A Multimodal Lifestyle Psychosocial Survivorship Program in Young Cancer Survivors: The CARE for CAYA Program-A Randomized Clinical Trial Embedded in a Longitudinal Cohort Study.

Importance: There is a lack of trials examining the effect of counseling interventions for child, adolescent, and younger adult (CAYA) cancer survivors. Objective: To assess lifestyle habits and the psychosocial situation of CAYAs to determine the efficacy of needs-based interventions in the CARE for CAYA program (CFC-P). Design, Setting, and Participants: The CFC-P was conducted as a multicenter program in 14 German outpatient clinics, mainly university cancer centers. Recruitment began January 1, 2018; a randomized clinical trial was conducted until July 15, 2019; and intervention was continued as a longitudinal cohort study until March 31, 2021. Data preparation was conducted from April 1, 2021, and analysis was conducted from August 14, 2021, to May 31, 2022. Herein, predefined confirmatory analyses pertain to the RCT and descriptive results relate to the overall longitudinal study. Data analysis was based on the full analysis set, which is as close as possible to the intention-to-treat principle. Intervention: A comprehensive assessment determined needs in physical activity, nutrition and psychooncology. Those with high needs participated in 1 to 3 modules. In the RCT, the IG received 5 counseling sessions plus newsletters, while the control group CG received 1 counseling session. Main Outcomes and Measures: The primary outcome was the change in the rate of CAYAs with high needs at 52 weeks. Secondary outcomes were feasibility, modular-specific end points, satisfaction, quality of life, and fatigue. Results: Of 1502 approached CAYAs aged 15 to 39 years, 692 declined participation. Another 22 CAYAs were excluded, resulting in 788 participants. In the randomized clinical trial, 359 CAYAs were randomized (intervention group [IG], n = 183; control group [CG], n = 176), and 274 were followed up. In the RCT, the median age was 25.0 (IQR, 19.9-32.2) years; 226 were female (63.0%) and 133 male (37.0%). After 52 weeks, 120 CAYAs (87.0%) in the IG and 115 (86.5%) in the CG still had a high need in at least 1 module (odds ratio, 1.04; 95% CI, 0.51-2.11; P = .91). Both groups reported reduced needs, improved quality of life, reduced fatigue, and high satisfaction with the CFC-P. Conclusions and Relevance: In this randomized clinical trial, the implementation of a lifestyle program in this cohort was deemed necessary, despite not meeting the primary outcome. The interventions did not alter the rate of high needs. The results may provide guidance for the development of multimodal interventions in the follow-up care of CAYAs. Trial Registration: German Clinical Trial Register: DRKS00012504.

Effects of an Integrative Day Care Clinic Program with a Focus on Nature Therapy in a Hospital Park Setting on Quality of Life in Oncological Patients-A Non-Randomized Controlled Study.

Cancer often causes long-term physical and psychological impairments. Lifestyle modification and nature-based interventions (NBIs) can have a positive impact on patients' quality of life (QOL). This participants-blinded, non-randomized controlled study assessed parameters at weeks 0, 12, and 24, including, as a primary endpoint, QOL in cancer patients on the Functional Assessment of Cancer Therapy-General (FACT-G) at week 12. QOL in breast cancer patients, fatigue, well-being, stress, anxiety/depression, socio-psychological well-being, benefits of nature interaction, insomnia, self-efficacy, mindfulness, and self-compassion were assessed as secondary endpoints. N = 107 cancer patients (96.3% women; 52.5 ± 9.3 years, 80.4% breast cancer) were assigned to either a 12-week nature-based (NDC; n = 56) or conventional (DC; n = 51) oncology day care clinic program, whereby the assignment group was not known to the participants. There was no significant group difference for the primary endpoint. At week 24, QOL, fatigue, mindfulness and self-compassion scores were significantly higher, and at weeks 12 and 24, the insomnia score was significantly lower in NDC compared to DC. In conclusion, this study indicates positive and clinically relevant effects of the program on QOL, fatigue, and psychological parameters. NBIs seem to have a more pronounced effect.

Effects of a structured counselling-based intervention to improve physical activity behaviour of adolescents and young adult cancer survivors - the randomized phase II Motivate AYA - MAYA trial.

OBJECTIVE: To explore whether a structured counselling-based intervention increases vigorous physical activity behaviour of adolescent and young adult cancer survivors. DESIGN: Randomized controlled phase II trial. SETTING: University Cancer Center Hamburg, Germany. SUBJECTS: Eighty-nine participants (mean age 24.1 ± 6.3) were randomized to control (n = 44) or intervention group (n = 45). INTERVENTIONS: The intervention group was consulted about physical activity behaviour via interview (week 0), and telephone counselling (weeks 1, 3 and 12). The control group only received general physical activity guidelines for cancer survivors (week 0). MAIN MEASURES: The primary outcome was the rate of participants with ⩾9 metabolic equivalent (MET)-hours per week of vigorous activity post-intervention, measured with the International Physical Activity Questionnaire. Secondary outcomes included assessing physical activity behaviour (e.g. amount and type of physical activity) and quality of life. Assessments were completed in weeks 0 (baseline), 12 (post-intervention) and 52 (follow-up). RESULTS: Sixty-nine participants completed the post-intervention- and 47 the follow-up-assessment. The rate of participants performing vigorous physical activity increased from baseline to post-intervention for both without differing significantly (P = 0.541). Both increased their total metabolic equivalent from baseline to post-intervention (intervention group from 55.2 ± 43.7 to 61.7 ± 29.4, control group from 75.3 ± 81.4 to 88.3 ± 80.2). At follow-up the intervention group (73.7 ± 80.2) was more active than baseline when compared to the control group (78.5 ± 50.0). CONCLUSIONS: A structured counselling-based physical activity intervention did not significantly impact the level of vigorous physical activity behaviour in adolescent and young adult cancer survivors.

Cell-derived extracellular vesicles can be used as a biomarker reservoir for glioblastoma tumor subtyping.

Glioblastoma (GBM) is one of the most aggressive solid tumors for which treatment options and biomarkers are limited. Small extracellular vesicles (sEVs) produced by both GBM and stromal cells are central in the inter-cellular communication that is taking place in the tumor bulk. As tumor sEVs are accessible in biofluids, recent reports have suggested that sEVs contain valuable biomarkers for GBM patient diagnosis and follow-up. The aim of the current study was to describe the protein content of sEVs produced by different GBM cell lines and patient-derived stem cells. Our results reveal that the content of the sEVs mirrors the phenotypic signature of the respective GBM cells, leading to the description of potential informative sEV-associated biomarkers for GBM subtyping, such as CD44. Overall, these data could assist future GBM in vitro studies and provide insights for the development of new diagnostic and therapeutic methods as well as personalized treatment strategies.

Impact of taste and smell training on taste disorders during chemotherapy - TASTE trial.

PURPOSE: Two-thirds of cancer patients report taste disorders during and after chemotherapy. Taste disorders impact on nutritional status which is highly relevant for treatment efficacy and overall prognosis. Improvement of taste disorder is of particular importance for cancer patients' outcomes, thus the TASTE trial was conducted to improve taste disorders with a taste and smell training. METHODS: In this trial, patients undergoing chemotherapy were screened for taste disorders. Subsequently, patients were allocated based on the detection of taste disorders (≤8 taste strips points) to an intervention group with a taste and smell training at baseline and week 3-5 or were only followed up, if no taste disorder was detected (≥9 taste strips points) (non-intervention group). At baseline, all patients received a nutritional counseling. The primary endpoint was the minimal clinically relevant improvement of taste strips score by 2 taste strips points in at least 50% of the patients with taste disorders. RESULTS: The trial included 62 patients (48 women [77%], 14 male [23%], age 54.5±11.6 years) who had gastrointestinal (n=29), breast (n=31), or lung cancer (n=2). Taste disorders were more frequent in gastrointestinal than in breast cancer patients. Out of 62 patients screened, 30 patients showed taste disorders. The primary endpoint was met with 92% (n=23 of 25) of the patients completing the intervention. In the intervention group, the patients' taste significantly improved from baseline (median taste strips: 7.0 points) to week 12 (median taste strips: 10.0 points) (P≤0.001). Patients of the non-intervention group who completed the reassessment (n=27 of 32) experienced no change in taste perception in the 3-month follow-up (P=0.897). CONCLUSION: Intensified nutritional counseling with taste and smell training may improve taste perception of patients undergoing chemotherapy. A confirmatory randomized trial is planned.

A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling.

The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases.

Low concentrations of antimony impair DNA damage signaling and the repair of radiation-induced DSB in HeLa S3 cells.

Antimony is utilized in a large variety of industrial applications, leading to significant environmental and occupational exposure. Mainly based on animal experiments, the IARC and MAK Commission have classified antimony and its inorganic compounds as Group 2B or 2 carcinogens, respectively. However, the underlying mode(s) of action are still largely unknown. In the present study, we investigated the impact of non-cytotoxic up to cytotoxic concentrations of SbCl3 on DNA DSB repair and cell cycle control in HeLa S3 cells. We induced DSB by γ-irradiation and analyzed inhibitory actions of antimony on potential molecular targets of the DSB repair machinery. Antimony disturbed cell cycle control, affecting phosphorylation of Chk1. Furthermore, the repair of DSB was impaired in the presence of antimony, as monitored by pulsed-field gel electrophoresis and γH2AX foci formation of cells in G1 and G2 phase. Specifically, BRCA1 and RAD51 were identified as molecular targets. Our results point towards an interference with both non-homologous end-joining (NHEJ) and homologous recombination (HR), and inhibitory effects may be explained by interactions with critical cysteine groups; this needs to be further investigated. Altogether, the results provide further evidence for the impairment of DNA repair processes as one underlying mechanism in antimony-induced carcinogenicity.

Mind-body medicine and lifestyle modification in supportive cancer care: A cohort study on a day care clinic program for cancer patients.

OBJECTIVE: We developed an integrative day care clinic program for cancer patients focusing on mind-body techniques and health-promoting lifestyle modification (7-hour once-per-week group sessions over 12 weeks). METHODS: A cohort study design with a waiting group was implemented. Outcome parameters were assessed at the beginning, at the end of the active program, and at a 6-month follow-up. Patients waiting >4 and <12 weeks before treatment start were allocated to the waiting group and additionally assessed at the start of their day care program. Outcome measures included quality of life (FACT-G, FACT-B/C, WHO-5), fatigue (FACIT-F), depression/anxiety (HADS), and mood states (ASTS). A per protocol analysis using mixed linear models was performed. RESULTS: One hundred patients were screened on-site for eligibility. Eighty-six cancer survivors (83% female; mean age 53.7 ± 9.7 years; 49% breast cancer) were included into the study. Sixty-two patients were allocated to the intervention group and 24 patients, to the waiting group (mean waiting time 5 ± 1 weeks). Sixty-six data sets were included in the final analysis. Significant improvements were observed in favor of the intervention group after 12 weeks compared with the waiting group at the end of the waiting period for quality of life, anxiety/depression, and fatigue. Results from the 6-month follow-up for the whole study population showed lasting improvement of quality of life. CONCLUSIONS: The program can be considered as an effective means to improve quality of life, fatigue, and mental health of cancer patients. Moreover, it appears to have a sustainable effect, which has to be proved in randomized trials.

Building a National Framework for Adolescent and Young Adult Hematology and Oncology and Transition from Pediatric to Adult Care: Report of the Inaugural Meeting of the "AjET" Working Group of the German Society for Pediatric Oncology and Hematology.

Adolescents and young adults (AYAs) with hemato-oncological problems constitute a heterogenous group with characteristic particularities, specific needs, and age-related clinical and unique psychosocial features. Strong collaboration between pediatric and adult hemato-oncology settings is essential to address their needs appropriately. This is not only true for patients who first become ill during adolescence or young adulthood, but equally so for people who contract hemato-oncological diseases congenitally or as younger children and who are now becoming old enough to leave the pediatric setting and have to transit into "adult" medical care. Efforts to create environments that meet the specific needs of the AYA population affected by hemato-oncological diseases have been initiated in many countries. Due to international variations between societies in general and healthcare infrastructures in particular, the challenges posed to creating such environments vary considerably from country to country. Aiming at addressing these on a national basis for Germany, a dedicated Working Group on Adolescents, Young Adults, and Transition (Arbeitsgemeinschaft Adoleszenten, junge Erwachsene, Transition, AjET) was established. This meeting report depicts the content and discussions of the first interdisciplinary conference on treatment, transition, and long-term follow-up in AYAs with cancer or chronic/inborn hematological diseases. The AjET group of the German Society for Pediatric Oncology and Hematology (GPOH) intends to increase the national awareness for AYAs; strengthen the collaboration of pediatric and adult care givers; and initiate, promote, and coordinate collaborative activities in the fields of basic and translational research, clinical care, and long-term follow-up aimed at improving the current situation.

Single nucleotide polymorphisms in DNA repair genes and putative cancer risk.

Single nucleotide polymorphisms (SNPs) are the most frequent type of genetic alterations between individuals. An SNP located within the coding sequence of a gene may lead to an amino acid substitution and in turn might alter protein function. Such a change in protein sequence could be functionally relevant and therefore might be associated with susceptibility to human diseases, such as cancer. DNA repair mechanisms are known to play an important role in cancer development, as shown in various human cancer syndromes, which arise due to mutations in DNA repair genes. This leads to the question whether subtle genetic changes such as SNPs in DNA repair genes may contribute to cancer susceptibility. In numerous epidemiological studies, efforts have been made to associate specific SNPs in DNA repair genes with altered DNA repair and cancer. The present review describes some of the common and most extensively studied SNPs in DNA repair genes and discusses whether they are functionally relevant and subsequently increase the likelihood that cancer will develop.

Ribosomal protein S3 interacts with the NF-κB inhibitor IκBα.

Ribosomal protein S3 (RPS3) is part of nuclear, transcriptionally active and cytoplasmic inhibitory complexes containing NF-κB variant p65. We show that in resting HEK293 cells, RPS3 interacts with NF-κB inhibitor IκBα. In contrast, efficient co-precipitation of p65 with RPS3 was only achieved in the presence of ectopic IκBα. In addition, a strong in vitro interaction was observed between RPS3 and IκBα, while binding between RPS3 and p65 was very weak. Furthermore, IκBα facilitated the reconstitution of p65 and RPS3 into one complex in vitro. Our results suggest that IκBα sequesters not only p65 but also RPS3 in the cytoplasm. This would ensure maintenance of an RPS3 pool for the NF-κB pathway as well as equimolar release of RPS3 and p65 upon stimulation.

The limitations of the G1-S checkpoint.

It has been proposed that the G(1)-S checkpoint is the critical regulator of genomic stability, preventing the cell cycle progression of cells with a single DNA double-strand break. Using fluorescence-activated cell sorting analysis of asynchronous cells and microscopic analysis of asynchronous and synchronized cells, we show that full blockage of S-phase entry is only observed >4 hours after irradiation. The process is ataxia-telangiectasia mutated (ATM) dependent and Chk1/2 independent and can be activated throughout G(1) phase. By monitoring S-phase entry of irradiated synchronized cells, we show that the duration of arrest is dose dependent, with S-phase entry recommencing after arrest with kinetics similar to that observed in unirradiated cells. Thus, G(1)-S checkpoint arrest is not always permanent. Following exposure to higher doses (> or =2 Gy), G(1)-S arrest is inefficiently maintained, allowing progression of G(1)-phase cells into G(2) with elevated gammaH2AX foci and chromosome breaks. At early times after irradiation (< or =4 h), G(1)-S checkpoint arrest is not established but cells enter S phase at a reduced rate. This early slowing in S-phase entry is ATM and Chk2 dependent and detectable after 100 mGy, showing a novel and sensitive damage response. However, the time needed to establish G(1)-S checkpoint arrest provides a window when cells can progress to G(2) and form chromosome breaks. Our findings detail the efficacy of the G(1)-S checkpoint and define two significant limitations: At early times after IR, the activated checkpoint fails to efficiently prevent S-phase entry, and at later times, the checkpoint is inefficiently maintained.