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BackgroundThe monoclonal antibody daratumumab, approved for treating myeloma, targets CD38, a protein on myeloma and also on CD34+ hematopoietic progenitor cells. Because mobilized CD34+ cells are critical for stem cell transplant, we investigated the in vitro activity of daratumumab on mobilized CD34+ cells from myeloma patients with no prior exposure to daratumumab.MethodsWe determined the number of CD38 molecules per CD34+ cell, and whether daratumumab bound to CD34+ cells, whether C1q bound to daratumumab-coated CD34+ cells and whether daratumumab-related complement-dependent cytotoxicity (CDC) occurred. We also examined CD34+ cell progenitor cell colony capacity in assays with pre-plating incubation of CD34+ cells with daratumumab alone or with daratumumab and the CD59 inhibitory antibody BRIC229, and also assessed CD34+ cell responses to increasing doses of daratumumab in caspase 3/7 activity assays.ResultsAlthough 75% of mobilized CD34+ cells co-express CD38, CD38 was minimally present on CD34+ cells compared to Daudi and KG-1 controls, C1q did not bind to daratumumab-coated CD34+ cells, and CDC did not occur. CD34+ cells incubated in complement-rich human serum with daratumumab alone or with daratumumab and BRIC229, and then plated in progenitor cell assays, produced similar numbers of colonies as controls. In progenitor cell assays with cryopreserved or fresh unselected or CD34-selected cells, daratumumab did not affect progenitor cell capacity, and in caspase 3/7 activity assays CD34+ cells were not affected by increasing doses of daratumumab.ConclusionIn vitro, daratumumab is not toxic to mobilized CD34+ progenitor cells from myeloma patients.

BackgroundMultiple myeloma/plasmacytoma-like posttransplantation lymphoproliferative disorder (PTLD-MM) is a rare complication of solid organ transplantation. Case series have shown variable outcomes, and survival data in the modern era are lacking.Patients and methodsA cohort of 212 PTLD-MM patients was identified in the Scientific Registry of Transplant Recipients between 1999 and 2011. Overall survival (OS) was estimated by the Kaplan-Meier method, and the effects of treatment and patient characteristics on OS were evaluated by Cox proportional hazards models. OS in 185 PTLD-MM patients was compared to 4048 matched controls with multiple myeloma (SEER-MM) derived from Surveillance, Epidemiology, and End Results (SEER) data.ResultsMen comprised 71% of patients; extramedullary disease was noted in 58%. Novel therapeutic agents were used in 19% of patients (more commonly during 2007-2011 vs. 1999-2006; P = .01), reduced immunosuppression in 55%, and chemotherapy in 32%. Median OS was 2.4 years and improved in the later time period (adjusted hazard ratio [aHR], 0.64, P = .05). Advanced age, creatinine > 2 g/dL, white race, and use of OKT3 were associated with inferior OS in multivariable analysis. OS of PTLD-MM patients is significantly inferior to SEER-MM patients (aHR, 1.6, P < .001). Improvements in OS over time differed between PTLD-MM and SEER-MM. Median OS of patients diagnosed from 2000 to 2005 was shorter for PTLD-MM than SEER-MM patients (18 vs. 47 months, P < .001). There was no difference among those diagnosed from 2006 to 2010 (44 months vs. median not reached, P = .5; interaction P = .08).ConclusionAge at diagnosis, elevated creatinine, white race, and OKT3 were associated with inferior survival in patients with PTLD-MM. Survival of PTLD-MM is inferior to SEER-MM, although significant improvements in survival have been documented.

Hodgkin lymphoma post-transplant lymphoproliferative disorder (HL-PTLD) is an uncommon PTLD with unclear prognosis and differences between HL-PTLD and immunocompetent HL are not well defined. Patient characteristics were compared among 192 patients with HL-PTLD from the Scientific Registry of Transplant Recipients and 13,847 HL patients in SEER (HL-SEER). Overall survival (OS) and disease-specific survival (DSS) were compared after exact matching. Additionally, multivariable analyses were used to identify prognostic markers of survival and associations between treatment and survival. Median time from transplant to HL-PTLD diagnosis was 88 months. When compared with HL-SEER, patients with HL-PTLD were older (median age, 52 vs. 36 years, P = 0.001), more likely male (73% vs. 54%, P

Human research projects must have a scientifically valid study design, analytic plan, and be operationally feasible in order to be successfully completed and thus to have translational impact. To ensure this, institutions that conduct clinical research should have a scientific review process prior to submission to the Institutional Review Committee (IRB). This paper reports the Clinical and Translational Science Award (CTSA) Consortium Scientific Review Committee (SRC) Consensus Working Group's proposed framework for a SRC process. Recommendations are provided for institutional support and roles of CTSAs, multisite research, criteria for selection of protocols that should be reviewed, roles of committee members, application process, and committee process. Additionally, to support the SCR process effectively, and to ensure efficiency, the Working Group recommends information technology infrastructures and evaluation metrics to determine outcomes are provided.

BACKGROUNDIn the setting of allogeneic stem cell transplantation (alloSCT), infusing natural killer (NK) cells from a major histocompatibility complex (MHC) mismatched donor can mediate an anti-leukemic effect. Graft versus tumor (GvT) effect following autologous stem cell transplantation (ASCT) may result in less disease relapse.STUDY DESIGN AND METHODSWe performed a phase I clinical trial to assess the safety and feasibility of infusing distantly processed donor NK enriched mononuclear cell (NK-MC) infusions from a MHC haplotype mismatched (haploidentical) donor to patients who recently underwent ASCT for a hematologic malignancy. On day 1, peripheral blood mononuclear cells (MC) were obtained by steady-state leukapheresis and sent from Boston to the Production Assistance for Cellular Therapies (PACT) facility at the University of Minnesota, where immunomagnetic depletion of CD3 cells was performed on day 2. NK-MC product were then returned to Boston on day 2 for infusion on day 3. Toxicity, cellular product characteristics and logistic events were monitored.RESULTSAt a median of 90 days (range, 49–191) following ASCT, thirteen patients were treated with escalating doses of NK-MC per kg from 105 to 2 ×107. Adverse effects included grade 2 rigors and muscle aches, but no grade 3 or 4 events, and no GvHD or marrow suppression. One air courier delay occurred. NK-MC products were viable with cytotoxic activity after transport.CONCLUSIONCD3-depleted, MHC mismatched allogeneic NK-MC infusions can be safely and feasibly administered to patients after ASCT following distant processing and transport, justifying further development of this approach.

The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo- and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies.

Although current edge-following schemes can be very efficient in determining coronary boundaries, they may fail when the feature to be followed is disconnected (and the scheme is unable to bridge the discontinuity) or branch points exist where the best path to follow is indeterminate. In this paper, we present new deformable spline algorithms for determining vessel boundaries, and enhancing their centerline features. A bank of even and odd S-Gabor filter pairs of different orientations are convolved with vascular images in order to create an external snake energy field. Each filter pair will give maximum response to the segment of vessel having the same orientation as the filters. The resulting responses across filters of different orientations are combined to create an external energy field for snake optimization. Vessels are represented by B-Spline snakes, and are optimized on filter outputs with dynamic programming. The points of minimal constriction and the percent-diameter stenosis are determined from a computed vessel centerline. The system has been statistically validated using fixed stenosis and flexible-tube phantoms. It has also been validated on 20 coronary lesions with two independent operators, and has been tested for interoperator and intraoperator variability and reproducibility. The system has been found to be specially robust in complex images involving vessel branchings and incomplete contrast filling. Index Terms - B-spline snakes, coronary angiography, deformable models, dynamic programming, Gabor filters.