal function. To conclude, in this study of elderly patients with multiple myeloma, ibandronate was well tolerated and did not compromise renal health, despite 86% (25/29) of patients having pre-existing renal insufficiency. This was evidenced by markers of tubular damage and renal function, which remained unchanged throughout the study period. Furthermore, a subset of patients who received repeated ibandronate infusions did not experience renal toxicity. The management of drug-related nephrotoxicity needs special attention in patients with multiple myeloma, and in the elderly. These data suggest that ibandronate may be suitable for use in high risk multiple myeloma patients with pre-existing renal impairment. Further studies in larger groups of patients are warranted.
Bisphosphonates and Osteonecrosis of the Jaws: Incidence in a Homogeneous Series of Patients with Newly Diagnosed Multiple Myeloma Treated with Zoledronic Acid.
Authors: Tosi Patrizia , Zamagni Elena , Cangini Delia , Tacchetti Paola , Offidani Massimo , Ronconi Sonia , Perrone Giulia , Ceccolini Michela , Baccarani Michele , Tura Sante , Cavo Michele 
Published: April 2020

Abstract
Osteonecrosis of the jaws (ONJ) is a rare complication that has been described as osteoradionecrosis in patients who had previously undergone radiotherapy for head and neck cancer or similar disorders. It has been recently reported that the incidence of ONJ has significantly increased since the wide application of bisphosphonates as specific therapy of cancer related bone disease. No consensus on diagnostic criteria does presently exist, the pathogenesis of this complication is unknown and the relative contribution of repeated trauma from dental procedures, poor oral hygiene, concomitant chemotherapy, and cancer bone involvement has not been clarified yet. All the same, no data have so far been presented concerning the incidence of ONJ in a homogeneous series of patients with respect to disease status and treatment received. For this purpose, we have retrospectively evaluated the occurrence of ONJ in patients with symptomatic newly diagnosed multiple myeloma enrolled in the “Bologna 2002” clinical trial. According to treatment protocol, all patients received four months of combined thalidomide (100mg/d for two weeks and 200mg/d thereafter) and dexamethasone (40mg/d on d 1–4, 9–12, 17–20/28d on odd cycles and on d 1–4 on even cycles) followed by cyclophosphamide 7g/m2 + G-CSF and PBSC collection, and two courses of Melphalan 200mg/mq and PBSC transplantation. Zoledronic acid was administered at 4mg/28 d throughout the whole study period and afterwards until disease progression. Out of 225 patients analyzed so far (median follow-up = 26 months), ONJ was diagnosed in 6 cases (2.7%), median time from start of treatment and occurrence of dental symptoms was 23 months (range 13–32 months). All the patients underwent dental extraction and/or oral/maxillofacial surgery that resulted in areas of non-healing bone with persistent purulent discharge. Bone biopsies confirmed bone necrosis and inflammation; in 1 case, however, a concomitant infiltration of monoclonal plasma cells was detected in the site of necrosis. In conclusion, results of this retrospective analysis indicate that the occurrence of ONJ among newly diagnosed MM patients receiving long-term (median: 2 years) zoledronic acid treatment was approximately 3%. Surgery can significantly impact patients outcome, so that, according to currently available recommendations on ONJ, dental procedures should be avoided. In addition, the role played by disease itself in the pathogenesis of this complication should not be overlooked.
Dysfunctional T Regulatory Cells in Myeloma: Molecular Mechanisms of Dysregulation.
Authors: Prabhala Rao H. , Neri Paola , Tassone Pierfrancesco , Bae Jooeun E. , Shammas Masood A. , Daley John F. , Song Weihua , Bertheau Robert , Chauhan Dharminder , Bachu Ramesh B. , Thatte Hemant , Anderson Kenneth , Munshi Nikhil C. 
Published: April 2020

Abstract
Multiple myeloma (MM) is characterized by production of monoclonal immunoglobulin, associated with suppressed uninvolved immunoglobulins and dysfunctional T cell responses. The biological basis of this dysfunction remains ill defined. Since T regulatory (Treg) cells play an important role in suppressing normal immune responses, we have here evaluated the potential role of Treg cells in immune dysfunction in MM. We observed a significant increase in CD4+CD25+ T cells in individuals with monoclonal gammopathy of undetermined significance (MGUS) and patients with MM compared to normal donors (25% and 26% versus 14%, respectively); however, Treg cells as measured by Foxp3 expression are significantly decreased in both MGUS (1.6±0.5%, p&lt;0.01) and MM (1.6±0.5%, p&lt;0.01) compared to normal donors (6.0±0.8%). Additionally, these Treg cells also do not function normally. Treg cells from patients with MM and MGUS even when added in higher proportions are unable to suppress anti-CD3-mediated T cell proliferation. This decreased number and function of Treg cells in MGUS and in MM may account, at least in part, for the non-specific increase in CD4+CD25+ T cells, thereby contributing to dysfunctional T cell responses. We have further analyzed the molecular basis for the Treg cell dysfunction in myeloma. Based on the preliminary results suggesting a role of IL-6 in Treg cell function and since both serum IL-6 and soluble IL-6 receptor levels are significantly elevated in MGUS and MM, we evaluated the role of IL-6 and its soluble receptor on Treg cell function. We observed that the addition of IL-6 and/or sIL-6 receptor to the culture leads to loss of Treg cell activity in normal donor cells similar to one observed in myeloma patients; and conversely, when Treg cells from MM patients are treated with the anti-IL-6 antibody or IL-6 receptor super antagonist, sant 7, the suppressive activity of Treg cells is restored. Additionally, we have preliminary evidence of expansion of Foxp3+ cell numbers in PBMC from MM patients following in vitro treatment with anti-IL-6 antibody. This data suggests a role of IL-6 and bone marrow microenvironment in dysfunctional Treg cells in MM and that inhibition of IL-6 signaling results in beneficial effects on T cell activity by increasing Treg cell activity. A blockade of IL-6 signaling thus emerges as a potential approach to establish immune homeostasis to improve immune function in MM.
Dendritic Cell Vaccines Are Superior to Idiotype-KLH Protein Vaccines at Priming a Therapeutic, Tumor-Specific Immunity Against Multiple Myeloma.
Authors: Yi Qing , Wang Siqing , Wezeman Michele , Qian Jianfei , Yang Jing 
Published: April 2020

Abstract
Idiotype (Id) protein secreted by myeloma cells is the best-characterized tumor-specific antigen and has been used in clinical vaccination trials administered either as Id-keyhole limpet hemocyanin (KLH) protein vaccines or as Id-pulsed dendritic cell (DC) vaccines. In this study, we used the 5TGM1 myeloma murine model to compare the efficacy of Id-KLH (protein vaccines) versus DCs pulsed with Id-KLH (DC vaccines), two formulas commonly used in clinical trials, to induce tumor-specific immunity, to protect mice from developing myeloma, and to treat myeloma-bearing mice. Vaccinations consisted of three weekly, subcutaneous injections of the protein conjugates (100 μg/injection) or Id-KLH-pulsed, bone marrow-derived mature DCs (106 cells/injection). Following each vaccination, GM-CSF (200 ng/day/mouse) was injected subcutaneously (adjacent to the vaccination sites) for three consecutive days. We found that, although the protein vaccines induced significantly higher titers of specific antibodies, DC vaccines were superior at inducing tumor-specific, cellular immune responses, evident by increased IFN-γ production, T cell proliferation, and cytotoxic T cell activities against the tumor cells. As prophylactic treatments, protein and DC vaccines were equally efficient at protecting mice from subsequent tumor challenge. However, only DC vaccines induced therapeutic immunity in tumor-bearing mice: DC vaccinations not only retarded tumor growth but also eradicated established tumors in more than 50% of mice, which was associated with an induction of potent, tumor-specific type-1 (IFN-γ) and type-2 (IL-4) T-cell responses. DC-vaccinated mice also showed a more pronounced increase in the percentages of CD8+ T cells in their spleens after in vitro stimulation with irradiated myeloma cells and increased tumor-specific cytotoxicity in enriched CD8+ T cells over the whole splenic cells, suggesting that CD8+ T cells play a major role in killing tumor cells in vivo. Furthermore, surviving mice were also protected from rechallenge with the myeloma cells, indicating that memory T cells existed and were functional. Thus, our results show that Id-based DC vaccines may be a favorable vaccine for immunotherapy in MM. Further studies are required to optimize DC vaccination protocols to achieve therapeutic efficacy in clinical trials.
Expression of Cancer/Testis Antigens CT10 and SSX in Multiple Myeloma: Promising Targets for Antigen-Specific Immunotherapy.
Authors: Atanackovic Djordje , Arfsten Julia , Cao Yanran , Wolschke Christine , Bartels Katrin , Faltz Christiane , Hossfeld Dieter K. , Zander Axel R. , Bokemeyer Carsten , Kroeger Nicolaus 
Published: April 2020

Abstract
Background: The introduction of autologous and allogeneic stem cell transplantation has resulted in improved responses to treatment in patients with multiple myeloma (MM). However, despite high remission rates, recurrences are frequent due to remaining minimal residual disease. Myeloma-specific immunotherapies would represent a potentially useful treatment option in these patients. Cancer/testis (CT) antigens are highly attractive targets for T cell-mediated immunotherapy of cancer, due to their immunogenicity and restricted tissue expression. We investigated the expression of a larger number of CT antigens, the expression of which is characteristically restricted to cancer and normal testis, in patients with MM.
Methods: We analyzed the expression of 9 different CT antigens (SSX-1 to SSX-5, CT10/MAGE-E1, BAGE, MAGE-3, NY-ESO-1) in 10 myeloma cell lines, 54 bone marrow samples from patients with stage II-III myeloma (plasma cell infiltration 10–100 %), and 18 bone marrow samples from healthy donors using rtPCR.
Results: Myeloma cell lines showed a remarkably high expression of the majority of CT antigens. All antigens, with the exception of SSX-3, were expressed in 80–100% of cell lines. SSX-3 was not expressed in any cell line. Analyzing bone marrow samples from MM patients, we observed that CT10 showed a very high expression level with 55% of all malignant samples expressing this antigen. The SSX gene family evidenced high expression levels with 40% (SSX-1), 17% (SSX-2), 13% (SSX-4), and 15% (SSX-5) of patient samples expressing the given SSX family member. SSX-3 was not expressed in any samples. In agreement with previous findings we observed a high expression of MAGE-3 (61%), an intermediate expression of BAGE (18%), and a comparably low expression of NY-ESO-1 (7%). With the exception of SSX-4, which was expressed in 18% of healthy bone marrow samples, none of the CT antigens were expressed in non-malignant samples.
Conclusions: We show here for the first time that CT10 and members of the SSX gene family are strongly and specifically expressed in multiple myeloma. Importantly, both CT10 and SSX have been shown to elicit spontaneous immune responses in patients with solid tumors. Therefore, CT10 and SSX-1, SSX-2, and SSX-5 might represent valuable targets for antigen-specific immunotherapy of multiple myeloma.
The Telomerase Template Antagonist GRN163L in Combination with Chemotherapeutics Reduces Tumor Volume in Multiple Myeloma Xenograft Models.
Authors: Ertem Server A. , Wu Kaida , Ponomarev Vladimir , Chin Allison C. , Moore Malcolm A.S. 
Published: April 2020

Abstract
Primary hematopoietic malignancies are characterized by short telomeres, suggesting that they would be acutely susceptible to telomerase inhibition. We have previously shown that treatment with GRN163L, a lipid-conjugated 13-mer thio-phosphoramidate oligonucleotide (Geron Corporation), inhibits the growth of human multiple myeloma (CAG) and ovarian carcinoma (OVCAR3) cell lines in vitro and in vivo (AACR 2005 Annual Meeting). The CAG multiple myeloma cell line (telomere length 2.7 Kb) was transfected with a retroviral vector encoding a triple fusion gene for HSV-TK, firefly luciferase and green fluorescence protein, and whole animal bioluminescence imaging was undertaken in either a subcutaneous or disseminated NOD/SCID model with extensive spinal cord and bone marrow tumor infiltration. In a subcutaneous model with CAG, GRN163L was administered three times per week (tiw) at 36 mg/kg for 4 weeks alone or in combination with either a single dose of melphalan (5 mg/kg) or 9 doses of Velcade (0.25 mg/kg tiw). Tumor mass was reduced 56% with GRN163L alone (p&lt;0.001), 60% with melphalan alone (p&lt;0.001), 89% with the combination of GRN163L and melphalan (p&lt;0.001). At the dose used, Velcade alone showed no efficacy, but the combination of GRN163L with Velcade reduced the tumor mass by 68% (p&lt;0.001) compared to controls. Data on the treatment with a mismatch control oligonucleotide in addition to dose optimization of GRN163L in combination with Melphalan and Velcade in subcutaneous and disseminated myeloma models (CAG, MM.1S) will be presented. Geron initiated a Phase I/II trial with GRN163L in chronic lymphocytic leukemia in July 2005. These data support the development of GRN163L as an effective and safe agent for therapy of hematopoietic malignancies.
Acquired Resistance to Activated Protein C (aAPCR) Is Associated with Increased Risk of Deep Vein Thrombosis in Multiple Myeloma.
Authors: Elice Francesca , Fink Louis , Tricot Guido J. , Milner Teresa J. , Barlogie Bart , Zangari Maurizio 
Published: April 2020

Abstract
Non factor V Leiden APC resistance (aAPCR) has been described in cancer patients and found to be associated with an increased risk of deep venous thrombosis (DVT). We analyzed the incidence and clinical impact of APC resistance in a large group of multiple myeloma patients. A total of 1178 myeloma patients were tested for APC resistance using an aPTT-based assay in the presence of excess of factor V-deficient plasma and the ratio with or without APC was calculated (≤ 2.00 was considered abnormal). PCR amplification of genomic DNA was used to detect Factor V Leiden.
Abnormal APC resistance was found in 109 patients (9.3%), 83 of those were tested for factor V Leiden, 31 had the mutation and 52 (63%) did not have it. Analyzing a subgroup of 254 chemotherapy naïve patients, APC ratio was abnormal in 11% of patients and two third of them were not carriers of factor V Leiden mutation. The presence of aAPC resistance was associated with an increased risk for DVT: 27.9% in patients with aAPCR vs.12.3% in the others (P = 0.008); 22.6% in patients with factor V Leiden mutation.
In 32 patients with abnormal aAPCR, the test was repeated: 31/32 patients normalized their APC ratio in sequential testing. Correlation between myeloma baseline markers (serum and urine M-component, beta2-microglobulin, CRP, IL-6), response to treatment and APC activity were studied. In this analysis active disease emerged as the most important factor associated with aAPCR, as 19 patients with normalization of the APC ratio had a concomitant clinical response to therapy. We concluded that aAPCR is a transient finding in myeloma patients that showed a significant correlation with development of DVT.
The JAK2 V617F Tyrosine Kinase Mutation in Myelofibrosis with Myeloid Metaplasia: Clinical Correlates and Prognostic Relevance in 157 Patients.
Authors: Tefferi Ayalew , Lasho Terra L. , Schwager Susan M. , Steensma David P. , Mesa Ruben A. , Li Chin Yang , Wadleigh Martha , Gilliland D. Gary 
Published: April 2020

Abstract
Background: The occurrence of an activating JAK2 mutation (JAK2 V617F) has been reported in a variable proportion of patients with bcr/abl-negative myeloproliferative disorders including myelofibrosis with myeloid metaplasia (MMM). In the current study, we report mutational frequencies in each of the 3 MMM variants as well as examine the prognostic relevance of the mutation in a large group of patients from a single institution.
Methods: Mutation analysis for JAK2 V617F was performed in DNA derived from peripheral blood mononuclear cells (PBMC) from all study patients (n=157). Concomitant analysis was also performed in DNA derived from purified granulocytes (n=57), CD34-positive cells (n=25), and T cells (n=19). Genomic DNA was amplified by PCR and fluorescent dye chemistry sequencing was performed using the same primers used for amplification.
Results: The study cohort included 157 consecutive patients with MMM including 117 with agnogenic (AMM), 22 with post polycythemic (PPMM), and 18 with post thrombocythemic (PTMM) myeloid metaplasia. The overall detection rate for JAK2 V617F in PBMC was 51% (homozygous in 5.7%) and was significantly (p=0.0002) higher in PPMM (91%; homozygous in 18%) compared to either AMM (45.3%; homozygous in 2.6%) or PTMM (38.9%; homozygous in 11.1%). In AMM (n=117), the presence of JAK2 V617F was significantly associated with an older age at diagnosis (p=0.03), and a history of both thrombosis (p=0.01) and pruritus (p=0.005). No other statistical associations were evident and the presence of the mutation did not predict leukemic transformation. Furthermore, multivariate analysis for overall survival of patients with AMM identified only age and the Dupriez prognostic score as independent prognostic factors; JAK2 V617F had no prognostic significance. Finally, the mutation was not found in T cells and its detection rate in either granulocytes or CD34-positive cells was similar to that in PBMC.
Conclusion: JAK2 V617F is a myeloid lineage-specific event, its incidence in MMM is significantly higher with an antecedent history of polycythemia vera, and its presence in AMM does not affect prognosis but is associated with PV-characteristic clinical features.