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The collagenase production of cultured skin fibroblasts from Scandinavian families with dominant (D-EBD) and recessive (R-EBD) epidermolysis bullosa dystrophica has been investigated. Heterogeneity as a result of body location origin has been ruled out as fibroblasts obtained from predilection sites produce the same amount of immunoreactive collagenase as those obtained from non-predilection sites of the same subjects. Large variations in in vitro collagenase production were found between individuals and families. Within the R-EBD group, four out of eighteen patients showed an in vitro elevated level of immunoreactive collagenase compared to their healthy relatives, other EB types, and the control group. This shows that an in vitro elevated collagenase production is not a marker for the entire disease group and that the disease denoted as R-EBD probably is etiologically and pathogenetically heterogeneous. [ABSTRACT FROM AUTHOR]

The use of gelatinase expression in dermal fibroblast cultures as a marker for generalized epidermolysis bullosa simplex (D-EBS-Köbner) has been tested. None of the 6 Köbner patients tested (from 3 families) produced reduced amounts of gelatinase compared with their healthy relatives and other control groups. This shows that a reduced production of gelatinase from dermal fibroblasts is not uniformly a marker for D-EBS-K. [ABSTRACT FROM AUTHOR]

The article focuses on clinical heterogeneity in epidermolysis bullosa (EB). A recent article presented an extensive review on the role of anchoring fibril changes in dystrophic epidermolysis bullosa, summarizing electron microscopic, biochemical and other evidence. Included were highly relevant points on clinical diagnosis, not the least of which was the difficulty in discriminating the local forms of the recessive type from sporadic dominant mutant cases. The focus in the article is on the clinical variations in different categories of EB, their possible causations, and consequences.

Breakpoint Cluster Region-Abelson kinase (BCR-Abl) is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells (LSCs), the cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. New strategies to target cancers driven by BCR-Abl are therefore urgently needed. We performed a small molecule screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells and identified several compounds that selectively impair the fitness of BCR-Abl-transformed cells. Interestingly, systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. DJ34-mediated c-Myc depletion occurred in a wide range of tumor cell types, including lymphoma, lung, glioblastoma, breast cancer, and several forms of leukemia, with primary LSCs being particularly sensitive to DJ34. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest, and cell differentiation. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against LSCs. [ABSTRACT FROM AUTHOR]

• The type of nutritional support seems to have relatively minor effects on the post-transplant metabolomic profile. • The metabolic profile of patients treated with standard-care nutritional support indicates an insufficient calorie intake compared with patients treated with individualized enteral nutritional support. Patients undergoing allogeneic stem cell transplantation usually require nutritional support. There is no consensus on whether enteral support through tube feeding should be preferred. A recent randomized study could not detect any difference between enteral and parenteral feeding with regard to post-transplant outcomes, whereas 2 retrospective studies described an association between enteral feeding and a favorable post-transplant outcome. We compared pre- and post-transplant plasma metabolomic profiles for 10 patients receiving mainly enteral nutritional support and 10 patients receiving mainly parenteral support. Samples were collected before conditioning and 3 weeks post-transplant; 824 metabolites were analyzed using mass spectrometry. The pretransplant metabolite profiles showed a significant overlap between the 2 groups. Post-transplant samples for both patient groups showed an increase of secondary bile acids and endocannabinoids, whereas reduced levels were seen for food preservatives, plasmalogens, and retinol metabolites. The main post-transplant differences between the groups were decreased levels of fatty acids and markers of mitochondrial activation in the control group, indicating that these patients had insufficient energy intake. A significant effect was also seen for heme/bilirubin metabolism for the parenteral support. To conclude, allotransplant recipients showed altered metabolic profiles early after transplantation; this was mainly due to the conditioning/transplantation/reconstitution, whereas the type of nutritional support had minor effects. [ABSTRACT FROM AUTHOR]

Steroid refractory acute graft-versus-host-disease of the gut is a serious complication associated with high mortality after allogeneic stem cell transplantation. Treatment options are limited and not predictably effective. We describe the treatment of steroid-refractory acute graft-versus-host-disease with vedolizumab, an antibody directed against integrin α4β7, in 6 patients. All patients responded, and 4 of 6 patients are alive with a median follow-up of 10 months. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia bearing a RUNX1 gene mutation (RUNX1 + AML) has been proposed as a provisional entity in the 2016 WHO classification. Clinically, it has been associated with inferior response rates and outcome after conventional chemotherapy. Accordingly, RUNX1 + AML is allocated in the unfavorable prognostic category of the 2017 European Leukemia Net classification. Following allogeneic stem cell transplantation (alloSCT), RUNX1 was an unfavorable factor in one study in MDS/secondary AML, while data in de novo AML are scarce. Here, we present a retrospective study by the EBMT Acute Leukemia Working Party, aiming to elucidate the prognostic value of RUNX1 mutation in patients undergoing alloSCT for AML in first complete remission (CR1). Adults undergoing alloSCT for AML in CR1 from matched related or unrelated donors between 2013 and 2018 with complete information on conventional cytogenetics and RUNX1 mutational status were selected from the EBMT registry. Variables of interest were overall and leukemia-free survival (OS/LFS), GvHD/relapse free survival (GRFS), cumulative relapse incidence (RI), non-relapse mortality (NRM) and GvHD. Log rank test, Gray test and Cox regression models were used. 128 RUNX+ and 388 RUNX- patients were identified, >80% of both subgroups presenting as de novo AML. As expected, RUNX1+ patients rarely had co-mutations in NPM1 (6% vs. 26%, p=10−3), and showed a positive correlation with ASXL1 mutations (50% vs. 16%, p=10−4). Cytogenetic categories and other mutations (FLT3 -ITD, CEBPA) were equally distributed between the two groups, as were age, donor and graft type, CMV, conditioning and T cell depletion (TCD). Median follow-up was 16.4 (RUNX+) and 19.8 (RUNX-) months. 2y OS/LFS of the entire cohort were 64% [59-69]/57% [52-62], with no difference between RUNX1 + and RUNX1 - patients either in univariate or multivariate analysis (2y OS: 67.9% [57.3-78.5] vs. 63.1%v[57.4-68.7]p=0.15; 2y LFS: 57.6% [46.4-68.7] vs. 57% [51.4-62.6], p=0.38], figure 1). RUNX1 mutation neither had any impact among patients with normal karyotype (figure 2). Similarly, no other outcome parameter was influenced by RUNX1 mutational status. Instead, multivariate analysis revealed age and donor type as risk factors for OS, LFS and NRM. Poor cytogenetic was associated with higher RI and inferior LFS/GRFS, in vivo TCD with a lower rate of aGvHD II-IV, cGvHD, and better GRFS. Among patients with available information, FLT3 -ITD was an independent risk factor for relapse, LFS and GRFS. RUNX1 did not modify the role of FLT3 -ITD. Within the limits of a retrospective registry analysis, we could not find a negative influence of RUNX1 mutation on outcome after allogeneic SCT in CR1. Hence, transplantation in CR1 might overcome the unfavorable prognostic value of RUNX1 mutation and can be recommended as consolidation treatment in this entity. [ABSTRACT FROM AUTHOR]

Plectin is one of the largest and most versatile cytolinker proteins known. In basal keratinocytes it links the intermediate filament network to cell membrane-associated hemidesmosomes. Several mutations in its gene have been identified that lead to the recessive disease epidermolysis bullosa with muscular dystrophy. We report here a mutation that leads to a dominant form of the disease, epidermolysis bullosa simplex Ogna. We found that the epidermolysis bullosa simplex Ogna phenotype is due to a site-specific missense mutation within plectin's rod domain. Further, we show that epidermolysis bullosa simplex Ogna is not restricted to a single Norwegian kindred as previously believed. A German family with the phenotypic hallmarks of epidermolysis bullosa simplex Ogna was found to carry an identical de novo mutation. These two mutations arose about 200 y apart in time. Consistent with the absence of muscular symptoms in these patients, muscle biopsies from several epidermolysis bullosa simplex Ogna members of the Norwegian kindred showed normal staining patterns using antibodies to plectin. Skin changes in epidermolysis bullosa simplex Ogna patients are documented on the ultrastructural level. [ABSTRACT FROM AUTHOR]

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is influenced by many factors (underlying disease, HLA-matching, patient and donor age, CMV serostatus, co-morbidities, conditioning regimen, GVHD prophylaxis and graft source and composition). The number of T-cells contained in the graft is associated with the incidence and severity of GvHD. The effect of CD34+ cell dose in HSCT on overall survival and incidence of acute and chronic GvHD is less well established. We analyzed transplant outcomes in 189 patients with hematological malignancy and sibling donor receiving G-CSF mobilized peripheral blood stem cell grafts. Myeloablative conditioning was given to 88 patients and reduced intensity conditioning to 101 patients. Median CD34+ cell dose was 5.6 × 106/kg (0.6-17.0). Anti-thymocyte globulin (ATG) was not given. Median time to neutrophil engraftment (ANC >0.5 × 109/L) was 17 days. In multivariate analysis <5 × 106/CD34+ cells/kg correlated to slower engraftment, measured as later than median days-to-engraftment (OR 2.62, 95% CI 1.27-5.41, p=0.008). The 5-year overall survival (OS) for all patients was 47%. The best 5-year OS (71%) was seen in patients receiving 6-7 × 106CD34+cells/kg (HR: 0.43, 95% CI: 0.24-0.78, p=0.005) (fig 1). Transplant related mortality at 1 and 5 years was 19% and 28%, respectively. The lowest TRM (15%) was found among patients given a CD34+ cell dose of 6-7 × 106cells/kg (HR: 0.41, 95% CI: 0.18-0.92, p=0.03). The cumulative incidence of relapse (RI) for all patients was 29%. Increased RI (41%) was found in patients who received <5 × 106cells/kg CD34+ cells (HR: 1.89, 95% CI: 1.09-3.29, p=0.024). In total, 86 (46%) and 92 (56%) patients developed acute and chronic GvHD, respectively. The cumulative incidence of acute GVHD grades II-IV in the whole cohort was 40%. The lowest incidence (33%) of aGVHD II-IV was found among patients receiving a high cell-dose. In the corrected multivariate analysis, a CD34+ cell dose of >6.5 × 106cells/kg was associated with a lower incidence of aGVHD II-IV (RH: 0. 53, 95% CI: 0.29-0.97, p=0.04). In the corrected multivariate analysis a CD34 cell dose of 6-7 × 106/kg was associated with better OS and lower TRM, while a CD34 cell-dose of <5 × 106/kg was associated with more relapse and less cGVHD. A high CD34 cell-dose (>7 × 106/kg) correlated to less aGVHD II-IV. The CD34 cell dose has impact on the outcome in sibling donor HSCT using peripheral-blood stem-cells. [ABSTRACT FROM AUTHOR]

The age of patients admitted to HSCT is increasing. The median age of adult patients is close to 60 years at many centers. With a sibling donor this means that in most cases an older donor will be used. There are reports that donor age is important for the outcome. Our hypothesis is that it may be better to select a young well matched (10/10 match) unrelated donor (MUD), if available, instead of an older matched related donor (MRD). In a homogenous material consisting of patients with myeloid malignancies (AML, MDS, MPN, CML) receiving a PBSC graft and myeloablative conditioning, CsA+MTX as GVHD prophylaxis without in vivo T-cell depletion (no ATG), we studied the effect of the donor age. For this reason we selected patients with a MRD and an older donor (≥40y) and a 10/10 MUD with a younger donor (<40y) for analysis. There were 53 patients with a MRD and 60 with a MUD. Among patients with a MRD the donor age was grouped into three separate categories: 40-50y (n=18), 51-60y (n=23) and >60y (n=12). In the MUD group donor age groups were: 18-25y (n=22) and 26-39y (n=38) (table 1). The best OS, RFS, TRM and GRFS were seen in the "MUD age 18-25y" group (Figure 1). No effect was seen on incidence of relapse and acute and chronic GVHD. In multivariate analysis, corrected for differences between the groups, we found that OS, RFS, TRM and GRFS were better in the "MUD age 18-25y" group, compared to the MRD groups (figure 1). In cases where an older sibling donor is available, it may be reasonable to search for a well-matched young (<25y) MUD. However, this is a limited small, single center study. Larger studies are warranted. [ABSTRACT FROM AUTHOR]