bluuebunny/crossref_metadata_2025_split huggingface dataset:
IgG and IgA Monoclonal Gammopathies of Undetermined Significance (MGUS) at Low Risk of Evolution: Proposal and Validation of a Prognostic Scoring System
Authors: Rossi Francesca Gaia , Marcheselli Luigi , Petrucci Maria Teresa , Rossi Davide , Callea Vincenzo , Guffanti Andrea , De Muro Marianna , Federico Vincenzo , Baraldi Anna , Musto Pellegrino , Bacigalupo Andrea , Gaidano Gianluca , Goldaniga Maria , Avvisati Giuseppe , Deliliers Giorgio Lambertenghi , Baldini Luca 
Published: April 2020

Abstract
PURPOSE: The presenting clinico-hematologic features of 1283 patients with IgG and IgA class monoclonal gammopathies of undetermined significance (MGUS) were correlated with the frequency of malignant transformation to evaluate the most important variables prognostically associated with its evolution into multiple myeloma (MM).
PATIENTS AND METHODS: Two IgG MGUS patient populations were evaluated: a study sample (553 pts) and a test sample (378 pts). The IgA MGUS population included 352 cases.
RESULTS: Considering IgG cases the median follow-up was 6.7 yrs in the study group vs 3.6 yrs in test group; in the first 47/553 pts developed MM vs 22/378 in the latter. At multivariate analysis serum monoclonal component (MC) £1.5 g/dl, absence of BJ proteinuria, normal serum polyclonal Ig levels and age less than 70 defined a prognostically favourable subset of patients. On the basis of these four variables, pts could be stratified into 3 different 10 yrs-evolution risk groups (HR 1.0, 4.28, 11.6; P&lt;0.001). This scoring system was validated in the test sample. Considering IgA cases, thirty out of 352 patients developed MM after a median follow-up of 4.8 yrs. At multivariate analysis, Hb &lt; 12.5 g/dl and serum polyclonal Ig reduction resulted related with neoplastic progression.
CONCLUSIONS: using simple variables, whose prognostic role we have previously described, we could validate a prognostic model useful to identify situations with different evolution risk in IgG MGUS. Considering IgA cases a possible prognostic role of Hb level emerged, while the negative one of monoclonal component class or serum levels was not confirmed.
Phenotypic Correction of Hemophilia a Using An Ips-Based Cellular Therapy
Authors: Xu Dan , Alipio Zaida , Yang Jianchang , Fink Louis M. , Xu Wilson , Ward David C , Ma Yupo 
Published: April 2020

Abstract
Hemophilia A, a sex-linked bleeding disorder, is caused by mutations within the genomic sequence of the Factor VIII (FVIII) gene. Mutations of FVIII lead to depleted or reduced protein production, and inefficient clotting. Because hemophilia A is caused by a single gene deficiency, several attempts at gene therapy have been made, including several phase I clinical trials. However, these have all failed for various reasons--including immune rejection. However, with the recent discovery of induced pluripotent stem (iPS) cells the immune rejection barrier can be circumvented. iPS cells can be generated from somatic cells by introducing the ectopic expression of three transcription factors Oct4, Sox2, Klf4 (Nakagawa et al., Nat Biotechnol.26: 101–106, 2008) To date, iPS cells have been indistinguishable from ES cells, and thus provide tremendous therapeutic potential. In this study, we differentiated iPS cells to endothelial and endothelial progenitor cells using the EB (embryonic bodies) differentiation method. iPS derived endothelial or endothelial progenitor cells express both endothelial or endothelial progenitor cell specific markers, such as CD31, and Flk1, as well as FVIII. These iPS-derived cells were directly injecting into the liver of irradiated hemophilia A model mice. Seven days after transplantation, hemophilia A and control mice were challenged by a tail-clip bleeding assay. Non-transplanted hemophilia A mice died within few hours, while transplanted mice survived for many weeks and more. Plasma FVIII expression in transplanted hemophilia A mice is significantly higher than in non-transplanted hemophilia mice and this elevated expression confers a correction on the hemophilia A phenotype in mice following a tail-clip. Our studies suggest that transplantation of iPS derived endothelial progenitor cells can rescue the phenotype of hemophilia in mouse models and thus potentially suitable for the future development of cell therapy of monogenetic disorders.
Serum free Light Chains Profile as Early Biomarker with Predictive Value after autologous Transplant in Multiple Myeloma
Authors: Recasens Valle , Rubio-Escuin Rebeca , Rubio-Martinez Araceli , Pascual Transito , Lopez Natividad , Sanjuan Mjose , Giraldo Pilar 
Published: April 2020

Abstract
Background: Serum free light chain Freelite® assays, is a quantitative method to measure serum free light chain (FLC) concentration, and could be a simple and accurately indicator to predict the early relapse in Multiple Myeloma(MM) patients with apparently complete response. FLC are small proteins that cross easily through the glomeruli pores, entering the proximal tubule, where they are reabsorbed and metabolised. In patients with a low tumour burden, the amount of FLC produced can remain below this reabsorption capacity and so have no detectable in urine. However, serum levels of FLC continue to rise and therefore become a good biomarker to detect an early progression.
Aims of study: To determine the predictive value of serum FLC concentration in MM patients in complete response after autologous stem cell transplant as a early biomarker of relapse.
Patients and Methods: Observational, analytical study performed in 24 MM patients included in an autologous stem cell transplant program during 2002–2006 in one center. All patients received induction therapy with VBCMP/VBAD (×4), follow by G-CSF movilization and collection of CD34+ cells. The infussion of CD34+(mean: 5.39×106/kg; range: 2.24–18.8) was performed after conditioning with high doses of Melphalan. Serum samples were collected on 0, +4, +7, +21, +30, +60 y +90 days and stored frozen at −80°C. Serum FLC were analysed in a nephelometer system following the manufacturer instructions. We have compare the increase of FLC according M-component subtype, number of CD34+ cells administered, time until immune reconstitution, administration of coadyuvant AM3-glycopeptical therapy, infections in early postrasplant period, maintenance therapy and time free relapsed survival. Descriptive statistical analysis, ANOVA comparative test and Kaplan-Meier survival study was performed.
Results: 24 patients, 47.0 % females, mean age 63.2 y (38–72), IgG (46.1%), IgA (15.4%), light chains (23.0%), non secretory (7.7%), time to immune reconstitution 15–17 days, kappa/lambda ratio at baseline 57.0 (CI95% 0.8,20.3), days: +4:37.3(CI95% 0.1,3.2), +7:1.85(CI95% 1,3), +21:2.37 (CI95% 0.4,2.0), +30:0.87 (CI95% 0.2,0.9), +60:0.4 (0.2, 2.1) and +90:1.26 (CI95% 0.3, 2.9). Mean relapsed free survival 27.6 m (CI95% 9,55), OS 59.0 m (CI95% 27,76), 7 patients have dead for progression. At day +21 opposite correlation kappa/lambda ratio and RFS was observed.
Comments: The early increase of free serum kappa/lambda chains ratio could be an useful biomarker to predict RFS and OS in MM patients in complete response after therapy.
CCL5 (RANTES) Is Suspected to Be the Key Chemokine to Understand the Bone Pathology of Multiple Myeloma
Authors: Hayashi Kunio , Nomura Shosaku , Hashimoto Seiji , Hideshima Teru 
Published: April 2020

Abstract
Background: It has been shown that CCL5 recruits Osteoclasts and Osteoblasts to active bone turnover regions to maintain bone remodeling. In healthy volunteers, CCL5 is higher in male than in female. Although CCL5 is highest in 20ys men, it becomes same level at 60ys in both male and female. These results suggest that the value of CCL5 correlates with the activity of the bone metabolism. In this study, we examined the significance of CCL5 level in MM, which may provide new insights in the bone pathology of this disease.
Patients and Methods: fourteen MM were enrolled in our study. Twelve were newly diagnosed and 2 were relapsed patients. We evaluated CCL5(serum) and bone alkaline phosphatase(BAP, serum), as well as type-I collagen N-telopeptide(NTX, urine) when patients were diagnosed and after the treatment. Regimens of the treatment are
Thalidomide 200mg/day and Dexamethasone(Dex) 40mg every 8th day within 21 days cycle, Velcade 1.3mg/m2 on days 1, 4, 8, 11 of a 3 weekly cycle with Dex 40mg, combination of Thalidomide, Velcade and Dex.
Result: We compare CCL5 of 60ys healthy volunteers, ITP patients, Stage 1 MM, Stage2 MM and Stage3 MM. We found highest CCL5 level in Stage 3 MM. Interestingly, BAP was almost same level between Stage1 and Stage3; however NTX level is higher in Stage3 than in Stage1, suggesting that increased CCL5 in Stage3 was predominantly from activated osteoclasts. Importantly increased CCL5 and BAP were recognized in patients who had CR or PR. Moreover, the increase of the number of megakaryocyts in the bone marrow was recognized in 7 patients. These megakaryocytes were strongly stained with anti-CCL5 Ab, suggesting that successful MM treatments could increase production of CCL5 by megakaryocytes.
Conclusion: CCL5 of Osteoclasts in active myeloma contributes bone resorption. On the other hand, in successfuly treated myeloma, CCL5 is produced by megakaryocytes which make Osteoblasts activate. CCL5 may be a novel marker of bone disease in myeloma.
Quality of Life Assessment at Diagnosis and after Different Treatment Phases in Multiple Myeloma Brazilian Patients
Authors: Silva Vanderleia Costa , Almeida Manuella Sampaio , Hungria Vania T. M. , Etto Leina Yukari , de Oliveira José Salvador Rodrigues , Barros José Carlos , Ciconelli Rozana , Colleoni Gisele W.B. 
Published: April 2020

Abstract
Multiple myeloma (MM) causes great impact in quality of life (Q/L), since patients become dependant of others even for routine activity execution and personal care.
Objectives: To characterize the impact of MM in the Q/L of patients treated in two public institutions of Sao Paulo State, Brazil, using a generic (SF-36) and a specific questionnaire for oncologic patient (QLQ-C30), applied in three different moments: at diagnosis, after the end of clinical treatment and at day +100 after autologous hematopoietic stem cell transplant (ASCT).
Patients and methods: From March 2006 to August 2007 we evaluated 49 patients with MM, using the two questionnaires. Analysis was made through ANOVA, Post hoc and T-paired test comparing the three groups.
Results: 88.6% of included patients have family budget lower than US$ 600.00/month (Economic Class C, D or E). The generic questionnaire SF-36 demonstrated that Physical Functioning, Role-Physical and Bodily Pain were statistically different in all three groups, favoring the day +100 post-ASCT group (ANOVA). SF-36 still demonstrated improvement in Role-Emotional when MM post treatment group was compared with the day + 100 post-ASCT group (T-paired Test). The QLQ-C30 questionnaire confirmed what had been demonstrated by the SF-36 in relation to the Physical Functioning and Bodily Pain plus improvement in the following aspects: Role Functioning, Fatigue, Lack of Appetite and Constipation, favoring the day + 100 post-ASCT group (ANOVA). QLQ-C30 also detected a significant improvement in Social Aspect in patients with MM after day +100 of ASCT.
Conclusion: The specific questionnaire for cancer patients QLQ-C30 seems to be more informative than the generic questionnaire SF-36 and reflects the real benefit of ASCT in Q/L of MM patients from two public Brazilian institutions, which provide assistance for economically challenged population.
The Effect of Bone Marrow Involvement on the Efficacy of Pegylated Liposomal Doxorubicin + Bortezomib Vs Bortezomib Alone in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Shah Jatin , Blade Joan , Miguel Jesus San , Sonneveld Pieter , Luo Donghan , Lantz Keith C , Lowery Colin , Harousseau Jean-Luc , Orlowski Robert Z. 
Published: April 2020

Abstract
Background: Patients with relapsed/refractory multiple myeloma (RRMM) often have a large tumor burden with significant bone marrow involvement, conferring a poor prognostic feature. Those patients with significant bone marrow involvement may benefit from combination regimens with increased activity. Orlowski et al. reported a phase III randomized trial with pegylated liposomal doxorubicin (PLD) + bortezomib (B) vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with the combination of PLD+B. (Orlowski, JCO 2007) We investigated the effect of bone marrow involvement on overall response rates and time to progression (TTP) of PLD+ B versus B alone in patients with RRMM.
Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with bone marrow involvement and those with &gt;30% involvement were analyzed retrospectively.
Results: A total of 379 patients had bone marrow involvement and 349 patients had &gt;30% bone marrow involvement compared with 259 with no bone marrow involvement. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with or without any bone marrow involvement or &gt;30% bone marrow involvement are listed in the table.
PLD+B B P valueb Hazard Ratioc a. Based on Kaplan-Meier product-limit estimates. b. Based on stratified Log-rank test. c. A hazard ratio &gt;1 indicates an advantage for PLD+B. d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. No bone marrow involvement, N 132 127 TTP, Median days (95% CI)a 251 (212, 282) 198 (162, 227) 0.0134 1.69 (1.11, 2.57) Total CR+PR, n/evaluable (%) 49/118 (42) 43/124 (35) 0.2887d Any bone marrow involvement, N 188 191 TTP 311 (264, 354) 197 (169, 222) .0001 1.91 (1.37, 2.67) Total CR+PR 94/183 (51) 88/182 (48) .5187d &gt;30% bone marrow involvement, N 172 177 TTP 276 (221, 415) 183 (158, 211) .0005 1.83 (1.30, 2.58) Total CR+PR 82/168 (49) 69/170 (41) .1446d
Regardless of bone marrow involvement or extent of bone marrow involvement, there was a statistically significant benefit in TTP for PLD+B vs. B alone. Safety profiles for the 2 regimens in the subsets of patients with or without bone marrow involvement were consistent with the known toxicities of the 2 agents.
Conclusions: These data suggest that the combination of PLD+B is an active salvage therapy and superior to B alone in patients with RRMM, regardless of the presence or extent of bone marrow involvement. Patients with significant bone marrow involvement and associated poor risk due to increased tumor burden may benefit from the addition of PLD.
Six Years of Experience and Outcome with Maintenance Therapy with Very Low Dose Thalidomide after Auto-SCT in Multiple Myeloma
Authors: Mettivier Vincenzo , Pezzullo Luca , Rocco Stefano , Finizio Olimpia , Musto Pellegrino , Nunziata Giuseppe , Bene Lucia , Mettivier Laura 
Published: April 2020

Abstract
New drugs and high dose therapy with auto-transplantation (auto-SCT) has improved prognosis of multiple myeloma (MM). New drugs are promising in upfront therapy while the role of maintenance is still debated. Thalidomide (thal) is an active drug in the treatment of myeloma, and is been investigated as first line therapy, the limit of this drug is the toxicity dependent dose and this determines a poor compliance. It could be useful in the control of minimal residual disease. We used low dose of thal as maintenance after autologous transplantation in patient with MM from January 2002 and here we bring our experience after six years of observation. From January 2002 to August 2008 17 patients (8 males and 9 females) with MM have been treated in our institution. Median age was 59,5 years (range 48–72). 10 were IgG, 3 IgA, 3 light chains and 1 plasma-cell leukaemia. Treatment was 4 cycles of VAD regimen followed by auto-SCT. 4/17 performed double auto-SCT. Three months after SCT these patients has begun the maintenance with thal 50 mg/die, to start thal maintenance 9 patients were in CR, 5 in PR and 3 in resistant disease and the median somministration of thal has been of 12 months (range 3–24 months). Median follow up from the beginning of maintenance therapy was 40 months (range 4–76) with 11/17 (64%) patients in CR or stable disease, with progression free survival (PFS) and overall survival (OS) projected at 75 months respectively of 53% and 51% from to start thal. In our experience we have observed a neurological toxicity (grade I–III) in the 65% of the patients but only 4 have had to suspend the treatment; a haematological toxicity of grade I in the 55% of the patients that have not behaved interruption of the treatment and finally in any case we have documented thrombotic episodes. Finally we have compared this group of patients with another group (18 patients) with the same clinical characteristics that we have observed in the same period but that have not effected maintenance with thal. In this last group 13/18 patients (72%) relapsed with median follow-up of 36 months (range 14–75) and median PFS and OS of 16 and 30 months respectively. The difference between the 2 groups is statistically significant for PFS (p: 0.003) and OS (p: 0.04). The median overall survival observed after progression, in the two groups, has been of 13 months in thal group and 17 months in the group of patients that have not effected the maintenance, this difference is not statistically different (p:0.06). In conclusion in 6 years of observation our experience has shown, even if the number of the patients is small, that maintenance with low doses of thal, after auto-transplantation, it not only has a good compliance but it improves the PFS and OS in this cohort and it doesn’t worsen the OS from the relapse.
Successful Salvage and Hematopoietic Reconstitution with Bortezomib and Melphalan in Relapsed and Refractory Multiple Myeloma
Authors: Mazumder Amitabha , Jagannath Sundar , Vesole David H. 
Published: April 2020

Abstract
The management of relapsed and refractory multiple myeloma (RRMM) patients who have failed older conventional and more recent novel agents remains challenging. Patients typically have short response duration, develop prolonged cytopenias and are usually not eligible for clinical trials due to inadequate bone marrow reserve. Furthermore, these patients often have inadequate numbers of stem cells (&lt;3 × 10(6) CD34/kg) remaining for a myeloablative transplant. In patients who have remaining stem cells in storage, we have developed an algorithm to enable the reconstitution of hematopopiesis to allow enrollment in clinical trials. In addition, our algorithm tests the synergy of bortezomib and non-myeloablative doses of melphalan with stem cell boost support. We have treated 6 patients with RRMM who have failed novel agents (including bortezomib) and chemotherapy (dexamethasone, cytoxan, etoposide, cisplatin, and doxil) and who have had limited duration of response previously with high dose melphalan. All patients were cytopenic (ANC &lt; 1000 and/or platelets &lt; 50,000/mcl) and thus not eligible for existing clinical trials. The melphalan was administered intravenously at 30–50 mg/m2 on days 1 and 4, dependent on the patient age and performance status. Bortezomib was administered 1.3 mg/m2 by intravenous push prior to the melphalan on the same schedule. The patients then received 1.5 to 2.2 × 10(6) CD34+ cells/kg. (depending upon the amount of remaining stem cells). All patients were treated in the outpatient clinic. 3 patients required hospitalization for neutropenic fever; the median hospitalization duration was 3 days (range 0 to 6). The overall response (MR, PR, VGPR) was 100% including: 5 PR and 1 VGPR.. More importantly, all patients achieved improved hematopoiesis with WBC &gt; 2000 and platelets &gt; 50,000/mcl. The median duration of response exceeded 2 months. All patients were able to proceed on to new clinical trials. We conclude that the combination of bortezomib and melphalan produces an effective salvage strategy, with hematopoietic reconstitution in RRMM. This non-myeloablative approach serves as a bridge for disease control and hematopoietic reconstitution to allow for subsequent eligibility on clinical trials. We recommend that during stem cell collection that sufficient hematopoietic stem cells be stored to support future myeloablative and similar non-myeloablative chemotherapy regimens.
Clinical Experience and Prognostic Factors with Bortezomib-Combined Regimen in 40 Patients with Multiple Myeloma
Authors: Li Juan , Zhao Ying 
Published: April 2020

Abstract
To explore the medical effects, prognostic factors relating to the effects and side effects of bortezomib-combined regimen in treatment of multiple myeloma (MM), and evaluate the safety of this regimen in patients with special conditions.
Methods: Forty newly diagnosed and relapsed or refractory MM treated with the regimen of combination of bortezomib and dexamethasone in a cycle of 3 weeks. All of the patients received a median of 3 (1–9) cycles of the treatment. Response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) and adverse events were graded according to the National Cancer Institute Common Toxicity Criteria.
Results: Total response rate was 75.0% (30/40), and the rate of CR+nCR was 42.5% (17/40). Eighty percent patients (24/30) showed effects after the first cycle, although the median time of best effect was 2 cycles. Compare to the other types, light-chain type had higher total response rate (100.0% vs. 65.5%, P=0.038)and CR rate (36.4% vs. 6.9%, P=0.039), and also responded earlier with 81.8% (9/11) patients reached the best effect after the first cycle. The factors which showed no relationship to the effects were age (&lt;65 years vs. &gt;65 years, P=0.081), sex (P=0.696), DS staging (P=1.0), ISS staging(P=0.969), newly or retreated (P=0.731), using thalidomide or not(P=0.338), renal function damage or not(P=0.401), PLT level(P=1.0), hypercalcemia or not(P=0.306), Hb level(P=0.70)and the ratio of tumor cells in bone marrow(P=0.693). Grade III~IV adverse effects in this VD regimen was low, including leucocytopenia, thrombocytopenia, diarrh ea and debility, could be relieved by symptomatic treatment or delay the chemotherapy. The rate of infection was high and which was one of the important cause of death. Renal function improvement could be showed in all of the 10 patients who had renal inadequacy, and compared with normal patients, the incidences of side and adverse effects had no statistical differences.
Conclusion: The Bortezomib combination regimen has significant effect in MM treatment. It shows more significant in light-chain type patients, and show earlier effect onset. This regimen can be tolerant in most patients, and is also safe in patients with renal inadequacy.