Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study.

ABSTRACT: Patients with hemophilia A require exogenous factor VIII (FVIII) or nonfactor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector-based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain-deleted human F8 gene. In the ongoing phase 1/2, dose-ranging Alta study, 4 sequential cohorts of male participants with severe hemophilia A received a single IV dose of giroctocogene fitelparvovec. The primary end points are safety and changes in circulating FVIII activity. Interim results up to 214 weeks after treatment for all participants are presented. Eleven participants were dosed. Increases in alanine and aspartate aminotransferases were the most common treatment-related adverse events (AEs), which resolved with corticosteroid administration. Two treatment-related serious AEs (hypotension and pyrexia) were reported in 1 participant within 6 hours of infusion and resolved within 24 hours after infusion. At the highest dose level (3 × 1013 vg/kg; n = 5), the mean circulating FVIII activity level at week 52 was 42.6% (range, 7.8%-122.3%), and at week 104 it was 25.4% (range, 0.9%-71.6%) based on a chromogenic assay. No liver masses, thrombotic events, or confirmed inhibitors were detected in any participant. These interim 104-week data suggest that giroctocogene fitelparvovec is generally well tolerated with appropriate clinical management and has the potential to provide clinically meaningful FVIII activity levels, as indicated by the low rate of bleeding events in the highest dose cohort. This trial was registered at www.clinicaltrials.gov as #NCT03061201.

Autoimmune haemolytic anaemia in a patient with advanced lung adenocarcinoma and chronic lymphocytic leukaemia receiving nivolumab and intravenous immunoglobulin.

We describe a rare case of severe autoimmune haemolytic anaemia (AIHA) in the setting of underlying chronic lymphocytic leukaemia receiving intravenous immunoglobulin, history of warm IgG autoantibody and treatment with nivolumab for advanced non-small cell lung cancer. In this report, we describe AIHA as a potential serious immune-related adverse event from immune checkpoint inhibitors, discuss other potential contributing factors and review previously described cases of AIHA in patients receiving programmed death 1 (PD-1) inhibitors. In the era of immunotherapy, we hope to add literature to raise awareness of potential immune-related sequelae such as AIHA. We aim to highlight the importance of close monitoring for prompt identification and management of potentially fatal AIHA and immune-related adverse events of PD-1 inhibitors by holding immunotherapy and treating with high-dose steroids, particularly in subgroups which may be at increased risk.

Catastrophic antiphospholipid syndrome with severe acute thrombotic microangiopathy and hemorrhagic complications.

The catastrophic antiphospholipid syndrome (CAPS) is a rare life-threatening form of the antiphospholipid syndrome characterized by disseminated vascular thrombosis resulting in multiorgan failure. On an exceedingly rare occasion, CAPS can be associated with severe hemorrhagic manifestations. We report a young woman with a history of several spontaneous miscarriages who presented with menorrhagia and hemoptysis. The patient developed respiratory failure due to diffuse alveolar hemorrhage. Laboratory tests demonstrated severe hemolytic anemia, profound thrombocytopenia, markedly elevated fibrin degradation products, and renal failure. Blood films revealed numerous schistocytes. Serologic tests disclosed hypocomplementemia and autoantibodies directed against several nuclear antigens. Coagulation studies revealed lupus anticoagulant. Echocardiography demonstrated reduced ejection fraction and moderate to severe mitral and tricuspid regurgitation. The patient was diagnosed with CAPS with hemorrhagic manifestations in the setting of new-onset SLE. The patient was treated with hemodialysis, high-dose glucocorticoids, plasma exchange, intravenous cyclophosphamide, and rituximab. Over the ensuing four weeks, the combination therapy led to hematological, cardiopulmonary, and renal recovery. This exceedingly rare case emphasizes that hemorrhagic manifestations, severe microangiopathic hemolytic anemia, and profound thrombocytopenia can dominate the clinical picture in CAPS.

Similar taxonomic richness but different communities of ectomycorrhizas in native forests and non-native plantation forests.

This investigation sought to examine if there was a difference between the ectomycorrhizal (ECM) communities in plots of native oak and introduced Scots pine and Sitka spruce forest. The ECM communities in four plots of each forest type were described, from five soil cores collected in each plot, by morphotyping, internal transcribed spacer (ITS)-restriction fragment length polymorphism matching of mycorrhizas and sporocarps and ITS sequencing. Fifty-one distinct taxa were distinguished; 25 were identified to species level, 11 to genus and 15 remained unidentified. Seventy-one ECM species were recorded as sporocarps from the forest plots; most (43 species) were found in the Sitka spruce plots. The below-ground ECM communities of the different forest types did not differ significantly with respect to species richness of taxa on roots, but differed in species composition. Multivariate analysis produced a clear separation of the communities of the different forest types using below-ground data, but the above-ground sporocarp data did not separate the forest types. Moreover, results of a Mantel test found no relationship between the above- and below-ground similarity matrices. The oak plots had the most distinctive ECM community, with Laccaria amethystina and Elaphomyces granulatus being frequent. The Sitka spruce plots showed the lowest intra-forest type similarity and were often dominated by "nursery type" ectomycorrhizas. There was only 10% similarity between the above- and below-ground ECM species in these plots, different colonisation methods of ectomycorrhizal taxa and insufficient below-ground sampling being possible reasons for this disparity. Our results indicate that plantations of non-native Sitka spruce can support similar levels of ECM diversity as native forests.

Developing an optimal river typology for biological elements within the Water Framework Directive.

The Water Framework Directive requires a river classification based on environmental variables (a typology) to be created as a structure for reporting ecological status. A single permutation procedure, utilising the same variables repeatedly but with different categorical divisions, enabled both the choice of variables and the boundary divisions for these variables to be optimised simultaneously in the development of the typology. This, in addition to a data set which appropriately combined different biological elements, enabled a typology to be developed which was far more effective than a System A, CCA-derived or expert opinion-based typology in segregating communities. This optimal typology could be used to improve the performance of ecological quality assessment methods.

Ectomycorrhizas associated with a relict population of Dryas octopetala in the Burren, western Ireland II. Composition, structure and temporal variation in the ectomycorrhizal community.

The composition, structure and temporal variation of ectomycorrhizal (EM) communities associated with mountain avens (Dryas octopetala) in grass heaths of the Burren, western Ireland were assessed by using soil core sampling in two permanent plots and 30 other sites (196 cores in total). Of the 34 different EM types observed, 11 were common and constituted over 80% of the EM biomass. Four EM types, Craterellus lutescens, Tomentella sp., Dryadirhiza fulgens and Cenococcum geophilum were the most abundant as measured by EM length and frequency of occurrence in cores. The species profile and relative abundances were very similar in cores from the permanent plots and different sites in the Burren, indicating that they were all representative of the same EM community. The below-ground EM community in both plots was compared with production of basidiomes, and the latter was found to be an unreliable indicator of EM community structure. Temporal variation in the EM community was assessed by repeated core sampling of the two permanent plots over a 14-month period (between March 1998 and May 1999). No statistically significant shifts in EM abundance were found between sampling dates, probably as a consequence of the large variation in EM abundance between core samples over the sampling period. No significant relationship was found between rainfall, soil moisture or soil temperature and fluctuations in EM abundance. Patterns of total EM abundance and fluctuations in EM diversity were strongly correlated between the two permanent plots over the sampling period. Temporal fluctuations in the dominant EM type, Craterellus lutescens, were similar in both plots with respect to mycorrhizal length, biomass and relative abundance, and the patterns between both plots were positively correlated. EM diversity was negatively correlated with biomass of ectomycorrhizas of Craterellus lutescens in both plots, but it was significant only in plot 1.

Ectomycorrhizas associated with a relict population of Dryas octopetala in the Burren, western Ireland. I. Distribution of ectomycorrhizas in relation to vegetation and soil characteristics.

The distribution of ectomycorrhizas on Dryas octopetala L in grass heaths of the 450 km2 karst region known as the Burren in Western Ireland was examined in relation to soil factors and vegetation type. Ectomycorrhizas were identified or characterised from 56 soil cores from 30 sites, and the occurrence of each ectomycorrhizal (EM) type was quantified by estimating the total length of mycorrhizal tips of each type. Soil organic matter, total nitrogen, extractable phosphorus, pH and depth were the soil factors determined. In total, 24 EM types were recorded. The EM community of Dryas roots was significantly more species-rich in one vegetation type--Hyperico-Dryadetum--than in others (Arctostaphylo-Dryadetum or Asperulo-Seslerietum). Multiple linear regression analyses indicated that soil organic matter and soil depth explained a significant portion of the variation in EM abundance, while soil organic matter and extractable phosphorus explained a significant portion of the variation in EM diversity. Canonical correspondence analysis showed that some individual EM types (e.g. Craterellus lutescens, Cenococcum geophilum, Tomentella sp., Boletus sp.) exhibited distinct soil preferences, most markedly in relation to soil organic matter, which, in this analysis, was the main significant soil variable distinguishing the three vegetation types.