Background: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. Methods: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15–39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. Discussion: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. Trial registration: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).

Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects.

This study lays the groundwork for future lentivirus-mediated gene therapy in patients with Diamond Blackfan anemia (DBA) caused by mutations in ribosomal protein S19 ( RPS19 ), showing evidence of a new safe and effective therapy. The data show that, unlike patients with Fanconi anemia (FA), the hematopoietic stem cell (HSC) reservoir of patients with DBA was not significantly reduced, suggesting that collection of these cells should not constitute a remarkable restriction for DBA gene therapy. Subsequently, 2 clinically applicable lentiviral vectors were developed. In the former lentiviral vector, PGK.CoRPS19 LV , a codon-optimized version of RPS19 was driven by the phosphoglycerate kinase promoter ( PGK ) already used in different gene therapy trials, including FA gene therapy. In the latter one, EF1 α .CoRPS19 LV , RPS19 expression was driven by the elongation factor alpha short promoter, EF1 α (s) . Preclinical experiments showed that transduction of DBA patient CD34 ⁺ cells with the PGK.CoRPS19 LV restored erythroid differentiation, and demonstrated the long-term repopulating properties of corrected DBA CD34 ⁺ cells, providing evidence of improved erythroid maturation. Concomitantly, long-term restoration of ribosomal biogenesis was verified using a potentially novel method applicable to patients’ blood cells, based on ribosomal RNA methylation analyses. Finally, in vivo safety studies and proviral insertion site analyses showed that lentivirus-mediated gene therapy was nontoxic.

Human plasmacytoid dendritic cells (PDCs) are present in solid tumor tissue and metastatic cervical lymph nodes (CLN) in head and neck squamous cell carcinoma (HNSCC). We recently showed that classical PDC functions are heavily disturbed in the tumor microenvironment. In this study we present a new approach to the subject by introducing 3 PDC subsets in HNSCC, characterized by the surface markers CD25, CD56 and CD203c. The first subset, positive for CD25, is significantly induced by HNSCC in vitro and present in metastatic lymph nodes in vivo. This subset can be phenotypically subdivided into matured cells and into a group expressing early T cell markers. Functionally this subgroup is associated with the secretion of IL-8. The second subset, positive for CD56, constitutes 4-5% of all PDCs and is significantly down-regulated by HNSCC. Furthermore, this population sporadically expresses perforin/granzyme B and is absent in metastatic lymph nodes. The third subset, positive for the basophile marker CD203c, is inducible by crosslinking BDCA-2 in the presence of HNSCC and IL-4. Future studies will have to clarify the in vivo relevance of the different PDC subsets in HNSCC.

Neonates demonstrate functional immaturity and dysregulation of immune responses leading to systemic inflammation and enhanced apoptosis of immune cells. Thalidomide has already been proven to differentially regulate immune responses and support anti-apoptosis in immunodeficiency syndromes. Thus, it was the aim of this study to evaluate the effects of thalidomide on the cytokine response and apoptosis of neonatal immune cells. After whole blood culture and stimulation of cord and adult blood samples, the intracytoplasmic expression and the secreted amounts of IL-2, TNF-α, IFN-γ, IL-6, IL-10 and IL-8 were assessed by flow cytometry and Cytokine Bead Array. Apoptosis was detected using Annexin-V staining. Bcl-2 expression was analysed using the Cytokine Bead Array Apoptosis Kit. Exposure to thalidomide (100 µg/ml) reduced the intracytoplasmic pro-inflammatory cytokine production of neonatal monocytes and the IFN-γ production of neonatal lymphocytes. In supernatants, the addition of thalidomide resulted in reduction of TNF-α, IL-6, IL-10 and, by trend, IFN-γ. While stimulated neonatal lymphocytes exhibited susceptibility to apoptosis, thalidomide tended to diminish apoptotic cells. Bcl-2 expression tended to be increased after addition of thalidomide. The potent anti-inflammatory effects of thalidomide and its anti-apoptotic properties in cord blood immune cells provide the basis for future strategies to optimise treatment of neonatal infections and immunodeficiency syndromes.