Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias

We investigated a large number of acute myeloid leukemia (AML) samples (n=959) for the presence of the JAK2 V617F mutation. We found a low incidence of the mutation in these AML samples (1%). JAK2 V617F mutations clustered in AML samples with an aberrant karyotype (

Anti-Vascular endothelial growth factor therapy impairs endothelial function of retinal microcirculation in colon cancer patients – an observational study

Background: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. Design and subjects: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. Results: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. Conclusions: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab

Genetic Variations of Interleukin-23R (1143A>G) and BPI (A645G), but Not of NOD2, Are Associated with Acute Graft-versus-Host Disease after Allogeneic Transplantation

Single nucleotide polymorphisms (SNPs) in genes of the immune system predict for aGVHD and mortality after allo-SCT. We investigated the effect of SNPs in the NOD2, BPI, and IL-23R genes on posttransplantation outcome in a cohort of 304 patients. NOD2 patient and donor genotype and BPI recipient genotype were not associated with the occurrence of aGVHD. However, IL-23R-SNP in the donor was correlated with less aGVHD. This association could be confirmed in multivariate analysis (odds ratio [OR], 0.39; P = .039), which identified in vivo T cell depletion (OR, 0.32; P < .001) and multiagent GVHD prophylaxis (OR, 0.51; P = .031) as other independent factors predicting for less-severe aGVHD. This multivariate model also revealed a trend toward less aGVHD in patients receiving a BPI G allele transplant (OR, 0.60; P = .067) and in those receiving a transplant from an HLA-matched donor (OR, 0.57; P = .058). In contrast, relapse was more frequent in patients with NOD2-SNPs (46.2% for SNP vs 33.2% for wild-type; P = .020). This association was found to be of borderline significance in multivariate analysis. Neither BPI nor IL-23R genotype predicted for relapse, and none of the investigated SNPs was correlated with 5-year overall survival. In our analysis, NOD2 SNPs did not predict aGVHD, but IL-23R(1142A>G) and BPI(A645G) SNPs appeared to be promising markers in this regard. The importance of these markers in prediction models for GVHD and relapse remain to be defined in large prospective clinical trials

Support of Unrelated Stem Cell Donor Searches by Donor Center-Initiated HLA Typing of Potentially Matching Donors

Large registries of potential unrelated stem cell donors have been established in order to enable stem cell transplantation for patients without HLA-identical related donors. Donor search is complicated by the fact that the stored HLA information of many registered donors is incomplete. We carried out a project that was aimed to improve chances of patients with ongoing donor searches to find an HLA-matched unrelated donor. For that purpose, we carried out additional donor center-initiated HLA-DRB1 typing of donors who were only typed for the HLA loci A and B so far and were potential matches for patients in need of a stem cell transplant. In total, 8,861 donors were contacted for donor center-initiated HLA-DRB1 typing within 1,089 donor searches. 12 of these donors have donated stem cells so far, 8 thereof for their respective target patients. We conclude that chances of patients with ongoing donor searches to find an HLA-matched unrelated donor can indeed be improved by donor-center initiated typing that is carried out in addition to the standard donor search process. Our results also raise questions regarding the appropriate use of incompletely typed donors within unrelated donor searches

Pharmacogenetic analysis of liver toxicity after busulfan/cyclophosphamide-based allogeneic hematopoietic stem cell transplantation

Unlabelled: THE AIM of this study was to evaluate the impact of genomic polymorphisms of methylene-tetrahydrofolate-reductase (MTHFR-C677T, MTHFR-A1298C) and various glutathione S-transferases (GSTP1-Ilel05Val, GSTA1*a/b, GSTM1, GSTT1) on the occurrence of liver toxicity in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Patients and methods: Eighty-four adult patients were enrolled in this retrospective study. All patients were treated with busulfan/cyclophosphamide as a conditioning regimen and received cyclosporine and short-course MTX for GvHD prophylaxis. Genotyping was performed using PCR based restriction-fragment-length-polymorphism (RFLP) techniques. Results: Multivariate analysis identified the MTHFR-A1298C polymorphism as an independent predictor for maximum levels of bilirubin (p=0.0025) and duration of hyperbilirubinaemia (p=0.013). Furthermore, there was an association between this polymorphism and the occurrence of the sinusoidal obstruction syndrome (SOS) (p=0.048). No significant associations between the MTHFR-C677T or the various GST polymorphisms and liver toxicity were observed. Conclusion: The MTHFR-A1298C polymorphism might be associated with liver toxicity in patients receiving allogeneic HSCT

Gemcitabine and Docetaxel for Epithelioid Sarcoma: Results from a Retrospective, Multi-Institutional Analysis

Objective: Epithelioid sarcoma (ES) presents unique clinical features in comparison to other sarcoma subtypes. Data regarding the benefits of chemotherapy are very limited. Combination regimens using gemcitabine and docetaxel (Gem/Doce) have proven to be effective, especially in uterine and nonuterine leiomyosarcoma. Yet, there is no available data on the efficacy of Gem/Doce in ES. Methods: A retrospective analysis of the three participating institutions was performed. Twenty-eight patients with an ES diagnosis presented at one of the participating institutions between 1989 and 2012. Of this group, 17 patients received chemotherapy. Results: Patients' median overall survival (OS) after the beginning of palliative chemotherapy was 21 months, and the 1-year OS was 87%. Twelve patients received Gem/Doce with a clinical benefit rate of 83%. The median progression-free survival (PFS) was 8 months for all patients receiving Gem/Doce. The best response was complete remission in 1 patient and partial remission in 6 patients. All 6 patients receiving Gem/Doce as a first-line treatment showed measurable responses with a median PFS of 9 months. Conclusions: In this retrospective study, Gem/Doce was an effective chemotherapeutic regimen for ES. Prospective studies are needed to better assess the effects of this combination drug therapy

Cryogel-supported stem cell factory for customized sustained release of bispecific antibodies for cancer immunotherapy

Combining stem cells with biomaterial scaffolds provides a promising strategy for the development of drug delivery systems. Here we propose an innovative immunotherapeutic organoid by housing human mesenchymal stromal cells (MSCs), gene-modified for the secretion of an anti-CD33-anti-CD3 bispecific antibody (bsAb), in a small biocompatible star-shaped poly(ethylene glycol)-heparin cryogel scaffold as a transplantable and low invasive therapeutic machinery for the treatment of acute myeloid leukemia (AML). The macroporous biohybrid cryogel platform displays effectiveness in supporting proliferation and survival of bsAb-releasing-MSCs overtime in vitro and in vivo, avoiding cell loss and ensuring a constant release of sustained and detectable levels of bsAb capable of triggering T-cell-mediated anti-tumor responses and a rapid regression of CD33 + AML blasts. This therapeutic device results as a promising and safe alternative to the continuous administration of short-lived immunoagents and paves the way for effective bsAb-based therapeutic strategies for future tumor treatments

Be smart against cancer! A school-based program covering cancer-related risk behavior

Background: Several studies suggest that most school-age children are poorly informed about cancer risk factors. This study examines the effectiveness of the ‘Be smart against cancer’ (BSAC) program in promoting cancer awareness and intentions to engage in health-promoting behavior. Methods: 235 seventh-grade students were randomized to either the intervention (N = 152) or the wait-control group (N = 83). The intervention included the modules: “What is cancer?,” “Sun protection,” “Non smoking,” and “Physical activity, Healthy nutrition, and Limited alcohol consumption.” Outcomes measured at baseline and at the end of the one week BSAC program included knowledge of cancer and its behavioral risk factors, health-promoting intentions, and reported risk behavior. Results: BSAC was effective in increasing knowledge about cancer and risk factors for cancer (p < .001), as well as in increasing intentions to engage in health-promoting behavior (p < .001), independent of a student’s risk profile. Knowledge did not serve as a mediator for intention building. Conclusions: The BSAC is an effective school-based program for raising awareness of cancer, associated risk factors and intentions to engage in cancer-preventive behavior. The results indicate that the effectiveness of BSAC is independent of a student’s risk profile. Therefore, it holds considerable promise as a broadly applicable program to raise cancer awareness and promote healthy behavior intentions

Retargeting of UniCAR T cells with an in vivo synthesized target module directed against CD19 positive tumor cells

Recent treatments of leukemias with T cells expressing chimeric antigen receptors (CARs) underline their impressive therapeutic potential but also their risk of severe side effects including cytokine release storms and tumor lysis syndrome. In case of cross-reactivities, CAR T cells may also attack healthy tissues. To overcome these limitations, we previously established a switchable CAR platform technology termed UniCAR. UniCARs are not directed against typical tumor-associated antigens (TAAs) but instead against a unique peptide epitope: Fusion of this peptide epitope to a recombinant antibody domain results in a target module (TM). TMs can cross-link UniCAR T cells with tumor cells and thereby lead to their destruction. So far, we constructed TMs with a short half-life. The fast turnover of such a TM allows to rapidly interrupt the treatment in case severe side effects occur. After elimination of most of the tumor cells, however, longer lasting TMs which have not to be applied via continous infusion would be more convenient for the patient. Here we describe and characterize a TM for retargeting UniCAR T cells to CD19 positive tumor cells. Moreover, we show that the TM can efficiently be produced in vivo from producer cells housed in a sponge-like biomimetic cryogel and, thereby, serving as an in vivo TM factory for an extended retargeting of UniCAR T cells to CD19 positive leukemic cells