bluuebunny/crossref_metadata_2025_split huggingface dataset:
Severe Osteomyelitis of the Jaws in Long Term Survivorsmultiple Myeloma Patients Treated with Biphosphonates.A New Clinical Entity.
Authors: Lugassy Gilles , Nemets Anatoly 
Published: April 2020

Abstract
Multiple Myeloma is a frequent and usually fatal lymphoproliferative disorder with a median survival of around 30 months.Supportive therapy includes monthly intravenous injections of biphosphonates as prevention, or therapy,of lytic bone disease.
We report three cases of Multiple Myeloma patients who developed severe osteomyelitis of the jaws while receiving prolonged biphosphonate therapy.All three patients are very long survivors of Myeloma,being alive 6 to 12 years after diagnosis.They have been treated with biphosphonates for more than 4 years, receiving large doses of Pamidronate(3420 to 4680 mg) and lesser doses of Zoledronate(16 to 72 mg).Jaw infection was unprovoked in wo parients and was cused by dental extraction in the third.Diagnosis of osteomyelitis was confirmed by histology in all three patients, while in two we could demonstrate the presence of Actinomyces.Therapy with hyperbaric oxygen of osteomyelitis refractory to prolonged antibiotherapy, was curative in one patient. To the best of our knowledge, these are the first cases of osteomyelitis of the jaw reported in the literature in Myeloma patients treated with chronic administration of intravenous biphosphonates.Recent reports have alerted physicians of a ’’ growing epidemics’’ of Pamidronate and Zoledronate induced avascular necrosis of the jaw, most of them provoked by teeth removal.Both of these biphosphonates have strong antiosteoclastic activity, and Zoledronate is antiangeogenic, all properties which contribute to the development of bone necrosis.Since the jaws are the only bones in the skeleton exposed to the external environment, the association of bone necrosis with secondary chronic infections may lead to osteomyelitis.Even though it is not possible to prove beyond doubt an etiological link between biphosphonate therapy and the occurrence of osteomyelitis of the jaws, the association of Myeloma with severe immunosupression, the very prolonged biphosphonate therapy in our three patients, and the localization to the jaw, are in favor of a clear relationship between therapy with Zolandronate, Pamidronate and osteomyelitis of the jaws. With the expected life prolongation of Myeloma patients due to recent therapeutic breakthroughs and the increasing use of antiangeogenic agents, it is crucial to be aware of the possibility of a rise in the number of osteomyelitis of the jaws in Myeloma patients.
Serum Free Light Chain (FLC) Measurement in Multiple Myeloma (MM) Patients (pts) Correlate with Known Monoclonal Paraprotein, Disease Stage and Therapy Response.
Authors: Engelhardt Monika , Räpple Daniel , Weis Andreas , Bisse Emanuel , Ihorst Gabriele 
Published: April 2020

Abstract
So far, data based on small patient (pt) population suggest that the measurement of serum FLC from MM pts undergoing high-dose chemotherapy (HDCT) with stem cell transplantation (SCT) may be a sensitive marker for monitoring therapy success and for early detection of relapse. For further evaluation of the impact of FLCs on the assessment of treatment efficacy of standard- (ST) and HDCT with SCT, we performed a prospective analysis on serial serum specimens from 86 MM and 9 control pts. Measurement of FLC concentration was performed with the commercially available Freelite™ kit (Binding Site). For statistical analysis, pts’ clinical history, age at diagnosis, sex, current state of disease, karyotype and serum parameters, such as ß2-microglobulin, calcium levels and serum creatinine were evaluated. In the control group (NHL=6, AML=1, non-hematological disease=2), median concentrations of kappa(k)- and lambda(l)- FLC were 9.8 mg/l and 12.8 mg/l, respectively, corresponding to reference intervals for healthy individuals with normal kappa(k)/lambda(l)-ratios. In MM, 40 (46.5%) pts displayed kappa(k)-FLC levels above the upper range of 19mg/l, 26 (30%) had lambda(l)-FLC levels above the upper range of 26 mg/l and 9 pts (10.4%) had both elevated kappa(k)- and lambda(l)-FLC serum levels. An abnormal kappa(k)/lambda(l)-ratio was observed in 45 (52,3%) MM pts. Pts with a known kappa(k)-paraprotein (n=58) had a median FLC kappa(k)-concentration of 38 mg/l, but lambda(l)-FLC within the normal range. For pts with a known lambda(l)-paraprotein (n=27), reciprocal findings (76.4 mg/l for lambda(l)- vs kappa(k)-FLC in the normal range) were observed. Pts with responsive disease (CR, PR and SD) had both kappa(k)- and lambda(l)- FLC levels within the normal range, whereas newly diagnosed pts (ED) and those with PD had kappa(k)- FLC levels approx. 3-times the normal range, with lambda(l)- FLC levels at the upper limit of normal. Pts receiving ST as compared with HDCT had higher FLC levels. This is also observed in pts with amyloidosis, renal impairment or PD. Our results suggest that serum FLC assay allows monitoring of the therapy response and early detection of relapse. Determination of FLCs is also important, when evaluating new therapeutic substances, and for detection of prognostic patterns for better risk-based stratification of treatment.
Osteoblastic Activation and Response to Velcade® in Patients with Relapsed/Refractory Multiple Myeloma (MM).
Authors: Zangari Maurizio , Lee Choon-Kee , Barlogie Bart , Najarian Kevin , Kang Seung-Hee , Yaccoby Shmuel , Esseltine Dixie , Stover Julie M. , Tricot Guido J. 
Published: April 2020

Abstract
The molecular targets of anti-tumor activity elicited by VELCADE may vary among tumor types. The extent to which each target is critical to the inhibition of tumor growth may also differ. In MM patients, we have previously reported a statistical correlation between the elevation of total alkaline phosphatase (ALP) levels (in the absence of liver function abnormalities) and response to combination treatment with VELCADE, Thalidomide, and Dexamethasone (Zangari, et al, Blood, 2003:102(11):687a). Changes in ALP levels have recently been analyzed in patients treated with single agent VELCADE on the Millennium-sponsored trial 025 evaluating sequential multi-chemistry profiles obtained from a total of 182 patients with relapsed/refractory MM. Median age was 58 years and 61% were male. Patients were divided into two groups based on their myeloma response. Group A included patients with no response and/or progressive disease following VELCADE therapy. Group B included patients who achieved ≥ 25% paraprotein reduction. Elevation of ALP, in the absence of liver function abnormalities, was observed exclusively in responding patients (Group B). Using the Wilcoxon Rank-Sum test, the difference in elevation of ALP after completion of two cycles of VELCADE between the two groups was statistically significant (P=0.02) [Figure1]. In an attempt to determine the source of the ALP increases, prospective serial measurements of ALP, bone-specific alkaline phosphatase (BALP) and intact parathyroid hormone (PTH) were obtained in three MM patients treated with single agent VELCADE at our institution. The rise in ALP activity was associated with rapid paraprotein response and to a parallel increase in BALP and PTH levels, indicating increased osteoblastic activity [Figure2]. Our experience represents the first clinical evidence in MM patients that VELCADE promotes osteoblastic activity, which typically correlates with anti-myeloma activity.
Cytokines Behaviour in Multiple Myeloma during Zoledronic Acid Treatment.
Authors: Avvisati Giuseppe , Petrucci Maria T. , Annibali Ombretta , Bartolozzi Francesco , Giannetti Barbara , Levi Anna , Battistoni Fabrizio , Gavasci Michele , Dicuonzo Giordano , Vincenzi Bruno , Santini Daniele , Foa Robin , Mandelli Franco 
Published: April 2020

Abstract
The main pathological feature underlying the bone disease in multiple myeloma is an uncoupling of bone resorption from bone formation so that resorption predominates. In the bone marrow (BM), MM plasmacells are in close contact with stromal elements and induce the release of several cytokines which modify the BM microenviroment, upregulating RANKL expression and secretion by both stroma and osteoblasts. Destruction of bone matrix induced by MM and its cellular interactions is accompanied by further release of cytokines. Bisphosphonates are chemical compounds which selectively concentrate at the interface of the active osteoclasts and the bone resorption surface where they inhibit osteoclast activity.
Recently, in solid tumors, Santini et al have demostred that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels (Clin Cancer Res2003;9:2893–7). Taking into account that angiogenesis plays an important role in MM progression, we have investigated the behaviour of IL6, PDGF, IGF, TNFα and VEGF in a cohort of 28 (16 males and 13 females) consecutive MM pts with lytic bone lesions treated with 4 mg of zoledronic acid. Venous blood samples were drawn just before the beginning of drug infusion and at 1,2,7,21 (before the subsequent infusion) days after the zoledronic acid infusion. Serum samples were then tested for PDGF, VEGF, IL6, TNFα , and IGF with the R & D quantitative kits (R & D Systems, Minneapolis, USA), according to the manufacturer’s instructions. Basal cytokine levels were compared with the values observed at 1, 2, 7 and 21 days using the Wilcoxon’s test for nonparametric-dependent continuous variables. Differently from what observed by Santini et al in solid tumors, serum VEGF median levels did not decrease;on the contrary, it significantly increased at days 7 (P=0.0047). Moreover, IL 6 and TNFα levels significantly increased after 1 (P=0.0000 and 0.0001 respectively) and 2, ( P=0.0000 and 0.0021 respectively) days. Furthermore, PDGF significantly decreased (P=0.005) after 2 days following zoledronic acid infusion. Among these pts, 8 (28.5%) were receiving also Interferon; no statistically significant differences in the levels of VEGF, IL6, TNFa and IGF between the two groups were observed. Only the PDGF levels have shown a statistically significant decrease in the interferon group at 0, 1, 2, 7, 21 days (P&lt;0.05). In conclusion, the cytokines’ behaviour after the administration of zoledronic acid in MM is different from that observed in solid tumors; in particular, we did not observe a decrease in VEGF levels. This behaviour may partially explain why zoledronic acid has no effect on MM progression as originally postulated.
Anti-NK Cell Treatment Induces Stable Mixed Chimerism in MHC-Mismatched, T-Cell Depleted, Nonmyeloablative Bone Marrow Transplantation.
Authors: Cho Seok Goo , Shuto Yukinobu , Soda Yasushi , Nakazaki Yukoh , Izawa Kyoko , Uchimaru Kaoru , Takahashi Satoshi , Tani Kenzaburo , Tojo Arinobu , Asano Shigetaka 
Published: April 2020

Abstract
Objective: To clarify Natural killer (NK) cell-mediated resistance under cytoreductive conditioning and T-cell depleted bone marrow transplantation (TCD-BMT), we investigated the effects of host NK cell depletion on engraftment and induction of stable mixed chimerism.
Methods: BALB/c mice (H-2kd) were injected intraperitoneally with anti-asialoGM1 antibody (anti-NK Ab) on day -1. On day 0, they received TBI at a dose of 500 cGy, followed by intravenous infusion of 2 x 107 T-cell-depleted (TCD) bone marrow (BM) cells from C57BL/6 mice (H-2kb). Early engraftment and chimerism were determined by the relative ratio of peripheral blood (PB) lymphocytes expressing either H-2kd or H-2kb on day +21. Long-term engraftment and chimerism were evaluated on PB and spleen by multi-color flow cytometry.
Results: Although no recipients treated with TBI alone showed engraftment, all the recipients conditioned with anti-NK Ab and TBI showed successful engraftment as well as a donor-dominant pattern of mixed chimerism in both PB and spleen. Spleen cells from recipients with mixed chimerism showed specific tolerance to both host and donor strains, but not to a third-party (C3H/He). None of the reconstituted mice showed signs of graft versus host disease, and all survived up to day +330.
Conclusion: These observations indicate that host NK cell depletion may be used to reduce the intensity of conditioning regimens for engraftment of TCD grafts, and can contribute to establishment of stable mixed chimerism in MHC-mismatched NMT.
Oligotide, a Defibrotide Derivative, Protects Human Microvascular Endothelial Cells Against Fludarabine-Induced Activation, Damage and Allogenicity.
Authors: Eissner Guenther , Iacobelli Massimo , Blueml Susanna , Andreesen Reinhard , Holler Ernst 
Published: April 2020

Abstract
Fludarabine is a non-myeloablative immunosuppressant increasingly used as a component of alternative reduced intensity conditioning regimens prior to allogeneic stem cell transplantation (SCT). However, we have previously shown that 2-Fluoroadenine 9-beta-D-arabinofuranoside (F-Ara) as the active metabolized form of fludarabine induces damage, activation, and allogenicity in human microvascular endothelial cells (HMEC). We had also identified the pharmaceutic compound Defibrotide (DF), originally used in the treatment of veno-occlusive disease and thrombotic microangiopathy, as being protective against F-Ara induced dysfunction of HMEC, importantly, without affecting the anti-leukemic effect of F-Ara. In the present report we show that a recently developed derivative of DF, Oligotide, similarly downregulates F-Ara induced activation and damage of HMEC as well as their antigenicity for allogeneic CD8+ T cells. In addition, Oligotide could also block F-Ara mediated transendothelial migration of peripheral blood cells across the HMEC barrier. Taken together, these observations argue for a potential clinical use of both, DF and Oligotide in pre transplant conditioning.
Antigen Specificity and Immunoregulation in Syngeneic Graft-Versus-Host Disease.
Authors: Hess Allan D. , Thoburn Christopher J. , Bright Emilie C. , Miura Yuji 
Published: April 2020

Abstract
Syngeneic graft-vs-host disease (SGVHD) is a T cell dependent autoaggression syndrome induced by administering Cyclosporine following syngeneic bone marrow transplantation. The SGVHD autoreactive T cells recognize the MHC class II-invariant chain peptide complex (MHC class II-CLIP) and can be separated into functional subsets based on their differential dependence on the N- and C-terminal peptide flanking domains of CLIP. The present studies were undertaken to determine whether the N- or C-terminal flanking domain dependent subsets of CLIP reactive T cells reside within the CD4+CD25+ regulatory compartment. Multi-color flow cytometry was used to identify and isolate CD4+ (FITC) CD25+ (PE) T cells. Antigen-specific T cells within this compartment were identified with a soluble MHC class II-Ig chimeric construct (bioinylated, Cychrome avidin counterstaining) loaded with variants of CLIP containing the MHC class II binding domain and having either the N- or C-terminal flanking regions (N-CLIP, CLIP-C). Approximately 8.5% of the cells within the normal CD4+ lymphocyte population were CD25+. Both N-CLIP (1.1%) and CLIP-C (4.8%) reactive T cells coould be detected in the CD4+CD25+ population. Assessment of CD28, CTLA4, B7.1 and B7.2 mRNA expression levels by quantitative PCR directly ex vivo, revealed remarkable differences between the N-CLIP and CLIP-C specific CD4+CD25+ T cells. Although CD28 mRNA levels were comparable for both subsets, B7.2 and CTLA4 mRNA transcript levels were significantly increased (&gt;50 fold) in the CLIP-C+CD4+CD25+ T cells compared to the N-CLIP specific subset. On the other hand, levels of B7.1 mRNA were increased &gt;10 fold in N-CLIP+CD4+CD25+ T cells. Additional studies assessing mRNA transcript levels for the regulatory transcription factor Foxp3, also revealed a disparity between the N-CLIP and C-CLIP specific subsets. mRNA transcript levels for Foxp3 were markedly increased (&gt;35 fold) in the CLIP-C dependent subset compared to the levels detected in N-CLIP+CD4+CD25+ T cells. Low levels of cytokine (IL-2, IL-4, interferon-γ) mRNA transcripts were detected in both subsets. Interestingly, intradermal immunization of normal animals with the peptides presented on dendritic cells increased mRNA transcript levels for type 1 cytokines in the N-CLIP reactive subset and type 2 cytokines in the CLIP-C dependent subset. Taken together, the results indicate that the CLIP-C antigen specific CD4+CD25+ cells have a profile consistent with regulatory T cells whereas the profile of the N-CLIP+CD4+CD25+ lymphocytes is more characteristic of activated T helper cells. The ability to identify and isolate regulatory T cells ex vivo and to modify their activity by immunization provides opportunities to both enhance and monitor the re-establishment of self-tolerance.
Can Addition of GM-CSF in Adult Haplo-Identical Transplant Who Cannot Benefit from NK Alloreactivity Improve the Relapse Rate of Advanced Leukemia: A 3 Step Study.
Authors: Lewalle Philippe , Delforge Alain , Nowak Berengere , Misplon Virginie , Lagneaux Laurence , Theunissen Koen , Bennani Jalil , Bron Dominique , Martiat Philippe 
Published: April 2020

Abstract
Haplo-identical transplant is now established as a procedure of choice for patients who lack a compatible donor. It might even be the best choice for AML, provided there is a GvH NK alloreactivity. However, patients are still referred too late, heavily pre-treated, at very advanced stages. We initiated a three-step phase I study trying improve transplant related mortality, relapse rate and immunity: (1): G-CSF + DLI, (2): GM-CSF + DLI, (3): patient and disease adapted strategy. Thirty-four consecutive leukemia patients, aged 18–55, were investigated (20 very poor risk, 11 poor risk and 3 better risk). GvH type NK alloreactivity was chosen when possible (19/34) and balanced across the 3 groups. In the first 9 patients, G-CSF was used pot-transplant and prophylactic DLI were given at month 1, 2 and 3. The use of G-CSF and 1 to 3 DLI (104 CD3/kg) was found safe. It resulted in faster CD4 recovery and a low rate of infections. However, it was insufficient to induce a protective GVL effect. In the next 12 patients, GM-CSF was used plus 1 DLI (104 CD3/kg) at day 30 unless aGVHD (3 pts). The comparison between the 2 first groups can be summarized as follows: G-CSF + DLI: TRM at day 100: 0, RR: 6/9, severe aGVHD:0. GM-CSF + 1 DLI group: RR: 1/12, TRM at day 100: 3, aGVHD grade 2 or more: 9/12; price to pay: GVHD resulting in 5 deaths in total. Median time to relapse in the 21 first patients was 6 months (range 4 to 9). Step 3 (14 patients) consists of a patient adapted strategy: no more aspecific DLI (selected anti-CMV and aspergillus DLI planned in all patients); in myeloid disorders with NK alloreactivity: no GF. In the other cases, GM-CSF (at a reduced total dose of 500 mcg) is given from day 5 to day 9. The follow-up of these 14 patients, although promising (2 relapses), is currently short (median 5 months), compared to the median of relapse in the 2 first groups (6 months) but will be updated for the meeting (10 months and 17 patients). Overall, TRM at day 100 is 3/29, reflecting the good tolerance of the conditioning in a heavily pre-treated population (median age : 43). Overall NR-mortality at one year is 8/26, but was greater in the GM-CSF + DLI group, reflecting the impact of severe aGVHD. In the current group, its is 2/14 at 3 months. We conclude that the third strategy might improve the outcome and the relapse rate without exposing patients to unnecessary severe GVHD.
Mechanisms of Alpha Hemoglobin Stabilizing Protein (AHSP) Actions.
Authors: Zhou Suiping , Gell David , Kong Yi , Li Jianqing , Mackay Joel P. , Weiss Mitchell J. , Gow Andres J. 
Published: April 2020

Abstract
Alpha hemoglobin stabilizing protein (AHSP) is an abundant erythroid factor that specifically binds and stabilizes free α hemoglobin (Kihm et al., Nature 417:758, Gell et al., JBC, 277:40602). In mice, AHSP deficiency causes oxidative stress, mild anemia, and reticulocytosis. Furthermore, loss of AHSP exacerbates α globin precipitation and anemia in a murine model for β thalassemia. These data suggest that AHSP operates as a molecular chaperone to stabilize free α hemoglobin and inhibit its ability to catalyze redox chemistry. We investigated how AHSP associates with α hemoglobin and thereby reduces its oxidative capacity. By NMR and mutational analysis, we determined the structure of AHSP and defined its α globin-interacting surfaces. AHSP consists of three linked α helices. Key α globin-binding residues lie along helices 1 and 2 in a region that resembles the G and H helical fold of β globin. Hence, AHSP presents a surface resembling that of β hemoglobin and thus promotes the formation of a “pseudo α/β interface”. To investigate how formation of this complex affects α hemoglobin-mediated redox chemistry, we examined the ability of AHSP to inhibit peroxide-mediated oxidation of the redox-sensitive dye TMPD. Oxy-α hemoglobin alone catalyzed TMPD oxidation at a rate of 140 μMmin−1; preincubation with AHSP reduced this rate significantly, to 65 μMmin−1. Furthermore, AHSP reduced both heme loss from α hemoglobin and its ability to oxidize hemoglobin A. AHSP binding to oxy- α hemoglobin induced a spectral shift in the UV/visible range, suggesting that stabilization might be associated with structural alterations in the heme moiety. Specifically, the Soret peak was reduced and shifted leftward, while the 541 and 576 nm peaks of the visible region were reduced with concomitant rises at 500 nm and at the region above 580 nm. These alterations suggest that heme-bound iron is converted to a ferric (Fe3+) form that is liganded at all 6 coordinate positions, and therefore, can no longer catalyze redox chemistry. Consistent with this possibility, addition of KCN to the α hemoglobin-AHSP complex produced cyanomethemoglobin-AHSP, but at a slower rate than reaction of KCN with ferric-α hemoglobin alone. In addition, electron paramagnetic resonance and resonance raman spectroscopy showed that the heme iron exists in a low spin state within the α hemoglobin-AHSP complex. The oxidized complex was insensitive to pH alteration, indicating that iron was not bound by hydroxyl ion, which typically occurs at alkaline conditions. Together, our findings illustrate a potential mechanism whereby AHSP renders α hemoglobin chemically inert by inhibiting the reactivity of heme-bound iron. We propose that within the AHSP-α hemoglobin dimer, the oxidized heme is held within a bi-histidyl form, thus blocking its ability to act as a redox catalyst.