Holger Christiansen

Salmonella SL7207 application is the most effective DNA vaccine delivery method for successful tumor eradication in a murine model for neuroblastoma

Attenuated Salmonella is an approved oral life vaccine that is currently entering pre-clinical cancer vaccination studies as a promising DNA carrier. In a syngeneic mouse model for neuroblastoma, oral gavage of Salmonella typhimurium (SL7207) carrying recent generated survivin DNA vaccines induced a stronger cellular anti-NB immune response than gene gun application or injection of lentivirally transduced bone marrow-derived DCs. The level of Salmonella-associated side effects was not significant as indicated by unaffected survivin-mediated hematopoiesis and wound healing. We believe that our findings provide an important baseline to translate Salmonella-based DNA vaccination into a clinical application for neuroblastoma.

Targeting of Heme Oxygenase‐1 as a novel immune regulator of neuroblastoma

Heme oxygenase (HO)−1 catalyzes the degradation of cytotoxic heme into biliverdin and blocks antitumor immune responses, thus protecting cancer against host defense. Whether this scenario also applies to neuroblastoma (NB), the most common extracranial solid childhood tumor, is not known. Here, we demonstrate for the first time a prognostic relevance of HO‐1 expression in samples from NB patients and show that targeting of HO‐1 prevents both cancer resistance against cellular stress and immune escape in the syngeneic NXS2 A/J mouse model of NB. High HO‐1 RNA expression in NB tissues emerged as unfavorable prognostic marker, in particular for patients older than 18 months as indicated by univariate as well as multivariate survival probability analyses including disease stage and MYCN status. On the basis of this observation we aimed to target HO‐1 by systemic as well as tumor‐specific zinc protoporphyrin‐mediated HO‐1 suppression in a syngeneic immunocompetent NB mouse model. This resulted in 50% reduction of primary tumor growth and a suppression of spontaneous liver metastases. Importantly, HO‐1 inhibition abrogated immune cell paralysis affecting CD4 and CD8 T‐effector cells. This in turn reverted HO‐1‐dependent immune escape mechanisms in NB by increasing NB apoptosis and improved DC maturation. In summary, HO‐1 emerges as a novel immune regulator in NB and emerges as a promising target for the development of therapeutic approaches.

Managing of oral medicines in paediatric oncology: can a handbook and a pharmaceutical counselling intervention for patients and their parents prevent knowledge deficits? A pilot study

Objectives To assess knowledge deficits of patients/parents and prevention strategies. Methods After receiving ethics approval, we performed a controlled, quasi-randomised, prospective intervention study. We enrolled patients/parents involved in managing oral medicines in three groups: control (routine care only), handbook intervention and pharmaceutical counselling intervention group. At baseline and after the interventions, we assessed patients’/parents’ knowledge deficits (incorrect or missing answers) by questionnaire. Results We enrolled 64 patients/parents. At baseline, knowledge deficits among the groups were similar: 17% in controls, 22% in the handbook group and 24% in the pharmaceutical counselling group. After the intervention, knowledge deficits decreased to 13% in the handbook group and to 8% in the pharmaceutical counselling group (NS; p=0.003 compared with controls, respectively). For controls, knowledge deficits remained almost unchanged (19%). Results for the pharmaceutical counselling group showed a strong correlation between baseline knowledge deficits and the extent of the deficit decrease after the intervention (τ=−0.74; p<0.001), whereas no significant correlation was found in the control or handbook group. Conclusions In paediatric oncology, patients’/parents’ knowledge of managing oral medicines was improved. Pharmaceutical counselling substantially reduced high knowledge deficits but no significant improvement was seen with the handbook approach. Pharmaceutical counselling should be offered to patients/parents with high knowledge deficits to reduce errors in managing medicines and increase safety.

Quantification of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) using amplicon-fusion-site polymerase chain reaction (AFS-PCR).

The amplification of putative oncogenes is a common finding within the genome of various cancer types. Identification and further targeting of specific junction sites within the sequence of genomic amplicons (amplicon fusion sites, AFS) by PCR (AFS-PCR) is suitable for quantification of minimal residual disease (MRD). This approach has recently been developed and described for MYCN amplified neuroblastomas. To compare AFS-PCR directly to routinely used MRD diagnostic strategies, we mapped the amplified genomic regions (ampGR) of an iAMP21-amplicon in high resolution of a patient with acute lymphoblastic leukemia (ALL). Successfully, we established AFS-PCR covering junction sites between ampGR within the iAMP21-amplicon. Quantification of MRD by AFS-PCR was directly comparable to IgH/TCR based real time quantitative PCR and fluorescence activated cell sorting (FACS) analysis in consecutive bone marrow (BM) specimens. Our data give an additional proof of concept of AFS-PCR for quantification of MRD. The method could be taken into account for ALL patients with genomic amplifications as alternative MRD diagnostic, if no or qualitatively poor Ig/TCR-PCRs are available.

Psychometric properties of the Fear of Progression Questionnaire for parents of children with cancer (FoP-Q-SF/PR)

OBJECTIVE Psychometric properties of the Fear of Progression Questionnaire - Short Form (FoP-Q-SF) were shown to be good in samples of adult cancer patients and their partners but have so far not been investigated in parents of children with cancer. This study therefore aimed to examine psychometric properties of the previously adapted parent version of the Fear of Progression Questionnaire (FoP-Q-SF/PR) in pediatric oncology. METHODS N=181 parents (119 mothers, 62 fathers) of n=128 children with diverse cancer entities, up to ten years after diagnosis were recruited at six hospitals and six registered parent associations in Germany and Austria between 06/2015 and 05/2016 (cross-sectional design). Parents provided medical information about their child and completed standardized questionnaires (Hospital Anxiety and Depression Scale, HADS; State-Trait Anxiety Inventory, STAI; Impact of Event Scale-Revised, IES-R; Ulm Quality of Life Inventory for Parents, ULQIE; Giessen Physical Complaints Inventory for children and adolescents, GBB-KJ). RESULTS Exploratory factor analysis yielded two factors (50.2% explained variance) and internal consistency was good (Cronbachs α=0.89). Significant medium to large correlations of the FoP-Q-SF/PR were observed with anxiety (HADS: r=0.68; STAI: r=0.60-0.61), depression (HADS: r=0.58), posttraumatic stress (IES-R: r=0.42-0.64) and quality of life (ULQIE: r=-0.59). The FoP-Q-SF/PR discriminated between sub-groups, e.g. parents with and without clinical anxiety levels (Cohens d=1.26). CONCLUSION The FoP-Q-SF/PR demonstrated good reliability and validity for parents of children with cancer. The FoP-Q-SF/PR is a feasible screening instrument, which is suitable for the assessment of parental FoP in pediatric oncology.

Erratum to: Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity.

The original publication contains the following errors: In the title, the words ‘oligodendroglial cell-like’ should read ‘oligodendroglial-like’. (The correct title is shown in this erratum.) The images in Figs. 3 and 4 were incorrect. The correct figures are shown below. All the figure citations except the citation of Fig. 1 were incorrect. All citations of Fig. 2 actually concern Fig. 5, all citations of Fig. 3 actually concern Fig. 6, all citations of Fig. 4 actually concern Fig. 2, all citations of Fig. 5 actually concern Fig. 3 and all citations of Fig. 6 actually concern Fig. 4.

Timely identification of children with cancer

Background. Cancer in childhood is rare, but nevertheless one of the most frequent causes of disease related death. Initial symptoms are often unspecific, frequently leading to a delay of cancer diagnosis. As a timely diagnosis can be crucial for the clinical outcome, our aim is to point out when unspecific symptoms should be considered suspect of being associated with specific cancer entities. Data sources. A systematic literature research in PubMed and current biliographies, as well as an evaluation of published epidemiologic data was performed. Results. This article reviews the typical presenting features and epidemiologic characteristics of the more common childhood malignancies, elucidates when specific and virtually unspecific symptoms require further evaluation, and gives advice how to start a rational diagnostic workup. Furthermore, genetic syndromes requiring increased watchfulness for cancer in childhood are demonstrated. Conclusion. Patients showing suspect symptoms should early be referred to specialized centres to assure optimal diagnostic and therapeutic capabilities.