Can patients with epilepsy become bone marrow donors? A case report of allogeneic hematopoietic stem transplantation from child with seizures

Hematopoietic stem cell (HSC) transplantation is an important treatment option for malignant and non-malignant hematopoietic disorder in adults and children. For long time epilepsy was temporary exclusion condition to voluntary donation, and donors had to be medication or seizure free. It is still unclear if people with history of epilepsy are indeed potential eligible donors, even if a significant increased risk of adverse events in these donors has not been demonstrated. We studied a 10-year-old boy with symptomatic focal epilepsy who was the only available donor for his monozycote twin, suffering from acute lymphoblastic leukemia. A total of 3.39 x 108/kg HSCs were collected and reinfused to the leukemic brother after conditioning treatment. At the end of follow-up, our epilepsy patient had no consequences and his brother is in complete remission of the disease at 3 years from the transplant procedure. Our observation confirms that a patient with epilepsy can be a donor, without consequences for himself and for the recipient

Photo-biomodulation as a prevention modality of oral mucositis in patients undergoing allogeneic hematopoietic stem cell transplantation

The aim of the study was to observe the eectiveness of a photo-biomodulation (PBM) protocol for the prevention of oral mucositis (OM) in patients undergoing allogeneic hematopoietic stem cell transplantation (aHSCT). A case-control study was conducted on 40 patients undergoing aHSCT. The patients were divided into two groups; the preventive group (PG) included 20 patients (7 females and 13 males) who were subjected to intra-oral PBM for five sessions a week, starting one day before the conditioning regimen and continuing until the 10th day after transplantation (D+10). In each session, ten points on the at-risk mucosal surfaces were irradiated using a double diode laser that emits two wavelengths simultaneously at 650 nm and at 904–910 nm with the following parameters at each point: energy of 4 J, and power of 88.9 mW. The control group (CG) included 20 patients (10 females and 10 males) who were not subjected to laser therapy and were selected retrospectively to compare the obtained results. For all patients, OM was assessed by the World Health Organization (WHO) grading scale. Eight patients in the PG did not experience OM during their hospitalization period (with grade 0). Severe OM was observed in 40% of the patients in the PG, while in the CG, severe OM was shown in 85% of the patients. The mean duration of OM in the PG was significantly lower than that of CG (4.7 days in the PG and 15 days in the CG) (p < 0.001). The study demonstrated that the preventive PBM protocol reduced the severity and duration of OM in patients undergoing aHSCT

A system-engineering model to analyze gap-FRAP in multicellular models.

International audienceIntroduction. Developed in the 70s, the Fluorescence Recovery After Photobleaching (FRAP) technique is based on the progressive increase of fluorescence intensity in a photobleaching area obtained after an illumination with a LASER beam. This enhancement corresponds to the gradual arrival (through gap junctions) of intact fluorescent molecules towards the targeted zone. This widely used method is principally dedicated to study fluorescent constituents mobility in cellular membranes and gap junctional intercellular communication (GJIC) at microscopic scale. Purpose. The final addressed question is to assess the relevance to use GJIC characteristics to discriminate different cancer cell lines. With this aim in view, we have proposed a model-based approach in which some parameters could be potentially used as decision statistics. As proof of concept, we have tested the applicability of a compartmental model to describe differences between gap-FRAP responses of two human head and neck carcinoma cell lines (FaDu and KB). . Methods and Materials. Cx43, a protein of the connexin family responsible for GJIC, distribution and intercellular communication of FaDu and KB cells were performed in monolayer cultured cells and spheroids. Six experiments were performed for each case and data were collected through an imaging system composed of a macroscope combined to a fluorescence excitation source (Hg) and a CCD camera. The pixel intensities were measured in three concentric Regions of Interest (ROI) every 15 seconds for 15 minutes on each images. The measured values were assumed to be proportional to the mean amount of photons emitted in each ROI. After normalization with respect to the fluorescence intensity values before photobleaching, the data were plotted across the time. Modeling method. To study gap-Fluorescence Recovery After Photobleaching (gap-FRAP), the perturbation-relaxation kinetic equation is commonly used but is sometimes unable to describe some parts of the fluorescence response. A new behavioral model is proposed to study fluorescence recovery. The latter is based on a three-compartment representation (one compartment for each ROI) and the rates between each compartment represent the flow coefficients of the different gap junctions. This model provides a set of differential equations for which the associated continuous-time second-order transfer function was identified using the Simplified Refined Instrumental Variable in Continuous-time (SRIVC) algorithm. The algorithm returns three estimated parameters (a static gain and two time constants) and their standard deviations. Results. Two model parameters have allowed us to discriminate gap junctions functionalities. Indeed, parameters of KB cells, which is positive for Cx43 expression, are significantly superior to those of FaDu cells in culture 2-D and 3-D. No significant differences were observed for KB cells data independently of culture type confirming negligible contribution from underlying layers during fluorescence restitution in Z plan by confocal microscopy. Conclusions. Our study exemplifies the contributions brought by dynamic models of biological phenomena to diagnostic applications in biomedicine

Anti-HLA donor-specific antibodies in allogeneic stem cell transplantation: management and desensitization protocol

The role of antibodies directed against the human leukocyte antigen (HLA) system has been well analyzed in rejection of solid organ transplantations [1, 2] and in transfusion medicine [3]. In the setting of allogeneic hematopoietic stem cells transplantation (HSCT), only in the recent years their importance has been better defined, even though anti-HLA antibodies are frequently detectable in hematologic patients, due to sensitization from multiple transfusions, usually before the introduction of online universal leukoreduction, previous transplantations, and pregnancies in female patients

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes

First recorded eruption of Nabro volcano, Eritrea, 2011

We present a synthesis of diverse observations of the first recorded eruption of Nabro volcano, Eritrea, which began on 12 June 2011. While no monitoring of the volcano was in effect at the time, it has been possible to reconstruct the nature and evolution of the eruption through analysis of re- gional seismological and infrasound data and satellite remote sensing data, supplemented by petrological analysis of erupted products and brief field surveys. The event is notable for the comparative rarity of recorded historical eruptions in the region and of caldera systems in general, for the prodi- gious quantity of SO2 emitted into the atmosphere and the significant human impacts that ensued notwithstanding the low population density of the Afar region. It is also relevant in understanding the broader magmatic and tectonic signifi- cance of the volcanic massif of which Nabro forms a part and which strikes obliquely to the principal rifting directions in the Red Sea and northern Afar. The whole-rock compositions of Editorial responsibility: G. Giordano the erupted lavas and tephra range from trachybasaltic to trachybasaltic andesite, and crystal-hosted melt inclusions contain up to 3,000 ppm of sulphur by weight. The eruption was preceded by significant seismicity, detected by regional networks of sensors and accompanied by sustained tremor. Substantial infrasound was recorded at distances of hundreds to thousands of kilometres from the vent, beginning at the onset of the eruption and continuing for weeks. Analysis of ground deformation suggests the eruption was fed by a shal- low, NW–SE-trending dike, which is consistent with field and satellite observations of vent distributions. Despite lack of prior planning and preparedness for volcanic events in the country, rapid coordination of the emergency response miti- gated the human costs of the eruption

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival