bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone
Authors: Tosi Patrizia , Zamagni Elena , Tacchetti Paola , Perrone Giulia , Ceccolini Michela , Brioli Anna Maria , Pallotti Maria Caterina , Pantani Lucia , Petrucci Alessandro , Baccarani Michele , Cavo Michele 
Published: April 2020

Abstract
Bone disease occurs in approximately 80% of patients with newly diagnosed multiple myeloma (MM) and is caused by the interaction of the neoplastic clone with bone marrow microenvironment, ultimately resulting in an altered balance between bone resorption and bone formation. It has been previously reported that therapies aimed at eradicating the myeloma clone could contribute to decrease bone resorption, even though bone formation remains impaired even in responding patients, due to the use of high-dose steroids. It has been recently demonstrated, both in vitro and in animal models, that Bortezomib improves bone formation by stimulating osteoblasts. In order to test whether this activity was retained also in vivo, we evaluated markers of bone resorption (serum crosslaps) and bone formation (serum osteocalcin-OC and bone alkaline phosphatase - BAP) in a series of patients who were enrolled in the “Bologna 2005” phase III clinical trial at our Center. By study design, after registration patients were randomized to receive three 21-days courses of induction therapy with either VTD (Bortezomib, 1.3 mg/sqm on d 1, 4, 8, and 11, plus Dexamethasone, 40 mg on each day of and after Bortezomib administration plus Thalidomide 200 mg/d from d 1 to 63.) or TD (Thalidomide as in VTD and Dexamethasone 40 mg/d on d 1–4 and 9–12 of every 21-d cycle), prior to stem cell collection and double autologous stem cell transplantation. As of January 2008, 27 patients (19 male and 8 female, median age = 57.5 yrs) entered the sub-study; of these, 15 and 12 patients were randomized in the VTD and TD arm, respectively. At diagnosis, both groups of patients showed a marked increase in serum crosslaps as compared to upper baseline limit (7321±1445pmol/L in the VTD arm and 11140±2576pmol/L in the TD arm) while both OC and BAP were reduced as compared to lower baseline limits. After completion of the induction therapy, serum crosslaps were significantly decreased in both treatment groups (2747±319pmol/L in VTD arm, p=0.007; 3686±1084pmol/L in the TD arm, p=0.0015). In the TD group a significant further reduction in bone formation markers was also observed (42% reduction in serum OC and 30% in BAP, p=0.03 and 0.04 as compared to pre-treatment values); on the contrary, in the VTD arm both OC and BAP were not significantly decreased as compared to baseline values (15% and 11% for OC and BAP, respectively). These data suggest that incorporation of Bortezomib into induction therapy counteracts the inhibitory effects of high-dose steroids on osteoblastogenesis, thus sparing bone formation.
Association of Elevated Circulating Proteasome Levels at Diagnosis with Poor Outcome in Multiple Myeloma
Authors: Liebisch Peter , Sixt Stephan , Bachmann Hagen S , Frey Ulrich H , Peters Juergen , Doehner Hartmut , Duehrsen Ulrich , Nückel Holger 
Published: April 2020

Abstract
Background: The proteasome is a proteolytic complex for intracellular degradation of ubiquitinated proteins which are involved in cell cycle regulation and apoptosis. A constitutively increased proteasome activity has been found in myeloma cells. Recent studies have shown that inhibition of the ubiquitin-proteasome system can be successfully used as a targeted therapy in multiple myeloma (MM). Recent data suggest a significant correlation between circulating proteasome levels (CPL) and outcome in patients with MM. Therefore, we investigated CPL in 110 patients in order to assess the role of CPL in MM.
Experimental design: CPL were measured in serum samples from healthy controls (N=10) as well as from patients with monoclonal gammopathies of undetermined significance (N=27), indolent MM (N=15) and symptomatic MM (N=68) using enzyme-linked immunoabsorbent assay (ELISA) techniques detecting circulating 20S proteasome components. All serum samples were collected at the University Hospital in Ulm at time of diagnosis.
Results: The median CPL were 123.5 ng/mL (range, 95–185 ng/mL) in healthy controls, 180 ng/mL (range, 100–485 ng/mL) in patients with MGUS (N=27) or indolent MM (N=15), and 227.5 ng/mL (range, 100–985 ng/mL) in patients with symptomatic MM (N=70). The CPL of patients with symptomatic MM were significantly elevated compared with healthy donors (p=0.0017) and to persons with asymptomatic gammopathies (p=0.046). While CPL were also significantly higher in the MGUS/indolent MM cohort as compared to controls (p=0.03), CPL in MGUS and indolent MM were comparable. Using ROC analysis in the symptomatic MM cohort patients with CPL &gt;150ng/mL (N=50) had a significantly shorter progression-free survival (PFS) time than patients (N=18) with CPL&lt;150 ng/mL levels (median PFS: 40 versus 57 months, log rank test p=0.026). Of note, all six patients who died in the observation interval had CPL &gt;150ng/mL.
Conclusions: Here we demonstrate that increased CPL at diagnosis correlates with poor outcome in symptomatic MM patients. Evaluation of the prognostic significance of CPL in a larger cohort of uniformly treated patients with symptomatic MM is currently under way. This data will be presented at the meeting.
The Evaluation of Light Chains USING ELISA Method
Authors: Vavrova Jaroslava , Friedecky Bedrich , Tichy Milos , Holeckova Magdalena , Maisnar Vladimir , Hajek Roman 
Published: April 2020

Abstract
Introduction: Free light chain assay (FLC) has moved into clinical practice based on the building evidence of its utility in multiple myeloma (MM) and other monoclonal gammopathies. The purpose of the study is to verify the effectiveness of the basic parameters relevant to serum free light chain analysis using ELISA method and to compare it with the well-established FreeLite assay.
Methodology and sample collection: ELISA method was tested using diagnostic kit developed by Biovendor (Czech Republic). Immunoturbidimetric measurement using the FreeLite kit (The Binding Site), adapted on the Modular P (Roche), and was used as a reference method. Regression analysis, developed by Passing and Bablok, expressed by equation Y = −9,84 + 1,53 X allowed to compare the two methods. In total, the results of serum FLC determination in 40 donors and in 202 patients with monoclonal gammopathies were compared.
Results: Reference intervals were tentatively determined based on an analysis of male and female blood donor samples. The ratio kappa/lambda was from 0.24 to 1.17 by use of ELISA method and from 0.53 to 1.92 by reference immunoturbidimetric method. Intermediate measurement precision was obtained as follows: (intermediate) kappa using ELISA 6,6–11,0 %, using immunoturbidimetric method 5,6–6,9 %; lambda using ELISA 7,3–8,6 %, using immunoturbidimetric method 6,1–9,2 %. Regression coefficient was R = 0, 73. We were observing the influence of sample dilution on the results and we confirmed the necessity to verify the degree of dilution in each pathologically changed sample. The main factors of a successful free light chain determination are: validity of the reference intervals, difference in diagnostic classification when using different methods. Considering the necessary dilution, every patient sample requires a special and individual attention. In many patients, an applicable result can be obtained only having repeated the measurements at different dilution levels; therefore, it is not possible to predict the number of examinations one kit can serve to.
Conclusion: The determination of serum free light chains cannot be considered as a routine procedure for the time being. This analysis requires careful sample preparation and high professional level of laboratory personal. Both methods used to determine serum FLC are suitable for laboratory practice; the comparability of their predictive value in clinical practice requires a further testing.
Assessment of Thalidomide Therapy Effect on Platelet Activation and Selected Blood Coagulation Parameters in Multiple Myeloma Patients
Authors: Robak Marta , Trelinski Jacek , Chojnowski Krzysztof 
Published: April 2020

Abstract
Background: Patients with multiple myeloma are at relatively high risk of developing thromboembolic events (TEE). These life-threatening complications may arise from hypercoagulability associated with malignancy and/or may be connected with anticancer therapy. The risk of developing TEE appears to be particularly high during treatment with thalidomide alone or combined with chemotherapy and/or high-dose dexamethasone. The pathogenesis of thalidomide-related thrombosis in myeloma patients remains unexplained. Some authors suggest that platelet activation can contribute to development of this complication in multiple myeloma patients on thalidomide therapy but until now it has not been a subject of investigation.
Patients and methods: The study was performed in 20 patients with multiple myeloma. The tests were done at diagnosis and after one month of thalidomide therapy at a dose of 100–200 mg/24h. All patients had normal renal function and did not take drugs affecting platelet function. The control group consisted of 15 healthy subjects of similar age. In each patient closure time with ADP/Collagen and Epinephrine/Collagen cartridges by PFA-100 method was assessed. Platelet expression of membrane activation marker P-selectin (CD62p) on resting platelets and after stimulation with ADP/Collagen and Epinephrine/Collagen was analyzed by flow cytometry. Additionally, activity of factor VII, factor VIII and von Willebrand factor (vWF), concentration of fibrinogen and D-dimer, and platelet count were evaluated.
Results: The mean PFA-100 closure time was significantly shortened with ADP/Collagen (87.2 ±17.1 s vs 100.4 ± 19.3 s, p=0.008) and Epinephrine/Collagen cartridges (118.5 ± 20.3 s vs 132.2 ± 27.9 s, p=0.04) after one month of therapy in comparison to baseline. The median CD62p percentage increased markedly after treatment-on resting platelets 5.1 (0.76–22.2) vs 3.6 (0.1–21.5) p=0.03. and after stimulation with Epinephrine/Collagen 16.6 (2.3–57.3) vs 11.1 (1.4–19.5) p=0.03. The observed increased P-selectin expression after ADP/Collagen stimulation 26.3 (8.5–42.8) vs 19.7 (1.0–35.4) was not statistically significant. The median values of P-selectin expression at diagnosis and after thalidomide therapy were also higher than in the control group. The results of factor VIII, vWF activity, fibrinogen and D-dimer concentration did not differ markedly before and after therapy. Significantly lower mean activity of factor VII (p=0.004) and higher mean platelet count (p=0.03) after therapy were observed.
Conclusions: These results demonstrate that platelet activation is one of the pathogenetic factor of thalidomide-related thrombotic complications and can explain some observations that acetylsalicylic acid may protect against TEE during myeloma treatment with thalidomide.
An Observational Post Authorization Study on the Use of Bortezomib in Multiple Myeloma Patients in the Netherlands: Results of An Interim Analysis
Authors: Lokhorst Henk , van Der Heul Cornelis , Roerdink Henk , de Weerdt Okke 
Published: April 2020

Abstract
Introduction: Bortezomib (Velcade) is a first-in-class proteasome inhibitor for the treatment of patients (pts) with multiple myeloma (MM). Most data on efficacy and safety are from randomised controlled studies in selected groups of pts with MM.
Aim of the study: To evaluate safety and efficacy of bortezomib in the real-life community oncology practice setting as a second-line therapy or in subsequent lines of therapy in pts with MM.
Materials and methods: In an observational, multicentre study, the efficacy and safety of treatment with bortezomib was assessed in MM pts. An interim analysis was performed on data of pts enrolled from November 04 until November 06 (109 pts).
Results: All results are given as median. The pts age was 67 yrs, Karnofsky Performance Score was 80%, time from initial diagnosis was 3.3 years, 62% of the pts had more than 2 previous lines of treatment, 85% of the pts had disease stage III. Pts were treated with median 4 cycles (95% CI: 4.1–5.0) of bortezomib. Median time to initial response was 50 days and median time to best response category was 84 days. Of all pts 43.2% achieved a partial response or better (2.8% CR, 6.4% nCR, 3.7% VGPR, 30.3% PR); 16 pts were not evaluable for response. The duration of response (DOR) was 6.3 months, PFS was 5.8 months and overall survival was 1.2 yrs. The treatment was generally well tolerated. Most common adverse events (all grades) in &gt;15% of the pts were, in order of decreasing frequency, thrombocytopenia, nausea, diarrhoea, fatigue, (poly)neuropathy, constipation, malaise, anaemia, pyrexia, vomiting and anorexia. For responding pts treatment discontinuation due to an AE occurred in 46.8% of the pts. For the three most common AE’s (polyneuropathy, fatigue/malaise, thrombocytopenia), resulting in discontinuation of the bortezomib treatment, the discontinuation was not preceded by a dose adjustment in almost half of the cases. In 9 pts (8.3%), Herpes zoster reactivation was reported. Twenty-two out of 109 pts were thalidomide naïve when starting bortezomib. 59.4% of these pts achieved a PR or better vs. 39% in thalidomide pre-treated pts, but thalidomide pre-treated pts had a longer time from initial diagnosis (3.5 vs 2.6 years) and had more previous treatment lines compared to thalidomide naïve pts (3 2 lines of previous therapy 97.7% vs 59.1% respectively).
Conclusion: Response rates in this study were comparable to those in other community studies and higher than reported in previous clinical studies. Overall the treatment with bortezomib was well tolerated. However, it seems dose adjustment as a strategy to continue treatment and to increase the quality of response, is still underutilized in clinical practice. Overall survival was as expected in this patient population. The thalidomide naïve group was yet too small to draw any conclusions on safety and efficacy as compared to the thalidomide pre-treated pts.
IgM Multiple Myeloma: A Rare Subtype Highly Sensitive to Lenalidomide
Authors: Moreno-Aspitia Alvaro , Charles Antony , Patel Tejal , Bueno Celine , Zubair Abba , Menke David 
Published: April 2020

Abstract
Background: IgM multiple myeloma (MM) are very rare plasmaproliferative disorders representing 0.5–1.2% of all cases of MM and &lt; 0.2% of all IgM monoclonal gammopathies. Clinical criterion are not always helpful in differentiating IgM MM from Waldenstrom macroglobulinemia. However, the presence of lytic bone lesions, absence of lymphadenopathy and/or hepatosplenomegaly, presence of translocation of the immunoglobulin heavy chain locus at 14q32 [t(11;14), t(14;16), t(4;14)], and strong expression of CD138 by the plasma cells are useful in the diagnosis of IgM MM. It has been our experience and of others that these cases have an aggressive behavior at presentation, shorter survival than IgG and IgA MM and poor response to therapy for lymphoplasmacytoid lymphomas. We present here 2 cases of IgM MM with a dramatic response to Lenalidomide and low dose dexamethasone (Rev/Dex)
Results: Baseline patient characteristics at time of diagnosis of IgM MM and therapy outcome are presented in the following 2 tables:
Table 1.
Case 1 2 Age and sex 72 (F) 73 (F) Serum M-spike (g/dL) 5.3 6.2 Urine M-spike (mg/dl/24 hrs) 72 412 Serum IgM (mg/dL) 8,590 11,000 BM plasma cells percentage 90 20 Plasma cell immunophenotyping CD138+++, partial CD20, CD56− CD138+++, partial CD20, CD56− Cytogenetics (Standard and/or FISH) Standard: normal FISH: not done on initial biopsy. On follow up there were insufficient number of plasma cells to perform test Standard: of 20 metaphases, 6 had a complex hypotetraploid karyotype with relative loss of 13q, 14, 15, 16, 20, and 22, and numerous unbalanced rearrangements. FISH: a plasma cell clone with monosomy 13 and IGH/c-MAF fusion, t(14;16). In addition, approximately 60% of plasma cells had a tetraploid clone with the same anomalies as well as relative loss of p53 Bone lesions Multiple non-traumatic spinal fractures and of stenum Several lytic lesions of long bones Renal insufficiency No No Anemia (Hbg g/dL) Yes (8.7) Yes (8.1) Hypercalcemia (Ca mg/dL) Yes (12.5) Yes (11.4) Beta 2 microglobulin (mg/dL) 5.79 8.51 Serum viscosity (cpoise) 5.9 4.8
Table 2. Best Response to therapy
Case Therapy Best Response Comments 1 Rituxan, then Fludarabine based therapy Transient response Rapid progression after partial and transient response to each therapy 1 Lenalidomide + LD-Dex sCR after cycle #6. Currently on CR 18 months later IgM declined from 8,590 to 43 mg/dL after 4 cycles of Rev/Dex. 2 Lenalidomide + LD-Dex VGPR after cycle #2 IgM declined from 11,000 to 463 mg/dL after cycle 3. Complete disappearance of M-spike in serum; BM to be done after cycle #4
Conclusions: This is the first report that we are aware of a rapid and dramatic response to lenalidomide and low dose dexamethasone in these rare cases of IgM MM with poor response to NHL-type treatment. Lenalidomide-based therapy might abrogate poor prognosis cytogenetics in this unusual subtype of MM (case #2), however, follow up for this patient is still very short.
The Role of An Early Interim 18 F-FDG PET/CT for Prediction of Outcomes of Patients with Peripheral T Cell Lymphoma
Authors: Choi Yoon Hee , Kang Byung Woog , Hong Hyun Soo , Kim Chul , Jang Geundoo , Lee Sung Sook , Ryu Jin Sook , Huh Jooryung , Lee Dae Ho , Kim Sang We , Lee Jung Shin , Suh Cheolwon 
Published: April 2020

Abstract
Background Recent studies have demonstrated that positron emission tomography (PET) performed after one to four cycles of multiagent chemotherapy predicts therapeutic outcome in lymphomas which are mainly diffuse large B cell lymphoma and Hodgkin’s lymphoma. However, interim 2-[18F] fluoro-2-deoxy-D-glucose (FDG) PET/CT has not yet been discussed in peripheral T cell lymphoma. In this study, we investigated the role of an interim 18 F-FDG PET/CT for the prediction of the progression free survival (PFS) and overall survival (OS) in peripheral T cell lymphoma.
Patients and methods We retrospectively analyzed the medical records of thirty-three patients with newly diagnosed, initially FDG-avid peripheral T cell lymphoma between 2004 and 2007 (median age of 44 years, 18 peripheral T cell lymphoma, unspecified, 9 anaplastic large cell lymphoma, 6 angioimmunoblastic T cell lymphoma) who underwent 18F-FDG PET/CT after one to four cycles of chemotherapy (interim scan). The maximal response to initial therapy was evaluated using conventional methods. Interim FDG-PET/CT results were correlated to the PFS and OS using Kaplan-Meier survival analysis. Cox regression analyses were performed for independence of prognostic factors.
Results The median follow up was 23 months (range, 2–52 months). In the initial therapy, 25 patients achieved CR, 5 patients showed progress and 3 patients died. Interim FDG-PET/CT was negative in 17 patients, positive in 9, and 7 patients showed minimal residual uptake (MRU). The CR rate of initial therapy was 100%, 85% (6/7) and 22% (2/9) in the FDG negative, MRU and positive group, respectively. The estimated 2 year PFS was 88.2% for the negative group, 38.3% for the MRU group, and 0% (median survival of 5.6 months) for the positive group. The log rank test showed strong associations between interim FDG-PET/CT results and PFS (P =0.001) and OS (P &lt;0.001). Also, univariate and multivariate analyses showed that the interim FDG-PET/CT was the only independent factor to predict outcomes among known prognostic factors such as age, elevated lactate dehydrogenase, the number of extranodal disease, stage, performance status (p=0.007).
Conclusion Interim FDG PET/CT is an excellent and independent predictor of outcomes of patients with peripheral T cell lymphoma and is suggested to be a useful tool to modify the therapy.
Prognostic Value of P-Glycoprotein (Pgp) in Non-Hodgkin’s Lymphoma
Authors: Pilleux Lilian M , Carrasco Cristian S , Pisón Claudia V , Valencia Yenny O , Lopez Mauricio G , Benavides Tatiana , Calderón Susana E 
Published: April 2020

Abstract
Multidrug resistance (MDR) is one of the greatests obstacles of cancer therapy. One of the most studied mechanisms of resistance is mediated by Pgp encoded by gene MDR-1. Studies in patients with Human Immunodeficiency Virus associated non-Hodgkin’s lymphoma (NHL) show that those MDR positive achieve lower rate of complete remission than those MDR negative. Reports in refractory or relapsed NHL have failed to reproduce this finding. In an attempt to confirm the relationship between Pgp and poor outcome in NHL we analyzed the expression of Pgp in patients treated in our cancer reference hospital.
Patients and Methods: We retrospectively analyzed a cohort of patients 15 years or older diagnosed with NHL in 1998–2002 quinquennium in Valdivia Public Hospital (VPH) treated in accordance with the protocols of the National Adults’ Antineoplastic Drugs Program (NAADP) with an emphasis on clinical response and histological features. An immunohistochemical staining (IH) with Pgp Clone C494 considering negative that one without positivity or &lt;5% of the cells, + positive: 5–25%, + + positivity 25–50% and + + + positivity 50–100%. We performed a descriptive analysis and Kaplan-Meier actuarial survival analysis using log-rank and Wilcoxon statistical tests for comparing curves. It was considered statistically significant value of p &lt;0.05.
Results: During the study period 96 patients were admitted to NAADP at VPH corresponding 82 to newly diagnosed cases confirmed histologically, 14 were excluded (6 relapses, 4 histology not NHL, 2 without biopsy, 2 not evaluable). At the time of analysis there were 49 cases of with Pgp IH. 63% of the cases were positive and 37% negative. Among the positive cases Pgp intensity was: + in 34.5%, + + in17.2% and + + + in 48.3%. When analizing survival curves according to Pgp positivity at 2 and 5 years, respectively, we observed that:
The overall survival (OS) showed a trend towards increased survival in the Pgp negative group, but without significant difference (log-rank p = 0.07; Wilcoxon p = 0.05). Disease-free survival (DFS) showed no differences (log-rank p = 0.49; Wilcoxon p = 0.65).
The OS according to intensity of Pgp positivity again showed no differences (log-rank p = 0.07; Wilcoxon p = 0.11). When analizing OS in Pgp positive cases according to localized (I and II) or advanced (III and IV) stages we observed it was higher in the first group (log-rank p = 0.01; Wilcoxon p = 0.03).
Conclusions: In our study the expression of Pgp or its intensity at the time of diagnosis in patients with NHL did not have prognostic value. We have to consider the limited number of cases analized and the low percentage of localized stages in it. Additionally histological subtypes Pgp negative cases were mostly aggressive. Further studies are needed to discard Pgp expression as another prognostic factor in NHL. (DID S-200725 Proyect)