bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural History of Skeletal-Related Events in Patients with Multiple Myeloma: Exploratory Analysis Based on Prior History of Skeletal Complications.
Authors: Hussein Mohamad A. , Kaminski Mary , Rosen Lee , Gordon David , Zheng Ming 
Published: October 2019

Abstract
Background: We previously reported the long-term efficacy and safety of 4 mg zoledronic acid compared with 90 mg pamidronate in patients with bone lesions from breast cancer or multiple myeloma (Rosen et al. Cancer. 2003;98:1735–1744). Bone lesions result in an increased risk of developing skeletal-related events (SREs), including pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia of malignancy. It has also been suggested anecdotally that patients who have experienced a prior SRE may be at increased risk for future SREs, but no data exist to support this hypothesis. We report here the results of a retrospective exploratory analysis to assess whether patients with a history of SREs before study entry had a higher incidence of on-study SREs and to assess the clinical benefit of zoledronic acid compared with pamidronate in advanced multiple myeloma patients based on SRE history.
Methods: The subset of multiple myeloma patients treated with zoledronic acid (4 mg) or pamidronate (90 mg) every 3 to 4 weeks was retrospectively stratified according to history of SREs before study entry. A total of 353 patients with multiple myeloma were randomized 1:1 to zoledronic acid or pamidronate for 12 months, and 138 patients elected to continue blinded treatment for an additional year.
Results: Before study entry, 284 (~80%) patients had experienced at least 1 SRE and these patients were more likely to develop an SRE on study than patients without a history of SREs (time to first SRE hazard ratio = 2.22; P <.0001). Across treatment groups, 56% of these patients had at least 1 SRE on study (after 25 months) versus only 35% patients with no SRE before study entry. Additionally, patients with an SRE before study entry had a shorter median time to first on-study SRE (median, 293 days for zoledronic acid and 218 days for pamidronate) compared with patients who had no prior SRE (median, 504 days for zoledronic acid and not reached for pamidronate). Among patients with an SRE before study entry, the zoledronic acid group had a decreased percentage of patients with an on-study SRE compared with the pamidronate group (53% for zoledronic acid versus 59% for pamidronate; P =.291). Zoledronic acid also delayed time to first SRE by 75 days compared with pamidronate (median 293 days for zoledronic acid versus 218 days for pamidronate; P =.679).
Conclusions: This exploratory analysis indicates that multiple myeloma patients with a history of SREs are at significantly higher risk of developing subsequent skeletal complications. Early intervention for prevention of SREs may provide considerable clinical benefit to these patients.
Anti-Thymocyte Globulin Increases Dramatically Natural Killer Cell Interferon Gamma Production While Respecting Other Functionnal Aspects of These Cells.
Authors: Dalle Jean-Hugues , Menezes José , Wagner Eric , Champagne Martin A. , Duval Michel 
Published: October 2019

Abstract
Rational: The beneficial effect of NK cells after clinical hematopoietic transplantation has been seen when anti-thymocyte globulin (ATG) was used within the conditioning regimen. We therefore investigated the effect of ATG on human NK cells. Materials and methods: Percentages of CD3+ and CD3−/CD56+ among PBMC from either normal adult volunteers or cord blood were assessed by flow cytometry. Negatively purified NK cells were cultured for 2–4 days either alone or in the presence of rabbit ATG (Thymoglobuline, Sangstat) and/or IL-15, and then assessed for cell viability and functional properties: apoptosis were investigated by Annexin V staining. Cell proliferation was assessed by CFSE dye dilution. IFN-gamma secretion was quantified by ELISA. Cytotoxicity against K562 cells was studied by a 51Cr release assay. Binding of monoclonal antibodies to NK cells was assessed alone or after competition with whole ATG or ATG-Fab’2 fragments.
Results: The percentage of CD3+ cells in PBMC was over 65% before or after culture without ATG. In contrast, no T cell was detected after culture with ATG, whereas the percentage of NK cells increased from less than 15% to more than 50%. Both whole ATG and Fab’2 fragments bound NK cells while rabbit Fc fragments did not. ATG did not modify apoptotic and necrotic NK cells percentages. Proliferation was not affected by ATG. IFN-gamma production was dramatically increased by ATG treatment (figure). ATG respected IL15 induced NK cell cytolytic activity. Competition assays showed that ATG did not alter CD2, CD11a, CD16, CD56, CD57, CD62L, CD94, CD158a, CD158b, NKG2a, NKG2d, HLA-DR expression. CD18 and NKp46 expression was slightly decreased.
Conclusion: Our data show that ATG may play a role in the results of KIR mismatch hematopoietic stem cell transplantation. It may be possible that ATG confers functional advantages to NK cells versus T cells.
Figure Figure
A Possible Association between the Presence of Interleukin-4-Secreting Cells and a Reduction in the Risk of Acute Graft-Versus-Host Disease.
Authors: Takabayashi Maki , Kanamori Heiwa , Takasaki Hirotaka , Yamaji Satoshi , Koharazawa Hideyuki , Taguchi Jun , Tomita Naoto , Fujimaki Katsumichi , Fujita Hiroyuki , Fujisawa Shin , Maruta Atsuo , Ishigatsubo Yoshiaki 
Published: October 2019

Abstract
We monitored interleukin-4 (IL-4), interferon-gamma (IFN-g), and tumor necrosis factor alpha (TNF-a)-secreting cells using an enzyme-linked immunospot (ELISPOT) assay in a prospective study to assess the cytokine network after transplantation. Peripheral blood mononuclear cells were collected from 23 patients who received allogeneic stem cell transplantation, from before the preconditioning regimen to 56 days after transplantation. The frequency of IL-4-secreting cells was significantly higher in 5 patients receiving peripheral blood stem cell transplantation (PBSCT) than that in 18 patients who received bone marrow transplantation (BMT). Based on IFN-g and TNF-a release, there was a trend toward a decrease in the number of cytokine-secreting cells in PBSCT. Furthermore, patients who did not develop acute graft-versus-host disease (GVHD, n = 5) showed a significantly higher number of IL-4-secreting cells compared with those who developed acute GVHD (n = 18). These results indicate that the high percentage of IL-4-secreting cells may be responsible for the inhibition of acute GVHD. In addition, the increased percentage of IL-4-secreting cells may be responsible for the unexpected low incidence of acute GVHD in PBSCT, despite the presence of large numbers of mature T cells in the donor infusion.
Effects of Amotosalen Hydrochloride and Ultraviolet a Light on CD4 and CD8 Cells.
Authors: Jordan Catherine T. , Zimring James C. , Roback John D. 
Published: October 2019

Abstract
Background: Graft versus host disease (GvHD) and infections by opportunistic pathogens, such as cytomegalovirus (CMV), are causes of significant morbidity and mortality in recipients of allogeneic bone marrow transplants (BMT). Thus, there is a need for methods of graft engineering that inhibit the alloreactive T cells responsible for lethal GvHD without compromising the activity of antiviral T cells. In a murine MHC-mismatched BMT model, we have previously demonstrated that adoptive transfer of polyclonal T cells from donors immunized to murine CMV (MCMV) can decrease viral load but cause lethal GvHD. However, pretreatment of these cells with the psoralen, amotosalen hydrochloride, and ultraviolet A (UVA) light prevents GvHD without compromising antiviral response. We have previously hypothesized that these effects were due to differential sensitivity of naïve and memory T cells to amotosalen/UVA. Recent investigations have demonstrated that CD4 T cells are most directly responsible for lethal GvHD in this model. This observation suggested an alternative hypothesis, equally consistent with previous data, that the observed in vivo effects of amotosalen/UVA treatment are due to differential effects on CD4 and CD8 T cells. The assessment of this new hypothesis is the focus of the current studies.
Methods: Two models of T cell activation/proliferation were utilized to test the effects of amotosalen/UVA treatment on CD4 and CD8 cells: stimulation of B6.PL (H-2b) cells with concavalinA, and primary mixed lymphocyte reaction (MLR) between MHC-mismatched B6.PL (H-2b) and BALB/c (H-2d). Responder cells were pretreated with 2nM amotosalen and varying doses of UVA light (0–5 minutes). Proliferation of CD4 and CD8 cells was measured by flow cytometric analysis of CFSE-labeled responder cells.
Results: In both systems, CD4 proliferation was effectively eliminated by immediately prior treatment with amotosalen and UVA doses of 1 minute or higher. CD8 proliferation was eliminated by amotosalen and UVA doses of 2 minutes and higher. Both the amount of division on a per cell basis and the overall number of cells that initiated division followed similar trends.
Conclusions: These data demonstrate that both CD4 and CD8 T cells are sensitive to treatment with amotosalen/UVA and suggest a subtle difference in sensitivity of CD4 and CD8 populations. Since division of both CD4 or CD8 cells is inhibited at doses of amotosalen/UVA that prevent GvHD but allow anti-viral activity in vivo, it is unlikely that the observed differential sensitivity of T-cell subsets is sufficient to explain the in vivo effects of amotosalen/UVA treatment in this model. Using similar methodologies, ongoing studies are assessing the hypothesis that amotosalen/UVA has differential effects on naïve and mature T cells.
Influence of Platelet Depletion on Immunomagnetic CD34+ Cell Selection for Haploidentical Transplants.
Authors: Del Fante Claudia , Viarengo Gianluca , Bergamaschi Paola , Marchesi Andrea , Bellotti Laura , Parisi Cristina , Tinelli Carmine , Salvaneschi Laura , Perotti Cesare 
Published: October 2019

Abstract
Introduction: Immunomagnetic CD34+ cell selection (ICS) is a widely employed technology in auto and allotransplant settings. In particular, when an haploidentical transplant is performed an high dose of purified CD34+ cells together with an efficient T and B cells depletion are requested to minimize the risks of GVHD and EBV related lymphoma. In order to ameliorate the performances of the ICS device, we compared 73 ICS performed following the customer’s recommendations vs 20 ICS performed after 3 centrifugations in order to increase the platelet depletion of the starting leukapheresis (LKF) product.
Matherials and Methods: 93 ICS (from single or fractioned LKF product) were carried out using the Miltenyi Clinimacs device on 76 LKF collected from 37 healty donors mobilized with G-CSF alone (12μg/kg). In tab 1 are summarized the characteristics of the starting 93 pre-immunoselection products in terms of TNC, CD34+ cells, plt and T and B lymphocyte content. 73 LKF were prepared following the standard manufacturer’s protocol and the remaining 20 with an adjunctive plt depletion obtained by 3 low speed centrifugations (900 rpm).
Results: a statistical significance in terms of CD34+ cells recovery, final TNC (x106) and CD34+ cell (x106) absolute count was found in favour of the modified immunoselection procedure (see tab.1).
Conclusions: ICS demonstrated to be an highly efficient procedure when the Miltenyi Clinimacs device is employed. Moreover, the modification of the standard manufacturer’s technique simply by adjunctive centrifugations on the starting LKF product can further improve the recovery of stem cells maintaining, at the same time, a good purity and not influencing the T and B cells log of depletion, thus demonstrating the negative influence of plt contamination on ICS. These results are more remarkable in the context of haploidentical transplant where the plt contamination of LKF is particularly high. Table 1
Standard procedure(n=73) Modified procedure (n=20) LKF content Pre-ICS Post-ICS Pre-ICS Post-ICS Mann Withney test TNC(x10e6) 58150 (24150–146700) 264 (73.1–784.5) 54250 (32790–87570) 330.41 (126.84–537.9) p 0.02 CD34+(x10e6) 354.25 (115.67–941.22) 245.55 (59.39–768.81) 377.52 (149.84–604.23) 310.38 (115.87–489.49) p 0.04 PLT(x10e9/L) 3220 (555–9320) - - 3522 (744–6600) - - n.s. LymphocytesT(x10e6) 12880 (1200–36050) 0.13 (0.01–0.6) 11820 (1690–25050) 0.38 (0.08–2.34) n.s. LymphocytesB(x10e6) 3180 (70–15000) 1.06 (0.02–8.42) 2810 (1120–6100) 0.82 (0.19–2.98) n.s. CD34+(%)recovery 70.98 (9.5–115.32) 82.34 (66.37–99.94) p 0.04 Purity(%) 92 (69–99) 94 (89–98) n.s. LogT-Depletion 5.1 (3.74–7.91) 4.6 (3.4–5.2) n.s. LogB-Depletion 3.65 (2.45–6.08) 3.55 (2.58–4.44) n.s.
The Role of Hemoglobin Barts in Umbilical Cord Blood Harvest and Transplantation.
Authors: Regan Donna M. , Wofford Jonathan D. , McCormick Kimberly A. , Alonso J. Mario F. , Creer Michael H. 
Published: October 2019

Abstract
The abnormal hemoglobin present during fetal development in individuals with four-gene deletion alpha-thalassemia was characterized at St. Bartholomew’s Hospital in London and hence was named “hemoglobin Barts (Hb Barts).” In the homozygous state, when all four alpha-globin genes on chromosomes 16 are affected, no normal fetal or adult hemoglobin can be produced and the fetus becomes profoundly anemic in utero. This typically leads to stillbirth or death soon after birth due to severe hydrops fetalis accompanied by pulmonary hypoplasia and cardiac failure. Various heterozygous states can also produce detectable levels of Hb Barts, but with less dramatic clinical manifestations. These variants can be detected and quantified in umbilical cord blood (UCB) in proportions indicating one-, two- or three-gene deletion alpha-thalassemia, respectively representing silent carrier, thalassemia trait, and Hemoglobin H disease states. Silent carriers, the largest group with Hb Barts at birth, have a normal CBC, no clinically detectable problems and less than 5% Hb Barts present in cord blood sample. Individuals with alpha-thalassemia minor (or trait) have a very mild microcytic anemia but no other clinical problems, and express 5 to 10% Hb Barts in cord blood. One- and two-gene alpha-globin deletions are very common in African, Mediterranean and Asian populations, ethnic groups targeted for cord blood bank inventories.
Sixteen UCB products containing Hb Barts at levels consistent with either one or two alpha-gene deletions were exported for stem cell transplant from the St. Louis Cord Blood Bank. Survival of recipients receiving Hb Barts-containing units was not significantly different from those receiving cord products with normal newborn hemoglobin electrophoretic patterns (P =.5707). To further evaluate the effect of transplanting units with Hb Barts variants, we propose an Institutional Review Board-approved study to evaluate erythropoiesis and the disappearance of fetal hemoglobin variants at designated post-transplant time points in patients who have been transplanted with these products.
In deliveries where the infant exhibits symptoms of hydrops fetalis, obvious perinatal complications would preclude cord blood harvest for the intended use of allogeneic transplantation. Considering the need for these unique and diverse HLA types, criteria for banking should allow inclusion of UCB units with Hb Barts content of less than 10% based on immunoelectrophoretic patterns. These units should pose minimal additional risk in transplantation and increase the ethnic diversity of bank inventories. Additionally, since recipients’ genetic material remains intact after transplantation, they cannot pass these variant hemoglobins to their children.
Influence of Pretreatment with Amphotericin B on Treatement-Related Mortality (TRM) Following Allogeneic Stem Cell Transplantations.
Authors: Trenschel Rudolf , Ditschkowski Markus , Steckel Nina K. , Hlinka Michal , Elmaagacli Ahmet , Ottinger Helmut , Flasshove Micheal , Beelen Dietrich W. 
Published: October 2019

Abstract
Conventional amphotericin B (C-AMB) is one of the most frequently used antifungal first line agents in patients with hematological malignancies diagnosed to have invasive fungal infections or persistent neutropenic fever despite of its well documented adverse effect profile. To evaluate the influence of pretreatment with C-AMB on the outcome of allogeneic HSCT, a retrospective analysis including 270 consecutive allogeneic HSCT between 1/2002 and 12/2003 at out institution was performed. Median patient age was 42 years, female to male ratio 46/51 and CMV positivity 83 %. Diagnosis was AML (n=90), ALL (n=72), CML (n=45), MDS (n=21), NHL (n=14), MM (n=8) or micellaneous (n=20). Sixty percent (164/270) of patients were in early, the remainders in advanced disease stages. Conditioning therapy was TBI or chemotherapy in 237 and 33 patients, respectively. Donors were identical siblings (n=110), non-identical family members (n=3), matched unrelated (n=116) or mismatched unrelated (n=41). Pretreatment with antimycotics was reported in 74 cases (C-AMB, n=73; voriconazole, n=1) for FUO (n=23), not specified fungal pneumonia (n=23), pneumonia due to aspergillus sp.(n=18), hepatosplenic candidiasis (n=6), fungemia (n=3), and IFI by scedosporium prolificans (n=1). A Cox regression model was used to test C-AMB pretreatment as an independent risk factor on TRM. Age in decades, disease stage, preceding neutropenia, renal impairment (creatinine > 1mg/dl) was also included. Only previous treatment with C-AMB (p=0.001; RR 3), and advanced disease stage (p=0.008; RR2,5) remaind statistically significant. Subsequently, to identify patients at increased risk, we defined following strata: 1. patients without previous neutropenia; 2. patients with previous neutropenia; 3. patients with C-AMB pretreatment, creatinin < 1,0 mg%; 4. patients with C-AMB pretreatment and creatinin > 1,0mg%; 5. patients with renal impairment for other causes; 6. patients with renal impairment or C-AMB pretreatment and antimycotic therapy during transplant procedure. TRM was 3.2%, 5.43%, 19.57%, 26.67%, 29.63% and 24.14%, respectively. We conclude that patients being pretreated with conventional C-AMB have an increased independent risk for TRM (RR 4; p<0.001).
Abandoning Care in Laminar Air Flow (LAF) Units and Routine High Dose Intravenous Immunoglobulines (IVIG) in Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Does Not Increase Mortality and Rate of Infections.
Authors: Cantoni Nathan , Passweg Jakob , Weisser Maja , Droll Armin , Christen Susanne , Widmer Andreas , Flueckiger Ursula , Frei Reno , Tichelli André , Gratwohl Alois 
Published: October 2019

Abstract
Nursing in LAF units and routine high dose IVIG were considered essential elements and standard of care in allogeneic HSCT during the 1980s. They were abandoned by many teams in view of high costs, lack of formal proof of evidence and improved diagnostic and therapeutic interventions against viral and fungal infections. A recent prospective study showed no benefit of routine IVIG but few data have analysed the consequences of the combined change in practice. We made these changes at our institution in two stages during a 10-year period: change from care in LAF rooms to single rooms (SR) and change from routine high dose IVIG to targeted IVIG replacement according to CDC guidelines. Basic strategies in supportive care and data collection remained unchanged. This resulted in a retrospective analysis of 357 allogeneic HSCT in three cohorts, i.e. LAF + IVIG, SR + IVIG and SR − IVIG (Table). Endpoints analysed were survival, transplant related mortality (TRM), relapse rate, incidence and severity of GvHD and infectious complication rates defined as: sepsis, septic thrombosis, urinary tract infections, pneumonias, and CMV reactivation. Results were adjusted by multivariate analyses for all the changes over time (see Table *significant difference between groups). There were more patients in advanced stage of disease and with higher age in more recent years. There were significantly fewer septicemias per hospital day but not per day in neutropenia in the LAF + IVIG group without impact on survival. There were no significant differences in any of the other outcomes analysed. Abandoning LAF and routine high dose IVIG use did not impact negatively on HSCT outcome. These data support current practice.
Group LAF + IVIG SR + IVIG SR, no IVIG Total N 116 134 107 357 Male 55% 51% 62% 59% Age, years* 34 34 40 35 Median, range 4–58 2–62 1–62 35 Diagnosis* Leukemias 85% 83% 82% 84% Lymphoproliferative 7% 13% 15% 11% Others 8% 4% 3% 5% Early disease* 46% 38% 29% – Late disease 54% 72% 71% 66% % RIC* 0% 10% 32% – Days in hospital* 53 32 28 38 Days in neutropenia* 16 15 11 14 Day 100 TRM 18% 20% 22% 20%
The Gut-Mucosa-Barrier-Function during Hematopoietic Stem-Cell Transplantation Predicts Acute Graft-Versus-Host Disease Severity.
Authors: Johansson Jan-Erik , Ekman Tor 
Published: October 2019

Abstract
Background
Graft-versus-host disease (GVHD) is the primary complication of allogeneic, haemopoietic, stem-cell transplantation (HSCT). From murine models, it has been revealed that gut toxicity increases the translocation of inflammatory mediators through the impaired intestinal barrier, which aggravates systemic GVHD. In patients, the intestinal barrier is disrupted after myeloablative conditioning but preserved after reduced intensity conditioning (RIC). The present study investigates, in a clinical situation, whether the severity of acute GVHD depends on intestinal-barrier function.
Methods
In 38 patients (21 myeloablative, 17 RIC), intestinal permeability was assessed before transplant and during the transplantation course (day −1 to +14). Blood levels of cytokines were assessed in parallel.
Results
Intestinal barrier integrity was preserved in RIC patients but disrupted in myeloablatively conditioned on day 4 (p = 0.0091) and on day 7 (p = 0.0014) compared with RIC patients. Patients with mild, acute GVHD (grades 0–1) had a significantly better preserved intestinal-barrier function (p = 0.042 on day 4) and lower TNF-a levels (p = 0.013 and 0.025 on day −1 and day +7 respectively), compared with patients with more pronounced GVHD (grades 2–4).
Conclusion
Intestinal barrier function predicts the severity of acute GVHD in patients and gives support to the assumption that gut protective strategies may diminish acute GVHD.