bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Therapy of Bortezomib with Low-Dose Bendamustine in Elderly Patients with Advanced Multiple Myeloma.
Authors: Hrusovsky Irena , Heidtmann Hans-Heinrich 
Published: April 2020

Abstract
Bortezomib has been approved for recurrent or therapy-resistent multiple myeloma in 2003. There is growing evidence that combination therapy of bortezomib with other agents considerably improves results (Richardson P, ASH 2004). Bendamustine is an alkylating agent widely used in Germany for treatment of multiple myeloma and indolent lymphoma. There is no cross-resistance to other alkylating agents. Weekly low dose application is well tolerated and highly effective in elderly patients with pretreated indolent lymphoma (Bremer K, ASCO 2003, Abstract 2410).
Treatment modalities: We treated 17 pts (8 female, 9 male, median age 70 yrs (range 51–82) with relapsed multiple myeloma. Previous therapies ranged from 2 to 7 (median 4), and included 15 x thalidomide, 2 x tandem high dose melphalan, 2 x bortezomib/dexamethasone.
Therapy regimen: bortezomib 1 – 1.3 mg/m2 d 1,4,8,11; bendamustine 60 mg/m2 d 1+8, dexamethasone 3x8 mg orally d 1–3 and d 8–10: ondansetrone 8 mg intravenously d 1,4,8,11. Cycles were repeated q3w until best response. The median number of cycles applied was 4 (range 3 – 6).
Results: Outcome was evaluated according to SWOG criteria.
ORR: 88%; CR (neg. immunofixation): 12% (n=2); PR 58% (n=10); MR 18% (n= 3); NC 12% (n=2). Median remission duration was 6+ months (range 3–12+ months). Until today, we observed 4 recurrences after 3 – 8 months.
Toxicity comprised mild fatigue and thrombopenia. Lowest platelet count was 55/pL without bleeding, spontaneously reversible within 1 week. Three cases of neuropathia occurred, with controllable symptoms, in patients pretreated with thalidomide or bortezomib mono.
Conclusion: Combination therapy of bortezomib with low dose bendamustine is well tolerated, induces a high rate of responses in spite of unfavourable patient characteristics, leads to early responses and can be limited to 3 months (i.e., 4 cycles), and can be done in an outpatient setting. Thus, bendamustine is a very promising agent to enhance bortezomib action, which warrants further study.
Trisenox (Arsenic Trioxide) in the Treatment for Multiple Myeloma after Bone Marrow Transplantation.
Authors: Gesundheit Benjamin , Shapira Michael Y. , Resnick Igor , Bitan Menachem , Ben-Yehuda Dina , Slavin Shimon , Or Reuven 
Published: April 2020

Abstract
Multiple myeloma (MM) remains an incurable disease, with median survival of 4–6 years despite various new therapeutic approaches including autologous and allogeneic bone marrow transplantation (BMT). New agents are studied and Arsenic Trioxide (ATO) seems to be a promising additional agent against progressive and refractory MM. Various mechanisms are described for the therapeutic effect of ATO: growth inhibition of myeloma cells; induction of apoptosis of drug resistant MM cell lines; inhibition of angiogenesis by blocking VEGF; interaction with BM microenvironment; immunologic mechanisms by a marked increase in lymphokine-activated Killer (LAK)-mediated killing and up-modulation of CD38 and CD54; inhibition of myeloma cells to stick to BM stromal cells by inhibiting IL-6. ATO is a form of arsenic, a naturally occurring element (As2O3), which was used for various therapeutic purposes for more than 2000 years. ATO was first approved by the FDA in 2000 for acute promyelocytic leukemia (APL), and is investigated for myelodysplastic syndrome (MDS) and other indications for ATO are currently under investigation.
We report our preliminary data from our clinical experience with ATO for 4 patients with MM after BMT, who had evidence of active and progressive disease. Other therapeutic approaches failed or were not relevant. ATO was given at low doses of 0.15 mg/kg/dose twice weekly and after respond at 0.3 mg/kg/dose once weekly. ATO was given intravenously in slow infusion over 2 hours together with intravenous lipids 500 ml (20%) to reduce ATO toxicity. ECG, markers for myeloma and possible adverse effects were monitored carefully. Oral ascorbic acid 500 mg twice daily was added to improve the effect of ATO. Our patients showed evidence of response to ATO both at the level of residual tumor mass and M-protein secretion. Furthermore, in one patient with severe GvHD we observed significant improvement of the GvHD manifestations concomittantly with Graft versus Myeloma effect.
Based on our data and the review of the literature regarding the use of ATO for MM, ATO might play in the future an established role in the treatment for MM. ATO might induce and augment immunomodulatory effects of Graft versus Myeloma. We discuss future research for the use of ATO in the treatment of MM.
A Mutation in Sec15l1 Disrupts the Transferrin Cycle and Causes Anemia in Hemoglobin Deficit (hbd) Mice.
Authors: Lim Jackie E. , Morgan Kelly , Wang Fudi , Fleming Mark D. , Andrews Nancy C. 
Published: April 2020

Abstract
Mouse mutants have been used to identify and characterize genes involved in iron homeostasis. The mouse mutant hemoglobin deficit (hbd), has inherited hypochromic, microcytic anemia and elevated zinc protoporphyrin in the setting of replete iron stores, consistent with a selective defect in erythroid iron assimilation. Circulating soluble transferrin receptor, a marker of iron-restricted erythropoiesis, is elevated out of proportion to the anemia. A mapping population of &gt;3300 backcross animals allowed assignment of the hbd locus to a 0.5 Mb region on chromosome 19. Seven candidate genes were identified in mouse genome databases. Only Sec15l1, encoding one of two mouse homologs of yeast Sec15p, carried a mutation unique to hbd. The mutation deleted 4.5 kb of Sec15l1 genomic DNA including a 69 bp exon. Two distinct antibodies elicited against murine Sec15l1 demonstrated that there was little or no Sec15l1 protein detectable in tissues from hbd animals, suggesting that the mutant form was unstable in vivo. To confirm that mutation of Sec15l1 was responsible for the hbd phenotype, hbd bone marrow cells were transduced with a retrovirus expressing wild type Sec15l1 and transplanted into hbd mice. Expression of the wild type protein partially corrected the anemia. For further confirmation, mice carrying a different, targeted mutation in Sec15l1 were bred with hbd mice. Compound mutant mice carrying both the targeted and hbd alleles recapitulated the hbd phenotype. Sec15l1 functions as a component of the mammalian multi-protein exocyst complex. Previous studies in model organisms suggested that the exocyst is critical for a variety of cellular functions; loss of other exocyst proteins caused early lethality. We speculate that Sec15l2, a mammalian homolog of Sec15l1, can substitute in non-erythroid tissues. Expression analysis showed that little or no Sec15l2 was present in hbd spleen, which is massively infiltrated with erythroid precursors. The exocyst is an effector for Rab11, a GTPase involved in recycling of transferrin cycle endosomes. In S. cerevisiae, Sec15p interacts both with Sec10p, another exocyst component, and with a yeast homolog of Rab11. Preliminary studies suggest that the hbd form of mammalian Sec15l1, expressed in yeast, retains its ability to interact with both of its mammalian partner proteins - Rab11 and Sec10. We conclude that depletion of Sec15 in hbd mice alters transferrin receptor recycling and, possibly, enhances transferrin receptor shedding. As a consequence, erythroid iron assimilation is impaired. Sec15L1 should be considered a candidate gene in patients with inherited iron-resistant iron deficiency anemia.
Treatment with Arsenic Trioxide, Ascorbic Acid and Dexamethasone in Advanced Myeloma Patients: Preliminary Findings of a Multicenter, Phase II Study.
Authors: Wu K. , van Droogenbroeck J. , Beksac M. , de Knegt Y. , Sonneveld P. 
Published: April 2020

Abstract
Recent studies have shown that arsenic trioxide (Trisenox, ATO) can induce apoptosis in myeloma cells and overcomes anti-apoptotic effects of interleukin-6. Pre-clinical studies reported profound anti-myeloma effects when ATO, ascorbic acid (AA) and dexamethasone are combined. Single nucleotide polymorphism (SNP) in metabolic enzymes may influence susceptibility of a treatment and the prognosis of multiple myeloma (MM).
We performed a multicenter phase II trial of ATO in patients with advanced MM. Patients with progressive disease following more than one line chemotherapy were included. The treatment regimen consists of four 28-days cycles. In 1st cycle, during 1st week: a loading-dose with ATO 0,25mg/kg IV, AA 1000mg IV and Dex 40mg orally on day 1–5. During 2nd and 3rd week: a maintenance-dose of twice weekly ATO 0,25mg/kg IV, AA 1000mg IV and Dex 20mg orally. During the 4th week no treatment is given. In the 2nd, 3rd and 4th cycle: a maintenance-dose of twice weekly ATO 0,25mg/kg IV, AA 1000mg IV and Dex 20mg orally in 1st, 2nd and 3rd week was administered followed by the 4th week as a rest period. Patients with a clinical response after the 4th cycle received two additional treatment cycles.
Preliminary results: The ongoing study currently has enrolled 20 pts, median age 63 yrs (range 42–76), who had received a median of 4 lines of prior treatments (range 1–6). There were 2 early deaths from pneumonia and gastro-intestinal bleeding. Fifteen patients were evaluable for response; PR in 2 pts, MR in 3 pts, SD in 3 pts and 7 pts had PD. Six patients died from progressive disease. Grade 3 or 4 adverse events included fluid retention (3), thrombocytopenia (2), neutropenia (1), increased ALT (2), peripheral neuropathy (1), bacterial pneumonia (2). In addition to standard clinical observations we did an analysis for Genetic Single Nucleotide polymorphisms of relevant metabolic enzymes in order to assess the relevance for toxicity and effect of ATO. A polymerase chain reaction followed by restriction enzyme digestion for GSTP1, CYP3A4, CYP3A5, MDR-1, GSTT1 and GSTM1 was performed. Responding patients vs non-responding patients showed the following wild-type(ww) / mutant (mm) / heterozygous (wm/mm) haplotype: GSTP1 1 / 2 / 1 vs 2 / 3 / 3; CYP3A4 1 / 0 / 3 vs 1 / 0 / 7; CYP3A5 0 / 4 / 0 vs 0 / 8 / 0; MDR1 0 / 3 / 1 vs 0 / 1 / 7 and deletion / normal genotype: GSTT1 1 / 3 vs 2/ 6; GSTM1 1 / 3 vs 4 / 4.
Conclusion: These preliminary results suggest that the ATO-AA-Dex regimen shows efficacy, with limited toxicity in advanced MM patients. An extended genotype analysis will be performed to characterize the role of metabolic enzymes in the effect of this regimen.
Identification and Expansion of Myeloma-Specific Cytotoxic T Cells In Vitro.
Authors: Michalek Jaroslav , Ocadlikova Darina , Zahradova Lenka , Kovarova Lucie , Penka Miroslav , Hajek Roman 
Published: April 2020

Abstract
Multiple myeloma (MM) has been considered as low immunogenic incurable disease. The attempts has been made to invert the immune status to recognize myeloma cells by T cells or other cells of the immune system. Here we studied biology of myeloma-specific T cells in vitro.
Irradiated myeloma cell line ARH 77 has been used as tumor antigen to stimulate peripheral blood mononuclear cells (PBMC) of 8 healthy volunteers. Dendritic Cells loaded by irradiated autologous MM cells has been used to stimulate PBMC of 10 MM patients. Activated responder T cells have been immunomagnetically separated based on surface expression of interferon gamma (Miltenyi Biotech) and expanded in 5 cases by phytohemaglutinin and repeated high-doses of interleukin 2. Cytotoxicity against the original myeloma cells has been tested after the expansion using propidium iodide or 7-amino actinomycin D. Responder T cells were labeled by CFSE to distinguish them from myeloma cells. Third-party PBMC and interferon gamma negative fraction of T cells served as controls.
The percentage of interferon gamma positive cells in healthy donors has been enriched from 2.8±0.9 and 2.6±0.8 to 48.6±23.4 and 73.2±25.9 of CD3+CD4+ and CD3+CD8+ T cells, respectively, by immunomagnetic separation. Interferon gamma positive T cells have been further expanded in vitro from 0.54x106 ± 0.05x106 to 214.00x106 ± 103.46x106 within 4 weeks. A specific cytotoxicity has been tested after expansion. The killing of myeloma cells by expanded IFN g+ T cells reached 68.1±14.2%, while interferon gamma negative fraction killed only 0.8±0.3% of myeloma cells. As another control, killing of third-party PBMC by expanded interferon gamma positive T cells was 6.9±2.5%. Similar observations were made in MM patients and will be presented at the meeting.
These data demonstrate a specific cytotoxic effect of expanded interferon gamma positive T cells against myeloma cell line ARH 77 and open the possibility for clinical use of tumor-specific T cells in MM.
Identification and Characterization of an Erythrocyte Endosomal Ferrireductase Critical for Transferrin Dependent Iron Uptake.
Authors: Ohgami Robert S. , Campagna Dean R. , Antiochos Brendan , Greer Eric , Fleming Mark D. 
Published: April 2020

Abstract
The transferrin cycle is a critical pathway for iron uptake by developing red blood cells. Defects in the cycle typically result in a hypochromic microcytic anemia due to ineffective hemoglobin synthesis. Recently we described a new microcytic mouse mutant, nm1054, with an autosomal recessive defect in transferrin mediated iron uptake. We now have identified the gene responsible for the defect through positional cloning and complementation experiments. The gene, mammalian ferrireductase 1 (Mfre1) encodes a predicted six pass transmembrane protein with homology to oxidoreductases of archaea and bacteria as well as homology to the yeast family of FRE proteins. Mfre1 is expressed highly in hematopoietic tissues and co-localizes with the transferrin cycle endosome of cells. Over-expression of Mfre1 in cultured cells stimulates reduction of iron while reticulocytes deficient in Mfre1 are defective in conversion of ferric iron to a ferrous form. Here we comprehensively describe the role of Mfre1 in iron metabolism and speculate on the role of several other novel homologues in iron homeostasis.
Osteomyelitis of the Jaw in Multiple Myeloma Patients as a Complication of the Treatment with Biphosphonates.
Authors: Nemets Anatoly , Bumental Rima , Ruchlemer Rosa , Marilus Rafael , Bennet Michael , Sofer Enat , Gordin Josef , Lugassy Gilles 
Published: April 2020

Abstract
Biphosphonates (zoledronate, pamidronate and clodronate) are frequently used for bone disease prevention and treatment in patients with multiple myeloma. Monthly biphosphonate therapy improves quality of life and in some reports survival. However, biphosponates are associated with adverse effects such as renal impairment and osteonecrosis of the jaws. We have recently described 3 myeloma patients who developed oseomyelitis of the jaw during chronic biphosphonate therapy. In a national survey we found 11 patients from 6 centers in Israel with osteomyelitis of the jaws probably due to prolonged therapy with intravenous biphosphonates. Nine were female. Median age at the time of diagnosis of myeloma was 67 years (range 59–86). nine patients suffered from IgG myeloma, and 2 had light chain disease. In five patients MGUS was known during 4 to 9 years before development of overt myeloma. All patients had received chemotherapy, and 2 underwent ABMT. Median time from diagnosis of myeloma to diagnosis of osteomyelitis of the jaw was 30 months (range 15–48). In six cases osteomyelitis was provoked by dental procedure. In all cases the diagnosis of osteomyelitis was confirmed by bone biopsy and in 7 colonies of Actinomyces Israeli were demonstrated. In one patient Pseudomonas Aeruginosa was also found. All patients had been treated with biphosphonates before diagnosis of osteomyelitis (13 to 48 months): eight with pamidronate, and 3 with zoledronate. The mean total dose of pamidronate was 3190 mg (range 1690–4680), and zoledronate- 72mg (range 16–96). Therapy for osteomyelitis included prolonged antibacterial treatment, surgical debridment, and hyperbaric oxygenation. Acute, and chronic, osteomyelitis of the jaws secondary to biphosphonate therapy, is frequently encountered among myeloma patients and should be reported separately from another complication of biphosphonates, osteonecrosis of the jaws.
CD56 Expression Is the Potent Prognostic Marker of the Thalidomide Efficacy in the Patients with Multiple Myeloma.
Authors: Mori Akio , Tsutsumi Yutaka , Hashino Satoshi , Kanamori Hiroe , Ibata Makoto , Mashiko Shinobu , Masauzi Nobuo , Asaka Masahiro , Imamura Masahiro 
Published: April 2020

Abstract
Thalidomide (Thal) alone or in combination with steroids achieves responses even in the setting of refractory multiple myeloma (MM), however, responses are still limited. The precise mechanism of Thal action is unknown, further, no distinct marker, which could prognosticate the efficacy of Thal, is known. Therefore, we evaluated the correlation between the efficacy of Thal and the potent prognostic factors in patients with refractory MM. Ten patients with refractory MM received Thal at doses of 50 or 100 mg per day and steroids, either dexamethasone (Dex) or prednisolone (PSL). Dex was administrated 20 mg per day, 4 days every 28 days, and PSL was administrated 10 mg per day. The median age was 71.5 years (range, 62–79 years) and 20 % were man, and all patients were diagnosed as clinical stage IIIA based on the Durie and Salmon classification. The therapeutic response was assessed according to the modified criteria of Southwest Oncology Group (SWOG). Among 10 patients, 7 patients were the responders; 2 had complete remission, 3 had partial remission, and 2 had minimal remission. There were no differences in the pretreatment characteristics of responders and nonresponders (age, sex, type and concentration of serum and/or urine monoclonal component, international prognostic index, presence of bone lesion, and chromosomal abnormalities). However, flow cytometric evaluation of the myeloma cells revealed that CD56, which is one of the adhesion molecules N-CAM, expressed more than 45 % in all responders, while those expressed less than 5 % in all nonresponders (84 ± 19 (±SD) % v/s 4 ± 2 %, P=0.017). Furthermore, CD56 expression of the myeloma cells was reduced from 84% to 70 ± 32 % after Thal therapy in all evaluated responders (P =0.048). These results suggest that CD56 expression of the myeloma cells could be the potent prognostic marker of the Thal efficacy. Moreover, it was reported that Thal reduced the expression of cell adhesion molecules, such as LFA-1 and ICAM-1, and abrogated the binding of MM cells to bone marrow stromal cells, that triggered the secretion of interleukin-6 and vascular endothelial growth factor. Taken together, it was suggested that Thal reduced the expression of CD56 and altered the MM cell adhesion to bone marrow stromal cells, and that could be one of the pathogenesis of anti-MM activity of Thal.
Low Dose Thalidomide for the Treatment of Multiple Myeloma.
Authors: Bittencourt Rosane , Almeida Andreia D. , Friederich Joao R. , Fernande Flavo , Fogliatto Laura , Paz Alessandra , Astigarraga Claudia , Leugeur Denise , Silla Lucia 
Published: April 2020

Abstract
In the last two decades, we have seen a radical change in the therapy and prognosis of Multiple Myeloma (MM). Recent research on the role of the bone marrow microenvironment as integrant part of the biology of MM and the possible therapeutic interference at this level are leading to control and regression of the malignant plasma cell clone with a recognized clinical impact. Thalidomide, an old drug thought to interfere on the bone marrow microenvironment, is active not only for the treatment of refractory patients but also, as was recently shown, for induction and/or remission maintenance therapy. Most of the side effects (somnolence, constipation, fatigue, tremor, bradycardia, edema, and neuropathy) can be managed by reducing the dose and most patients need a dose reduction. The appropriate dose of thalidomide in myeloma is unknown. We treated thirty-five patients with MM with low-dose thalidomide (200mg or less). Twenty four patients were on maintenance therapy (13 after bone marrow transplantation, and 11 after chemotherapy with VCAP/VMCP); 5 patients were treated after relapse, 4 with refractory disease and 2 for remission induction as a first line therapy. Patients were treated at the Hematology and Bone Marrow Transplantation Service of the Hospital de Clínicas de Porto Alegre, RS, Brazil, from march/2001 to December/2003. The response as measured by hemoglobin level, immunoglobulin (M component) or urinary light chain concentration and bone marrow examination was evaluated before, 3, 6, and 12 months after the beginning of thalidomide.
Results: All patients are alive and well. Fifty one percent are on 100mg schedule; of the patients on maintenance therapy 90% are on complete remission or on a sustained plateau. A Wilcoxon ranks test for the immunoglobulin level before and after 6 months for the entire group showed p=0.001 (25–75%).
Conclusion: Low dose thalidomide is tolerable and effective.
Efficacy of Single-Agent Bortezomib Versus Thalidomide in Patients with Relapsed or Refractory Multiple Myeloma: A Systematic Review.
Authors: Prince Miles , Adena Michael , Smith Dell Kingsford , Hertel Judy 
Published: April 2020

Abstract
Aim: To perform a systematic review of the efficacy of monotherapy with bortezomib versus thalidomide in patients with relapsed or refractory multiple myeloma.
Methods: Published English literature from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag Pty Ltd data-on-file, and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of any treatment group with n ≥ 30 and using continuing or variable thalidomide dosing were included. Studies adding dexamethasone for non-responders were excluded. Outcomes were analysed on an intent-to-treat basis. Statistical pooling was performed where possible for the following outcome measures: primary outcome of response rate, defined by a serum M-protein reduction ≥50% (A) and strict (e.g. EBMT) criteria (B), and for the secondary outcomes of overall survival and progression-free survival.
Results: One bortezomib (n=333, APEX, NEJM2005, 352; 2487–98) and 15 thalidomide (n=1007) studies were included. Patient baseline characteristics including age, gender, IgG:IgA, disease duration and β2M were well matched, except that 48% of bortezomib patients had received prior thalidomide. On an intent-to-treat basis, the overall estimate for response rate (A) was 53% for patients receiving bortezomib versus 32% for thalidomide (p&lt;0.001, n=10 studies). For response rate (B) the estimate was 36% for patients receiving bortezomib versus 22% for thalidomide (p&lt;0.001, n=4 studies). One-year survival was 81% for patients receiving bortezomib versus 67% for thalidomide (p&lt;0.001, n=6 studies). Due to differences in disease monitoring and definitions of progression, it was not possible to compare results for progression-free survival.
Conclusion: In patients with relapsed or refractory multiple myeloma, bortezomib achieved significantly higher response rates and longer one-year survival than thalidomide, despite 48% of bortezomib-treated patients having received prior thalidomide.