Graft-versus-host disease of the skin: life and death on the epidermal edge

AbstractDespite impressive advances in the field of allogeneic hematopoietic transplantation, graft versus host disease (GVHD) remains a significant obstacle to be overcome; it would enhance the safety and efficacy of this life-saving therapy. This review provides a framework for understanding the molecular and cellular basis underlying GVHD. We propose a 3-phase model of GVHD that highlights the importance of the conditioning regimen on the recipient tissues administered prior to infusion of donor bone marrow inoculum. A novel skin explant model, designed to take into consideration the immunobiological consequences of conditioning regimens on resident host cells, is proposed to advance our understanding of GVHD and serve as a potential prognostic tool when allogeneic recipient/donor combinations are being contemplated in the clinic. Within this review, specific emphasis is placed on the importance of defining the apoptotic machinery engaged in epidermal keratinocytes triggered by both conditioning regimens, and by host resident and recruited immunocytes and soluble mediators produced at sites of injury. The review is completed with a working model for cutaneous GVHD. Although the skin is highlighted because of its accessibility for clinical observations and serial sampling opportunities, lessons learned from studies of cutaneous GVHD are likely to provide valuable insights into GVHD occurring in the gastrointestinal tract, lung, and liver. With new insights designed to better predict and prevent GVHD and novel agents designed to treat GVHD, overcoming this current impediment to successful bone marrow transplantation should become increasingly feasible

Long-lived submicrometric bubbles in very diluted alkali halide water solutions

Solutions of LiCl and of NaCl in ultrapure water were studied through Rayleigh/Brillouin scattering as a function of the concentration (molarity, M) of dissolved salt from 0.2M to extremely low concentration (2.10^-17 M ). The Landau-Placzek ratio, R/B, of the Rayleigh scattering intensity over the total Brillouin, was measured thanks to the dynamically controlled stability of the used Fabry-Perot interferometer. It was observed that the R/B ratio follows two stages as a function of increasing dilution rate: after a strong decrease between 0.2M and 2.10^-5 M, it increases to reach a maximum between 10^-9 M and 10^-16 M. The first stage corresponds to the decrease of the Rayleigh scattering by the ion concentration fluctuations with the decrease of salt concentration. The second stage, at lower concentrations, is consistent with the increase of the Rayleigh scattering by long-lived sub-microscopic bubbles with the decrease of ion concentration. The origin of these sub-microscopic bubbles is the shaking of the solutions which was carried out after each centesimal dilution. The very long lifetime of the sub-microscopic bubbles and the effects of aging originate in the electric charge of bubbles. The increase of R/B with the decrease of the low salt concentration corresponds to the increase of the sub-microscopic bubble size with the decrease of concentration, that is imposed by the bubble stability due to the covering of the surface bubble by negative ions.Comment: 6 figures. To be published in Physical Chemistry and Chemical Physics (PCCP

FLT3L and Plerixafor Combination Increases Hematopoietic Stem Cell Mobilization and Leads to Improved Transplantation Outcome

AbstractHematopoietic stem cell (HSC) transplantation has curative potential for patients with hematological malignancies. Clinically, HSCs derived from mobilized peripheral blood are used more frequently than bone marrow. However, current standard mobilizing agents yield grafts that may not contain sufficient HSCs. Here, using murine models, we discovered that FLT3L synergized with plerixafor to mobilize phenotypically defined HSCs and their combination (FP) was superior to granulocyte colony-stimulating factor (G-CSF) alone or in combination with plerixafor (GP). Additionally, FP mobilized more regulatory T cells, natural killer cells, and plasmacytoid dendritic cells compared with G-CSF alone or GP. Both syngeneic and allogeneic grafts mobilized by FP led to long-term survival in transplanted mice. Collectively, FP represents a promising novel and potent mobilization regimen with potential clinical application in both the autologous and allogeneic transplantation settings

A phase I trial of Flavopiridol in relapsed multiple myeloma

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myelom

Long Term Therapy with Lenalidomide in a patient with POEMS Syndrome

Lenalidomide is an effective therapy against malignant plasma cells and a potent agent against proinflammatory and proangiogenic cytokines. The use of lenalidomide in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein with plasma cells, skin changes) has been reported, but its benefit in long-term use is not well established. A 55-year-old man with POEMS and debilitating polyneuropathy was treated with lenalidomide and dexamethasone followed by maintenance lenalidomide. He remains in haematologic remission and in complete recovery of functional status 3.5 years after diagnosis. This case supports the long-term use of lenalidomide in patients with POEMS syndrome

Improved Nonrelapse Mortality and Infection Rate with Lower Dose of Antithymocyte Globulin in Patients Undergoing Reduced-Intensity Conditioning Allogeneic Transplantation for Hematologic Malignancies

We sought to reduce the risk of infectious complications and nonrelapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (aGVHD) in patients undergoing reduced-intensity conditioning (RIC) transplantation. As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n = 39) to 6.0 mg/kg of ATG (r-ATG) (n = 33) in association with fludarabine (Flu) and busulfan (BU) RIC transplantation and then monitored patients for adverse events, relapse, and survival. Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in posttransplantation full donor-cell chimerism rates were observed between the 2 ATG-dose groups (P > .05). When R-ATG versus r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II-IV aGVHD (32% versus 27%; P = .73) or grade III-IV aGVHD (23% versus 11%; P = .28). However, the r-ATG group had significantly less cytomegalovirus (CMV) reactivation (64% versus 30%; P = .005) and bacterial infections (56% versus 18%; P = .001), a better 1-year cumulative incidence of NRM (18% versus 3%; P = .03), and a trend for better 1-year overall survival (OS) (64% versus 84%; P = .07) compared to R-ATG patients. A seemingly modest reduction in the dose of rabbit ATG did not compromise control of aGVHD or achievement of donor chimerism, but led to a significant decrease in the risk of serious infections and NRM in high-risk RIC allograft recipients

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/1/bjh15394.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/2/bjh15394_am.pd

Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS)

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