bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Concentrations of Vitamin B-12 and Alkaline Phosphatase in Newly Diagnosed Multiple Myeloma Patients.
Authors: Elice Francesca , Zangari Maurizio , Barlogie Bart , Burns Michael J. , Tricot Guido J. , Roberti Sara , Rodeghiero Francesco , Hine R. Jean 
Published: April 2020

Abstract
Background: A controversy about a possible link between vitamin B12 deficiency and multiple myeloma (MM) has persisted since the 1970s. Vitamin B12 (B12) deficiency can cause anemia, neuropathy and has been associated with osteoporosis and reduced bone density. Therefore, B12 deficiency might worsen some clinical symptoms of MM.
Methods: We evaluated serum B12 concentrations in 393 untreated MM patients included in the Myeloma Institute Program (October 1998 to March 2005). Total serum B12 was assessed by using ADVIA Centaur immunoassay with chemiluminescent detection; laboratory B12 deficiency was defined as serum B12 levels &lt; 156 mmol/L. Serum alkaline phosphatase (ALP) was determined by a kinetic rate method. Neuropathy was assessed clinically according to NIH guidelines. Correlations of serum B12 concentrations with bone density (radial T- and Z -score) and thalidomide-related neuropathy were investigated. Categorical variables were compared using chi-square and Fisher’s exact test, while correlation coefficient was used for quantitative variables.
Results: The sample was 57% male, median age = 58 years, stage III 70%, median creatinine 1.0 mg/dL, IgG 52%, IgA 24%, and light chain disease 19%. Prevalence of laboratory B12 deficiency was 3.5%, prevalence of functional deficiency (B12 &lt; 241 mmol/L) was 20.4%. No influence of age or MM isotype on B12 levels was observed. Sixty seven percent (264) of the patients received thalidomide in combination with chemotherapy. Levels of B12 did not affect the development of grade ≥ 2 neuropathy after thalidomide treatment (p=0.49). No significant association was observed between serum B12 and the radial T- and Z score at bone densitometry (n= 270). There was a highly significant correlation between serum B-12 and ALP levels (correlation coefficient 0.25, p &lt; 0.0001).
Conclusions: Laboratory B12 deficiency was not common in our series of newly untreated MM patients. B12 levels did not predict the development of thalidomide-related neuropathy, nor are they associated with reduced bone density. The most striking finding of our study was a highly significant correlation between serum B12 and ALP concentrations; clinical significance of this observation requires further evaluation.
Ambulatory Blood Pressure Monitoring in Multiple Myeloma Patients Treated with VAD Protocol.
Authors: Pyszel Angelika , Biedron Monika , Poreba Rafal , Wrobel Tomasz , Mazur Grzegorz , Szuba Andrzej , Kucharski Wojciech , Podgorski Maciej , Kuliczkowski Kazimierz , Andrzejak Ryszard 
Published: April 2020

Abstract
BACKGROUND: Corticosteroids are still a cornerstone in multiple myeloma (MM) therapy, both as a single agent and as a part of many protocols, including VAD regimen (vincristine, adriblastine, dexamethasone). Corticosteroids are known to be involved in blood pressure (BP) regulation and to affect this parameter. The impact of dexamethasone (Dex) administration on BP in MM patients during VAD protocol treatment is poorly documented.
AIM: The purpose of the study was to evaluate the blood pressure changes during Dex administration in patients treated with VAD protocol due to MM.
METHODS: Thirteen patients with MM (7 men and 6 women; mean age 62,45 ± 8,14) were assessed. Primary hypertensive patients (7 persons) were not excluded. They were administered Dex in standard dose of 40 mg (day 1–4, 9–12, 17–21) according to VAD protocol. Blood pressure was assessed by the use of commercially available instruments of Ambulatory Blood Pressure Monitoring (ABPM). The BP recordings lasted 48 hours, were started on the day before the first day of VAD and were obtained every 10 minutes during mornings, every 15 minutes during the rest of days and every 20 minutes during nights. Average of systolic and diastolic blood pressure (SBP/DBP) were estimated for the 2-hour time before Dex and for the 14-hour time in the 2-hour periods after Dex. Minimal and maximal range of SBP/DBP increase and the mean amount of SBP/DBP increase were also determined.
RESULTS: 48-hour BP recordings revealed a significant increase in systolic and diastolic blood pressure after Dex administration in all patients. SBP and DBP began to increase after 3 hours after Dex, then rose continually and reached the peak in the period from 6 to 10 hour after Dex. In comparison to 2-hour period before Dex, in which SBP/DBP amounted 139,63/82,92 ± 23,47/9,38 mmHg, the mean SBP/DBP increase rate was: in the 2–4 hour period after Dex - 146,68/88,15 ± 24,38/10,51 mmHg (p&lt;0,05), in the 6–8 – 148,07/92,66 ± 14,07/9,04 mmHg (ns), in the 8–10 – 147,8/87,99 ± 14,07/9,04 mmHg (p&lt;0,01), in the 10–12 – 143,44/86,12 ± 17,22/9,77 mmHg (p&lt;0,05) and in the 12–14 – 144,47/88,59 ± 17,04/12,54 mmHg (p&lt;0,01). The minimal range of SBP/DBP increase was 10,50/−2,00 mmHg, maximal range of SBP/DBP increase was 35,43/40,00 mmHg and the mean amount of SBP/DBP increase was 20,06/11,6 ± 8,36/14,23 mmHg.
CONCLUSION: Our preliminary study revealed that Dex administration causes an increase in BP in all patients. The mean increase in BP amounted 20,06/11,6 ± 8,36/14,23 mmHg and was similar in all patients, regardless their initial value of BP. So our study demonstrates the need of individualized hypertension treatment with strict control of BP in hypertensive patients when corticosteroid therapy is indicated.
Thalidomide in Relapsed or Refractory Patients with Multiple Myeloma: Monotherapy or Combination Therapy? A Report from Systematic Reviews.
Authors: Glasmacher Axel , Hahn Corinna , Hoffmann Florian , Furkert Kerstin , von Lilienfeld-Toal Marie , Orlopp Katjana , Naumann Ralph , Goldschmidt Hartmut , Schmidt-Wolf Ingo G.H. , Gorschlueter Marcus 
Published: April 2020

Abstract
The activity of thalidomide monotherapy in relapsed or refractory disease is widely accepted but many haematologists have observed better response rates with combination therapies. This communication aims to give an overview on the efficacy of these alternatives.
Methods: Our group has performed two systematic reviews (thalidomide monotherapy: Glasmacher et al., Brit. J. Haematol., 2005; 129 suppl 1: 24; thalidomide and dexamethasone combination therapy: submitted to ASH 2005). Furthermore a search of trials combining thalidomide, cyclophosphamide and dexamethasone (with or without further drugs) was performed. Only trials that included patients with relapsed or refractory multiple myeloma could be evaluated. Response was defined as a reduction of the monoclonal component by more than 50% in the absence of any sign of disease progression. Proportions and 95% confidence intervals were reported (Confidence Interval Analysis, Version 2.1.1, Southampton, UK, 2000).
Results: Thalidomide monotherapy was administered in doses between 50–600 mg/d (median doses). Thalidomide in combination with dexamethasone was given in doses of 100–400 mg/d (median doses), dexamethasone was given 40 mg/d d1–4 every 3–4 weeks in 7 of 8 trials. Thalidomide dosage and combination therapy of trials adding Cy to thalidomide and dexamethasone are shown in Table 1. The response rates of the three different thalidomide applications are demonstrated Table 2.
Conclusion: This compilation of data from phase II trials cannot replace a randomized trial and may be biased. With this limitation it seems that thalidomide combined with dexamethasone (response rate 51%) is more effective than monotherapy (response rate 29%) as the 95% confidence intervals for the response rates do not overlap. Whether a combination of thalidomide, dexamethasone and cyclophosphamide is more effective than thalidomide and dexamethasone alone cannot be decided from the current data.
Table 1: Studies with thalidomide and combination chemotherapy Study Intervention No. of pts. Response (95%CI) Abb.: Cy, cyclophosphamide; Eto, etoposide; T, thalidomide; Dex, dexamethasone; Ida, idarubicin. Values are mg/m2 per course for Cy, Eto, Ida; mg per course for Dex, mg/d for T. Moehler et al. 2003 Cy 1600, Eto 160, T 400, Dex 160 119 55% (46–65) Kropff et al., 2003 Cy 1800, T 400, Dex 240 60 70% (57–81) Dimopoulos et al. 2003 Cy 1500, T 400, Dex 160 43 67% (51–81) Gracia-Sanz et al. 2004 Cy 50 daily, T 800, Dex 160 71 57% (45–67) Glasmacher et al. 2005 Cy 800, Ida 40, T 400, Dex 320 39 57% (41–73) Table 2: Response of different thalidomide combinations Intervention No. of trials No. of pts. Response (95%CI) Abb.: see Table 1 T monotherapy 42 1629 29% (27–32) T + Dex 8 283 51% (45–57) T + Cy + Dex 5 332 60% (55–65)
Anti-Myeloma Effects of a Novel Synthetic Retinoid Am80 (Tamibarotene) through Inhibition of Angiogenesis.
Authors: Sanda Takaomi , Iida Shinsuke , Kuwano Takashi , Ono Mayumi , Ueda Ryuzo 
Published: April 2020

Abstract
In multiple myeloma (MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells (HUVECs). Myeloma cell lines produced varying amounts of vascular endothelial growth factor (VEGF), and migration of HUVECs was induced by co-culture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 (Tamibarotene) on both myeloma cells and HUVECs. Am80 remarkably inhibited the growth of HUVECs stimulated by VEGF and blocked migration of HUVECs by co-cultured myeloma cells. In addition, VEGF-induced formation of tube-like structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. Am80 downregulated both interleukin-6 (IL-6) and IL-6 receptor, and blocked VEGF-induced phosphorylation of VEGF receptor. Furthermore, microarray analysis suggested that Am80 has immunomodulatory effects on myeloma cells. These findings demonstrate that Am80 might be a useful therapeutic agent against MM.
Valproic Acid Induces Non Apoptotic Cell Death in Myeloma Cells and Cell Lines.
Authors: Schwartz Chantal , Palissot Valérie , Brons Rene I. , Leners Bernadette , Bosseler Manon , Dicato Mario A. , Berchem Guy J. 
Published: April 2020

Abstract
Multiple myeloma is, despite the emergence of new treatment strategies in recent years, still a lethal disease in 2005. Over the last several years, significant insights into the dysregulation of various signal transduction pathways of MM have emerged and have evolved the development of new agents. Histone deacetylase inhibitors as valproic acid are compounds that inhibit HDACs enzymes that, in conjunction with histone acetylases, regulate the acetylation state of histones and, by extension, the conformational status of chromatin. VPA is clinically known to be used in treatment of different types of epileptic disease. Effects and signal transduction pathways of cell death have been studied in cells harvested and purified from routine bone marrow aspirates of several patients with multiple myeloma, as well as on myeloma cell lines (OPM2, U266) treated with a physiologic dose range of valproic acid (1–4 mM). We observe significant in vitro toxicity starting at doses of 1 mM for 24h in cell lines as well as in patient cells
using an XTT based cytotoxicity assay. The question we adressed was the mechanisms by which the MM died. Flow cytometric analysis with PI / Annexin V staining does not show apoptosis features, nor do TUNEL staining or DNA fragmentation assays, suggesting non activation of the intrinsic apoptosis pathway. In contrast, cell morphology of treated cells stained with May-Gruenwald-Giemsa staining show increase in multinucleated giant cells. Multinucleation has often been described in cells which die through mitotic catastrophe. Further experiments exploring this hypothesis will be conducted.
Effect of 48h valproic ac on myeloma cell lines Effect of 48h valproic ac on myeloma cell lines Effect of 48h valproic ac on CD138 cells from myeloma patients Effect of 48h valproic ac on CD138 cells from myeloma patients
Treatment Strategy and Prognosis of Myeloma Patients According to ISS Stage at Diagnosis.
Authors: Hatta Yoshihiro , Nishinarita Susumu , Itoh Takeyoshi , Takeuchi Jin , Sawada Umihiko 
Published: April 2020

Abstract
Background: Recently, a new ISS staging system for myeloma has been developed. By analyzing over 10,000 patients, ISS is a simple and useful system to estimate prognosis. However, by ISS, survival time was evaluated only for the time after chemotherapy. The prognosis of untreated patients and survival time after initial diagnosis were not well understood by ISS. Our aim was to evaluate the prognosis and define treatment strategy for newly diagnosed, untreated myeloma patients using ISS at diagnosis. Especially, treatment strategy for ISS stage I was received attention.
Methods: 127 newly diagnosed, untreated myeloma patients referred to Nihon University Itabashi Hospital between 1994 and 2004 were retrospectively analyzed. ISS stage was determined with the laboratory data at diagnosis. Median age of the patients was 62 y (range 30–88). Median follow-up duration was 32.5 months (range 0–171). Transplanted patients were censored at the time of transplantation.
Results: 50% survival duration after initial diagnosis for stage I (n=54), II (n=26), and III (n=47) were 106, 36, and 14.5 months, respectively. For stage I patients given chemotherapy, both 50% survival times after initial diagnosis and after chemotherapy were the same, 85 months, suggesting that stage I patients required chemotherapy were treated early after diagnosis. Fifteen stage I patients have not been treated and all of them are alive. Of these 15 patients, 14 were in Durie-Salmon stage I and one was in Durie-Salmon stage II at diagnosis. 50% progression time from ISS stage I to II in untreated patients was 2 months. For the patients treated at ISS stage I, 50% progression time from stage I to II and I to III were 61 and 155 months, respectively. These data suggest that the progression from stage I to II could be postponed by early chemotherapy. However, overall survival duration of the patients treated at stage I and of those treated after progression to stage II was not different.
Conclusion: We defined treatment strategy for myeloma using ISS at diagnosis. Certain amounts of myeloma patients with Durie-Salmon stage I and ISS stage I concomitantly at diagnosis were not required chemotherapy. Administration of chemotherapy for ISS stage I patients at diagnosis are recommended after they progress to stage II.
A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide [Revlimidä (R), CC-5013] in Combination with Doxorubicin and Dexamethasone (RAD) in Patients with Relapsed or Refractory Multiple Myeloma.
Authors: Gerecke C. , Knop S. , Topp M.S. , Kotkiewitz S. , Gollasch H. , Liebisch P. , Hess G. , Watters K. , Einsele H. , Bargou R.C. 
Published: April 2020

Abstract
Introdution:
Lenalidomide (Revlimid™) is Celgene’s lead clinical compound in a new group of drugs called IMiDs, which have immunomodularory properties. The drug has been evaluated in phase-I, II, and III clinical trials for the treatment of multiple myeloma (MM). Lenalidomide shows substantial anti-tumor activity in patients with refractory or relapsed MM and significantly prolongs time to tumor progression (TTP) compared to standard therapy in these patients. Lenalidomide was well tolerated in these trials, the only dose limiting toxicity in a phase-I trial was myelosuppression. In order to further improve therapeutic efficacy and to overcome drug resistance we are currently evaluating Lenalidomide (Revlimid™) in combination with doxorubicin and dexamethasone (RAD) for the treatment of patients with refracrory or relapsed MM in a phase-I/II trial.
Methods:
Patients with relapsed or refractory multiple myeloma recieve a fixed dose of either 10 mg or 15 mg Revlimid Revlimid™ given daily for 21 days (d 1–21) in combination with doxorubicin (adriamycin) and dexamethasone, to be repeated on day 29. Three dose levels of doxorubicin (adramycin) are planned: 4 mg/m2 day 1–4, 6 mg/m2 day 1–4 and 9 mg/m2 day 1–4. 40 mg dexamethasone is given orally day 1–4 and day 17–20 at a fixed dose. 3– 6 cycles are applicated unless severe toxicity or disease progression occurs.
Results:
RAD treatment was well tolerated at dose level 1 and dose level 2. Therefore, current dose escalation is continued. All patients treated at the first two dose levels (6/6) responded to RAD treatment. Further updated results on this trial will be presented.
Salvage Thalidomide Improves Survival of Relapsed Multiple Myeloma Patients When Compared to Other Salvage Chemotherapies: A Retrospective Analysis.
Authors: Bahlis Nizar J. , Savoie Lynn , Chaudhry Ahsan , Valentine Karen , Jenkins Deidre , Brown Christopher , Russell Jim , Stewart Douglas 
Published: April 2020

Abstract
Thalidomide has become one of the standard treatments of multiple myeloma patients either at diagnosis or in relapse and refractory disease. Up to date there are no randomized trials comparing the efficacy of thalidomide to other chemotherapy combinations in relapsed and refractory disease. We have conducted a retrospective analysis comparing the outcome of patients (n=141) younger than 65 years old who received either thalidomide (Group A; n=58) or non-thalidomide containing regimens including dexamethasone, cylophosphamide, melphalan+ prednisone, VAD (Group B; n=83) at first or second relapse post autologous stem cell transplant. The two groups were comparable in respect to age at relapse, Durie Salmon staging, IPS staging, serum beta-2 microglobulin, serum albumin and ECOG performance status. The median time to relapse from the date of initiation of salvage therapy in the thalidomide group was 12.1 months vs 6.5 months in the non-thalidomide group (p &lt; 0.05). The median overall survival from the time of diagnosis was significantly longer in the thalidomide group (median survival = 131 months) vs the non-thalidomide group (median survival 50 months) (p =0.0055) (Figure below). In summary our retrospective analysis supports the superiority of thalidomide in the treatment of younger relapsed and refractory myeloma patients when compared to other previously established salvage chemotherapy regimen.
Figure Figure
The Histone Deacetylase Inhibitor Sodium Valproate Has In Vitro Anti-Neoplastic Activity Against Primary Multiple Myeloma Cells and Cell Lines Both Alone and in Combination with Velcade.
Authors: Basu Supratik , Khanim F. L. , Hayden R. E. , Barkhuinzen A. , MacWhannel A. , Jacob A. , Handa S. , Craddock C. , Drayson M. T. 
Published: April 2020

Abstract
There is growing evidence that histone deacetylase inhibitors (HDAC-I) may have benefit in the treatment of multiple myeloma (MM). We assessed the in vitro responses of the MM cell lines H929, JJN3, KMS11 and U266 to the HDAC-Is trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and sodium valproate (SV). All three HDAC-Is induced dose dependent cell killing and the ranked sensitivity of the lines was remarkably constant with U266 cells being most resistant to all three inhibitors. Real time RT-PCR based analyses of the HDAC expression profiles, identified that the greater resistence of U266 cells was associated with 5–10 fold increased expression of a single HDAC from the sirtuin family of deacetylases (SIRT5). Each HDAC-I displayed different potencies against the cell lines; TSA killed in the range 0.1–1μM, SAHA in the range 1–10μM and SV at the higher doses of 1–10mM. Despite being less potent, the doses of SV are commensurate with those that can be achieved in vivo. Furthermore, we have identified synergy/cooperation between suboptimal SV concentrations and the proteasome inhibitor Velcade (Bortezomib). MTT assays using JJN3 cells, demonstrated that 1mM SV had little effect reducing survival to 89% whereas 0.6 nM velcade reduced cell survival to 42±5.5%. Killing by velcade was not significantly enhanced by the additional presence of 1μM dexamethasone (Dex)(36±3.4%). However, the combination of SV, Dex and Velcade resulted in near total cell killing (4.7±2.6% survival). Collectively, these observations suggested that SV may have value in MM therapy. However, we wished to also investigate the potency of SV against primary MM cells. We have developed an in vitro culture system in which primary MM plasma cells survive for up to 30 days. In this culture system we have observed efficient and selective killing of MM cells by 1mM SV that has been comparable or indeed greater than that observed in response to 1μM SAHA. Thus it appears that primary MM cells are more SV sensitive than MM cell lines. Together our findings indicate that SV may have value in MM therapy and in particular when combined with proteasome inhibitors. Our data also indicate that SIRT5 overexpression may be a resistance factor against such therapies.
Arsenic Trioxide Targets the Interleukin-6 Cascade in Multiple Myeloma by Promoting Lysosomal Degradation of the Interleukin-6 Receptor Complex.
Authors: Cheung Wai Chung , Kwong Yok Lam 
Published: April 2020

Abstract
Introduction. Treatment of multiple myeloma (MM), a B-cell neoplasm characterized by clonal expansion of plasma cells in the bone marrow, remains unsuccessful in a significant proportion of patients, so that innovative strategies are needed. Arsenic trioxide (As2O3) has shown notable efficacy against MM in vitro and in clinical studies. Multiple cellular pathways in MM are targeted by As2O3. As cellular growth of MM cells is interleukin-6 (IL-6) dependent, we investigated if As2O3 also targeted the IL-6 cascade. Materials and methods. The IL-6-dependent MM cell line U266 was used as an in vitro model. Cell growth was measured by MTT assay, and apoptosis by flow cytometry. Protein phosphorylation was studied by Western blotting with specific antibodies. Expression of IL-6 receptor (IL-6R) was investigated by Western blotting and flow cytometry. Gene expression was detected by quantitative polymerase chain reaction (Q-PCR). Results. As2O3 showed a time and dose related inhibition of U266 cellular proliferation by induction of apoptosis. At clinically achievable concentrations (2 – 4 μmol/L), As2O3-induced apoptosis was associated with inhibition of constitutive tyrosine phosphorylation of JAK2 and STAT3, in a time and dose-dependent manner. Furthermore, pre-treatment of U266 cells with As2O3 prevented rescue of phosphorylation of JAK2 and STAT3 by exogenous IL-6, implying that the IL-6 cascade was targeted. Using Western blot analysis, we showed that As2O3 induced a time and dose-dependent down-regulation of both components of the IL-6R complex: IL-6R alpha subunit (IL-6Rα) and gp130 signal transducer. These results were confirmed by flow cytometry, showing that As2O3 treatment led to a down-regulation of surface expression of the IL-6Rα. Interestingly, Q-PCR did not reveal any change in the mRNA levels of the two genes with As2O3 treatment, suggesting that As2O3 downregulated IL-6R complex via a post-transcriptional mechanism. It is known that under physiological conditions, the IL-6R complex is internalized upon ligand binding and is targeted to lysosomes for degradation. Treatment of the U266 cell line with the lysosome inhibitor ammonium chloride totally abrogated As2O3-induced degradation of IL-6Rα and gp130. These results suggested that As2O3 might promote lysosomal degradation of IL-6Rα and gp130 by inducing a ligand-independent internalization of the receptor complex. Conclusion. Our results demonstrated that As2O3 suppressed IL-6-induced JAK/STAT3 signaling pathway in MM cells and this might be, at least partly, mediated by promoting ligand-independent internalization and lysosomal degradation of the IL-6R complex. These results have significant implications on the use of As2O3 in the treatment of patients with MM and other malignancies that are IL-6 dependent.