Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review.

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).

In vivo assessment of placental and brain volumes in growth-restricted fetuses with and without fetal Doppler changes using quantitative 3D MRI.

OBJECTIVE: The relationship between placental and fetal brain growth is poorly understood and difficult to assess. The objective of this study was to interrogate placental and fetal brain growth in healthy pregnancies and those complicated by fetal growth restriction (FGR). STUDY DESIGN: In a prospective, observational study, pregnant women with normal pregnancies or pregnancies complicated by FGR underwent fetal magnetic resonance imaging (MRI). Placental, global and regional brain volumes were calculated. RESULTS: A total of 114 women (79 controls and 35 FGR) underwent MRI (median gestational age (GA) 30 weeks, range 18 to 39). All measured volumes increased exponentially with advancing GA. Placental, total brain, cerebral and cerebellar volumes were smaller in FGR compared with controls (P<0.05). Increasing placental volume was associated with increasing cerebral and cerebellar volumes (P<0.05). CONCLUSION: Quantitative fetal MRI can accurately detect decreased placental and brain volumes in pregnancies with FGR and may provide insight into the timing and mechanisms of brain injury in FGR.

Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy.

OBJECTIVE: To determine whether systemic inflammation-modulating cytokine expression is related to heart rate variability (HRV) in newborns with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: The data from 30 newborns with HIE were analyzed. Cytokine levels (IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-1ß, TNF-α, IFN-λ) were measured either at 24 h of cooling (n=5), 72 h of cooling (n=4) or at both timepoints (n=21). The following HRV metrics were quantified in the time domain: alpha_S, alpha_L, root mean square (RMS) at short time scales (RMS_S), RMS at long time scales (RMS_L), while low-frequency power (LF) and high-frequency power (HF) were quantified in the frequency domain. The relationships between HRV metrics and cytokines were evaluated using mixed-models. RESULT: IL-6, IL-8, IL-10, and IL-13 levels were inversely related to selected HRV metrics. CONCLUSION: Inflammation-modulating cytokines may be important mediators in the autonomic dysfunction observed in newborns with HIE.

Cerebral modulation of the autonomic nervous system in term infants.

OBJECTIVE: Central topography of autonomic nervous system (ANS) function has yet to be fully deciphered. In adults it has been shown to lateralize sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. We examined functional topography of central ANS in newborn subjects utilizing spectral analysis of heart rate variability (HRV), an established measure of ANS function. STUDY DESIGN: We studied newborns with hypoxic-ischemic encephalopathy participating in a prospective study undergoing a therapeutic hypothermia protocol.We included subjects with continuous heart rate data over the first 3 h of normothermia (post rewarming) and brain magnetic resonance imaging, which was reviewed and scored according to a 4 region scheme. HRV was evaluated by spectral analysis in the low-frequency (0.05 to 0.25 Hz) and high-frequency (0.3 to 1 Hz) ranges. The relationship between injured brain regions and HRV was studied using multiple regressions. RESULTS: Forty eight newborns were included. When examined in isolation, right hemisphere injury had a significant negative effect on HRV (-0.088; 95% CI: -0.225,-0.008). The combination of posterior fossa region injury with right hemispheric injury or left hemispheric injury demonstrated significant positive (0.299; 95% CI: 0.065, 0.518) and negative (-0.475; 95% CI: -0.852, -0.128) influences on HRV, respectively. The association between brain injury location and HRV in the high-frequency range did not reach significance. CONCLUSION: Our data support the notion that lateralized cerebral modulation of the ANS, specifically of its sympathetic component, is present in the term newborn, and suggest complex modulation of these tracts by components of the posterior fossa.

Cyanophenyl vs. pyridine substituent: impact on the adlayer structure and formation on HOPG and Au(111).

A new cyano substituted bis(terpyridine) derivative CN-BTP was synthesized and its adsorption on highly oriented pyrolytic graphite (HOPG) and Au(111) was investigated. CN-BTP is closely related to the previously investigated 2,4'-BTP, where the cyanophenyl groups are replaced by pyridine moieties. The scanning tunneling microscopy (STM) investigation of CN-BTP at the liquid|HOPG interface shows a highly ordered herringbone structure that is stabilized by double weak intermolecular C-HN hydrogen bonds, partially through the -CN substituents, which is different from the most stable square structure of 2,4'-BTP. The adsorption processes were investigated using cyclic voltammetry (CV) on Au(111) in a neutral phosphate buffer. A fast and full adlayer formation could be observed with CN-BTP, whereas an extremely slow process with 2,4'-BTP under the same conditions was found. Our data show that the CN substituents on BTP not only change the structure of the monolayer at the liquid|HOPG interface, but also accelerate the phase transition process in the electrolyte dramatically. This could be explained by the adlayer-substrate interactions, which is supported by DFT calculations. Our findings might be extended more generally to further pyridine comprising self-assembling molecules to fine-tune the adlayer structure and phase transition/adsorption kinetics by replacing pyridine by cyanophenyl moieties.

Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia.

OBJECTIVE: To evaluate whether heart rate variability (HRV) measures are predictive of neurological outcome in babies with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: This case-control investigation included 20 term encephalopathic newborns treated with systemic hypothermia in a regional neonatal intensive care unit. Electrocardiographic data were collected continuously during hypothermia. Spectral analysis of beat-to-beat heart rate interval was used to quantify HRV. HRV measures were compared between infants with adverse outcome (death or neurodevelopmental impairment at 15 months, n = 10) and those with favorable outcome (survivors without impairment, n = 10). RESULT: HRV differentiated infants by outcome during hypothermia through post-rewarming, with the best distinction between groups at 24 h and after 80 h of life. CONCLUSION: HRV during hypothermia treatment distinguished HIE babies who subsequently died or had neurodevelopmental impairment from intact survivors. This physiological biomarker may identify infants in need of adjuvant neuroprotective interventions. These findings warrant further investigation in a larger population of infants with HIE.

Malignant peritoneal mesothelioma in a 16-year-old girl: presentation of a rare disease.

Malignant peritoneal mesothelioma is extremely rarely seen in young patients.A 16 year-old girl presented with appendicitis-like acute abdominal pain. Intra-operatively, multiple confluent peritoneal nodules were seen on the entire greater omentum and in the pelvis infiltrating the uterus and both ovaries. Biopsies were obtained and interpreted as serous ovarian carcinoma. Radical surgical resection and hyperthermic intraperitoneal chemotherapy -(HIPEC) with carboplatin was performed and followed by 2 cycles of carboplatin/paclitaxel. Histological reevaluation showed characteristic features of epithelioid peritoneal mesothelioma and ruled out serous ovarian cancer. Therapy was continued with 6 cycles of pemetrexed/cisplatin.3 months after end of chemotherapy vital tumor tissue was found in the recess behind the liver, which could be resected completely. The patient is currently disease-free 17 months after initial diagnosis.Malignant peritoneal mesothelioma in young female patients might be under-recognized and possibly misdiagnosed as ovarian serous carcinoma in some cases. International and interdisciplinary cooperation is necessary in order to provide evidence based guidelines for diagnosis and treatment in the future.

Targeted therapeutics in treatment of children and young adults with solid tumors: an expert survey and review of the literature.

Although prognosis of children with solid tumors is steadily improving, long-term survival is not achievable in all patients, especially in patients with recurrent or refractory disease. Despite the increasing number of targeted therapeutics (TT), only very few TT have been introduced into clinical protocols. Accordingly, clinical experience concerning the efficacy and safety of these drugs is limited. This may possibly discourage oncologists from administering TT to children.We performed a comprehensive review of the literature to identify TT that may be considered for treatment of children and young adults with solid tumors. Moreover, we interviewed an expert panel of the Society for Pediatric Oncology and Hematology (GPOH) using questionnaires in a modified Delphi process in order to describe the experts' experiences in the use of these TT.Among 30 TT identified to be possibly useful in children and young adults, imatinib, bevacizumab and rapamycin were most widely used. These drugs were reported as having mostly little to no severe adverse events and seem to induce at least partial responses in a subset of patients. In addition, our study confirms and expands the present knowledge about adverse events and the potential efficacy of 5 other commonly used TT in this population.This information may be useful for oncologists when administering these TT to children and young adults with solid tumors. Controlled clinical trials are urgently needed to test their safety and efficacy.

Mouse hepatoma cell lines differing in aryl hydrocarbon receptor-mediated signaling have different activities for glucuronidation.

For studies on the aryl hydrocarbon receptor (AhR)-dependent toxicity of the mycotoxins alternariol (AOH) and alternariol methyl ether (AME), three mouse hepatoma (Hepa-1) cell lines with intact and with compromised AhR signaling were compared with respect to their activities for hydroxylation, methylation, and glucuronidation. Whereas the activities of cytochrome P450-mediated monooxygenase and catechol-O-methyl transferase were very low and did not differ between the three cell lines, a pronounced difference was observed for UDP-glucuronosyl transferase activity, which was much higher in Hepa-1c1c4 than in c1c7 and c1c12 cells. In all three cell types, the rate of glucuronidation of AOH was about four times higher than that of AME. Whereas AME caused a concentration-dependent G2/M arrest in each cell line, AOH arrested Hepa-1c1c7 and c1c12 cells but not c1c4 cells. However, Hepa-1c1c4 cells were arrested by AOH when ß-glucuronidase was added to the incubation medium in order to reverse the formation of AOH glucuronides. We conclude that the failure of AOH to cause cell cycle inhibition in Hepa-1c1c4 cells is due to its efficient glucuronidation. The considerable UDP-glucuronosyl transferase activity of Hepa-1c1c4 cells should be taken into account when other compounds are studied in this cell line. Moreover, we demonstrate that differences in glucuronide formation between cell types can be overcome by the addition of ß-glucuronidase to the cell culture medium.

A bi-prism interferometer for hard X-ray photons.

Micro-fabricated bi-prisms have been used to create an interference pattern from an incident hard X-ray beam, and the intensity of the pattern probed with fluorescence from a 30 nm-thick metal film. Maximum fringe visibility exceeded 0.9 owing to the nano-sized probe and the choice of single-crystal prism material. A full near-field analysis is necessary to describe the fringe field intensities, and the transverse coherence lengths were extracted at APS beamline 8-ID-I. It is also shown that the maximum number of fringes is dependent only on the complex refractive index of the prism material.

In vitro mammalian metabolism of the mitosis inhibitor zoxamide and the relationship to its in vitro toxicity.

The in vitro mammalian metabolism of the fungicide zoxamide is related to its in vitro mammalian toxicity. After incubation of zoxamide with rat liver microsomes leading to practically 100% metabolism (mostly hydroxylated zoxamide), the cytotoxicity (methyl thiazole tetrazolium (MTT) test) and the mitosis-inhibiting potential (shown by cell count and by cell cycle analysis) for V79 were not distinguishable from those of zoxamide, demonstrating that the hydroxylation of zoxamide did not change the cytotoxicity or mitosis-inhibiting potential as determined by these assays. After incubation of zoxamide with rat liver S9 predominantly leading to conjugation with glutathione, and after incubation of zoxamide with rat liver slices predominantly leading to the glucuronide of the hydroxylated zoxamide, these activities were eliminated demonstrating that the glutathione conjugate and the glucuronide had lost the activities in these assays due either to no intrinsic potential of these conjugates or to their inability to penetrate the plasma membrane of mammalian cells. It is concluded that the metabolic hydroxylation of zoxamide did not change its activity in the assays used for investigating its influence on cell proliferation, cell cycle and cytotoxicity, while the formation of conjugates with glutathione or glucuronic acid led to the apparent loss of these activities. Thus, with zoxamide as a prototype, it was shown that, in principle, mammalian metabolism and its relationship to mammalian detoxication of fungicidal mitosis inhibitors may be reasonably anticipated from in vitro studies. In addition, the results provide a rational for the observed absence of typically mitosis inhibition-associated toxicities of zoxamide in mammals in vivo.