Incorporation of patient-reported outcomes in early-phase clinical trials for childhood and adolescent cancer.

INTRODUCTION: The assessment of quality of life (QoL) should be one of the main objectives in paediatric clinical trials. Even though researchers, regulators and advocates support the use of patient-reported outcomes (PROs), this has not been fully implemented. The aim of this study is to assess the measurement of QoL and the usage of PROs, palatability assessments and medication diaries in early-phase clinical trials for childhood and adolescent cancer. METHODS: Early-phase clinical trials for children and adolescents with cancer opened between 2005 and 2022 at the Royal Marsden Hospital (London, UK) and Vall d'Hebron University Hospital (Barcelona, Spain) were interrogated for trial characteristics and the use of QoL questionnaires, PROs, palatability assessments and medication diaries. RESULTS: Overall, 72 clinical trials were analysed: 12 (16.7%) evaluated QoL and eight (11.1%) evaluated PROs. Palatability was tested in 21/40 (52.5%) trials of oral drugs and 23/72 (31.9%) incorporated medication diaries. No studies mentioned patient involvement in the trial protocol. Use of PROs increased from one of 36 (2.8%) to seven of 36 (19.4%) between the first period (2005-2016) and the second period (2017-2022) (p = .02). Implementation of medication diaries increased from seven of 36 (19.4%) to 16/36 (44.4%) in each period, respectively (p = .02). CONCLUSION: Only a minor proportion of the international/multicentric early-phase trials evaluated included QoL/PROs and medication diaries or palatability questionnaires to help assess these, although this trend seems to be increasing over recent years. Greater implementation of QoL/PROs has the potential to improve the patient's wellbeing and facilitate symptom control, to enhance patient/parent involvement in future trial designs and to provide information for drug prioritisation.

Updating our understanding of health-related quality of life issues in children with cancer: a systematic review of patient-reported outcome measures and qualitative studies.

BACKGROUND: Health-related quality of life (HRQOL) is a key concept in pediatric oncology. This systematic review aims to update the conceptual HRQOL model by Anthony et al. (Qual Life Res 23(3):771-789, 2014), covering physical, emotional, social and general HRQOL aspects, and to present a comprehensive overview of age- and disease-specific HRQOL issues in children with cancer. METHODS: Medline, PsychINFO, the Cochrane Database for Systematic Reviews (CDSR), and the COSMIN database were searched (up to 31.12.2020) for publications using patient-reported outcome measures (PROMs) and qualitative studies in children with cancer (8-14-year) or their parents. Items and quotations were extracted and mapped onto the conceptual model for HRQOL in children with cancer mentioned above. RESULTS: Of 2038 identified studies, 221 were included for data extraction. We identified 96 PROMS with 2641 items and extracted 798 quotations from 45 qualitative studies. Most items and quotations (94.8%) could be mapped onto the conceptual model. However, some adaptations were made and the model was complemented by (sub)domains for 'treatment burden', 'treatment involvement', and 'financial issues'. Physical and psychological aspects were more frequently covered than social issues. DISCUSSION: This review provides a comprehensive overview of HRQOL issues for children with cancer. Our findings mostly support the HRQOL model by Anthony et al. (Qual Life Res 23(3):771-789, 2014), but some adaptations are suggested. This review may be considered a starting point for a refinement of our understanding of HRQOL in children with cancer. Further qualitative research will help to evaluate the comprehensiveness of the HRQOL model and the relevance of the issues it encompasses.

Clinical research tools in pediatric oncology: challenges and opportunities.

Survival for childhood cancers has improved significantly over the last decades. However, patient outcomes have plateaued over the last decade for difficult-to-treat diseases. With high cure rates, decreasing long-term toxicities and sequelae remains crucial. Since many advances in childhood cancer research come from the adult oncology world, one of the key areas is improving the adaptation of tools that are essential for clinical trial conduct that were developed for adults into pediatrics. These include tools to evaluate toxicity, quality of life, radiological response, statistical methodology, or indicators of cancer care quality. In this review, we present ongoing international efforts to validate and adapt these tools for children and adolescents and discuss remaining challenges. These efforts will hopefully accelerate and improve the quality of pediatric oncology research in the upcoming years.

Elevated Fatty Liver Index as a Risk Factor for All-Cause Mortality in Human Immunodeficiency Virus-Hepatitis C Virus-Coinfected Patients (ANRS CO13 HEPAVIH Cohort Study).

BACKGROUND AND AIMS: Human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected patients are at high risk of metabolic complications and liver-related events, which are both associated with hepatic steatosis and its progressive form, nonalcoholic steatohepatitis, a known risk factor for mortality. The fatty liver index (FLI), a noninvasive steatosis biomarker, has recently drawn attention for its clinical prognostic value, although its capacity to predict mortality risk in HIV-HCV-coinfected patients has never been investigated. Using a Cox proportional hazards model for mortality from all causes, with data from the French National Agency for Research on Aids and Viral Hepatitis CO13 HEPAVIH cohort (983 patients, 4,432 visits), we tested whether elevated FLI (≥60) was associated with all-cause mortality. APPROACH AND RESULTS: After multiple adjustment, individuals with FLI ≥ 60 had almost double the risk of all-cause mortality (adjusted hazard ratio [95% confidence interval], 1.91 [1.17-3.12], P = 0.009), independently of the following factors: HCV cure (0.21 [0.07-0.61], P = 0.004), advanced fibrosis (1.77 [1.00-3.14], P = 0.05), history of hepatocellular carcinoma and/or liver transplantation (7.74 [3.82-15.69], P < 10-3 ), history of indirect clinical signs of cirrhosis (2.80 [1.22-6.41], P = 0.015), and HIV Centers for Disease Control and Prevention clinical stage C (2.88 [1.74-4.79], P < 10-3 ). CONCLUSIONS: An elevated FLI (≥60) is a risk factor for all-cause mortality in HIV-HCV-coinfected patients independently of liver fibrosis and HCV cure. In the present era of nearly 100% HCV cure rates thanks to direct-acting antivirals, these findings encourage the more systematic use of noninvasive steatosis biomarkers to help identify coinfected patients with higher mortality risk.

Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study.

STUDY QUESTION: What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors? SUMMARY ANSWER: We observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors. WHAT IS KNOWN ALREADY: Survival after childhood ALL is currently >90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies. STUDY DESIGN, SIZE, DURATION: Childhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, <18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: The median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10-17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046). LIMITATIONS, REASONS FOR CAUTION: The interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males' partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls. WIDER IMPLICATIONS OF THE FINDINGS: Fertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors. STUDY FUNDING/COMPETING INTEREST(S): This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared. TRIAL REGISTRATION NUMBER: NCT01298388 (clinicaltrials.gov).

Determinants of Second Primary Cancer Type in Survivors of Virus-Related and Non-Virus-Related Cancer Living With HIV in the French Dat'AIDS Cohort.

OBJECTIVES: People who survive after primary cancer are at an increased risk for subsequent primary cancers. We aimed to investigate the possible determinants of second primary cancer (SPC) in HIV-positive cancer survivors. METHODS: This was a multicenter retrospective study using longitudinal data from the French Dat'AIDS cohort. Subjects who developed at least 2 primary cancers were selected. Cancer cases were identified using ICD10 codes and distributed in 3 cancer categories: AIDS-defining cancer (ADC), virus-related non-ADC (VR-NADC), and virus-unrelated-NADC (VU-NADC). The possible determinants considered were the first primary cancer category, sex, age, HIV transmission route, duration of HIV infection follow-up, duration of ART exposure, nadir CD4+ T cell count, and hepatitis C and hepatitis B serostatus. RESULTS: Among the 44642 patients in the Dat'AIDS cohort, 4855 were diagnosed with cancer between 1 December 1983 and 31 December 2015, of whom 444 (9.1%) developed at least 2 primary cancers: 130 ADCs, 85 VR-NADCs, and 229 VU-NADCs. A longer delay between the first primary cancer and the SPC was associated with an increased risk of occurrence of a VR-NADC rather than a secondary ADC. Having had a first primary VU-NADC, an older age, and a longer delay between the HIV diagnosis and the first primary cancer as well as between the first primary cancer and the SPC were associated with an increased risk of VU-NADC rather than ADC. CONCLUSION: SPCs are now a major concern in HIV-positive cancer survivors justifying the development of monitoring strategies after a first cancer.

EORTC SPECTA-AYA: A unique molecular profiling platform for adolescents and young adults with cancer in Europe.

For most adolescent and young adult (AYA) cancers, age-specific molecular features are poorly understood. EORTC-SPECTA, an academic translational research infrastructure for biomaterial collection, will explicitly recruit AYA patients and will therefore collect empirical data to bridge the molecular gap between pediatric and adult oncology. The initial pilot study, activated in February 2019 across Europe, will recruit 100 AYA patients (aged 12-29 years) with newly diagnosed or relapsed high-grade gliomas and high-grade bone and soft tissue sarcomas. The primary objective of the pilot is to determine feasibility and recruitment rates. Formalin-fixed tumor tissue and whole blood from study participants will be prospectively collected with clinical data and stored centrally at the Integrated BioBank of Luxembourg. Whole exome sequencing of matched tumor and blood, and tumor RNA sequencing and DNA methylation profiling will be performed at the German Cancer Research Center, Heidelberg, Germany. Virtual central pathology review of scanned diagnostic slides will be undertaken by an international expert panel, and diagnostic material returned to the participating centers. A multidisciplinary molecular tumor board will release a clinically validated report to referring clinicians within 4-6 weeks after biopsy. SPECTA-AYA constitutes a major opportunity to gain knowledge about the tumor biology of this unique age group. It incorporates notable innovative aspects: AYA specificity, pan-European academic collaboration, centralized biobanking, comprehensive molecular profiling and virtual central pathology review, among others. SPECTA-AYA will help untangle the tumor particularities of AYAs with cancer and aims to improve their access to novel drugs and personalized medicine.

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

Solid lubricant behavior of MoS2 and WSe2-based nanocomposite coatings.

Tribological coatings made of MoS2 and WSe2 phases and their corresponding combinations with tungsten carbide (WC) were prepared by non-reactive magnetron sputtering of individual targets of similar composition. A comparative tribological analysis of these multiphase coatings was done in both ambient air (30-40% relative humidity, RH) and dry nitrogen (RH<7%) environments using the same tribometer and testing conditions. A nanostructural study using advanced transmission electron microscopy of the initial coatings and examination of the counterfaces after the friction test using different analytical tools helped to elucidate what governs the tribological behavior for each type of environment. This allowed conclusions to be made about the influence of the coating microstructure and composition on the tribological response. The best performance obtained with a WSex film (specific wear rate of 2 × 10-8 mm3 N-1m-1 and a friction coefficient of 0.03-0.05) was compared with that of the well-established MoS2 lubricant material.

A 13-Year Retrospective Study on Primary Liver Cancer in Cambodia: A Strikingly High Hepatitis C Occurrence among Hepatocellular Carcinoma Cases.

OBJECTIVES: Hepatocellular carcinoma (HCC) is the main type of primary liver cancer (PLC) worldwide, but cholangiocarcinoma (CCA) may be predominant in some specific regions of Southeast Asia. The aim of the present study was to delineate a pattern of Cambodian PLC patients attending the Calmette Hospital in the Cambodian capital Phnom Penh. MATERIALS AND METHODS: A total of 553 medical charts diagnosing PLCs from January 2003 to May 2015 were obtained from both the Oncology and Hepato-Gastroenterology Departments of the Calmette Hospital. RESULTS: HCC was the predominant type of PLC recorded, with 511 cases (92.4%), whereas CCA represented merely 7.6% (42 cases) of the overall series. Hepatitis B virus (HBV; 44.3%) and hepatitis C virus (HCV; 43%) infection rates were similar among the HCC patients, while small subsets of CCA patients were infected with HBV (15.4%) or HCV (11.5%). Most HCC (84%) and CCA (73.8%) patients received palliative treatment only. CONCLUSION: The present study indicates that HCC is the main form of primary hepatic neoplasm among PLC patients attending a hospital in Cambodia. HBV and HCV infections represented equivalent burdens and major contributing factors to HCC. Therefore, the implementation of prevention programs for these infectious agents should become a priority for health policy makers in the country.

Temporal dynamics of airborne fungi in Havana (Cuba) during dry and rainy seasons: influence of meteorological parameters.

The aim of this paper was to determine for first time the influence of the main meteorological parameters on the atmospheric fungal spore concentration in Havana (Cuba). This city is characterized by a subtropical climate with two different marked annual rainfall seasons during the year: a "dry season" and a "rainy season". A nonviable volumetric methodology (Lanzoni VPPS-2000 sampler) was used to sample airborne spores. The total number of spores counted during the 2 years of study was 293,594, belonging to 30 different genera and five spore types. Relative humidity was the meteorological parameter most influencing the atmospheric concentration of the spores, mainly during the rainy season of the year. Winds coming from the SW direction also increased the spore concentration in the air. In terms of spore intradiurnal variation we found three different patterns: morning maximum values for Cladosporium, night peaks for Coprinus and Leptosphaeria, and uniform behavior throughout the whole day for Aspergillus/Penicillium."

A nanoscale characterization with electron microscopy of multilayered CrAlYN coatings: a singular functional nanostructure.

A combination of transmission electron microscopy techniques and spatially resolved microanalysis is used to investigate the nanostructure, constituting phases, and chemical elemental distribution in CrAlYN multilayered coatings. The location of the metallic elements and their chemical state are needed to understand their functional properties. Samples were prepared with variable Al (4-12 at%) and Y (2-5 at%) contents by direct current reactive magnetron sputtering on silicon substrates using metallic targets and Ar/N2 mixtures under different deposition parameters (power applied to the target and rotation speed of the sample holder). The changes produced in the nanostructure and chemical distribution were investigated. Nanoscale resolution electron microscopy analysis has shown that these coatings present a singular nanostructure formed by multilayers containing at a certain periodicity nanovoids filled with molecular nitrogen. Spatially resolved energy dispersive spectroscopy and electron energy loss elemental mappings and profiles showed that the chromium, aluminum, and yttrium atoms are distributed in a sequential way following the position of the targets inside the deposition chamber. Analysis of the different atomic distribution and phases formed at the nanoscale is discussed depending on the deposition parameters.

Rescuing Drugs That are Discontinued in Adult Oncology Development for the Benefit of Children and Adolescents With Cancer - An ACCELERATE Multistakeholder Consensus.

Better therapies for childhood cancer remain an unmet need to improve the dismal prognosis of certain malignancies and to reduce the burden of toxicity. Rescuing discontinued or shelved drugs for children, adolescents, and young adults is a strategy to identify new uses for approved or investigational medicines outside the scope of their original medical indication. Our proposed multistakeholder consensus focuses on the development of innovative, patent-protected targeted agents, sourced from previously shelved or discontinued programs that have the potential to provide significant benefit to underserved patient populations, with unmet medical needs. There are several challenges to continuing/rescuing drugs for pediatric oncology development, which include the lack of information for decision making, corporate strategy considerations underlying the decision to invest in pediatric development, and the contracting and technology transfer complexities required to enable divestment and subsequent development. The multistakeholder approach for drug development has the advantage of conveying a consensus among academia, patient advocates, and importantly industry itself. We propose three areas of action to facilitate rescuing potentially beneficial drugs for children and adolescents with cancer: (i) initiatives to provide information to companies considering developing these drugs and a standards framework; (ii) incentives both in Europe and in the United States to encourage companies to develop pediatric-only drugs, with the reform of the EU Pharmaceutical Legislation posing an important opportunity; and (iii) communication of the issues to all stakeholders. Ultimately, this will benefit children and adolescents with cancer.

Synthesis and Characterization of Multilayered CrAlN/Al2O3 Tandem Coating Using HiPIMS for Solar Selective Applications at High Temperature.

The effect of applying a negative bias during deposition of a previously designed multilayer solar selective absorber coating was studied on two types of substrates (316L stainless steel and Inconel 625). The solar selective coating is composed of different chromium aluminum nitride layers deposited using a combination of radiofrequency (RF), direct current (DC), and high-power impulse magnetron sputtering (HiPIMS) technologies. The chemical composition is varied to generate an infrared reflective/absorber layer (with low Al addition and N vacancies) and two CrAlN intermediate layers with medium and high aluminum content (Al/Cr = 0.6 and 1.2). A top aluminum oxide layer (Al2O3) is deposited as an antireflective layer. In this work, a simultaneous DC-pulsed bias (-100 V, 250 kHz) was applied to the substrates in order to increase the film density. The optical performance, thermal stability, and oxidation resistance was evaluated and compared with the performance obtained with similar unbiased coating and a commercial Pyromark paint reference at 600, 700, and 800 °C. The coating remained stable after 200 h of annealing at 600 °C, with solar absorptance (α) values of 93% and 92% for samples deposited on stainless steel and Inconel, respectively, and a thermal emittance ε25°C of 18%. The introduction of additional ion bombardment during film growth through bias assistance resulted in increased durability, thermal stability, and working temperature limits compared with unbiased coatings. The solar-to-mechanical energy conversion efficiency at 800 °C was found to be up to 2 times higher than Pyromark at C = 100 and comparable at C = 1000.

Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development.

In a landscape of an increasing number of products and histology and age agnostic trials for rare patient cancer, prioritization of products is required. Paediatric Strategy Forums, organized by ACCELERATE and the European Medicines Agency with participation of the US Food and Drug Administration, are multi-stakeholder meetings that share information to best inform pediatric drug development strategies and subsequent clinical trial decisions. Academia, industry, regulators, and patient advocates are equal members, with patient advocates highlighting unmet needs of children and adolescents with cancer. The 11 Paediatric Strategy Forums since 2017 have made specific and general conclusions to accelerate drug development. Conclusions on product prioritization meetings, as well as global master protocols, have been outputs of these meetings. Forums have provided information for regulatory discussions and decisions by industry to facilitate development of high-priority products; for example, 62% of high-priority assets (agreed at a Forum) in contrast to 5% of those assets not considered high priority have been the subject of a Paediatric Investigational Plan or Written Request. Where there are multiple products of the same class, Forums have recommended a focused and sequential approach. Class prioritization resulted in an increase in waivers for non-prioritized B-cell products (44% to 75%) and a decrease in monotherapy trials, proposed in Paediatric Investigation Plans (PIP) submissions of checkpoint inhibitors from 53% to 19%. Strategy Forums could play a role in defining unmet medical needs. Multi-stakeholder forums, such as the Paediatric Strategy Forum, serve as a model to improve collaboration in the oncology drug development paradigm.

Conformal TiO2 Aerogel-Like Films by Plasma Deposition: from Omniphobic Antireflective Coatings to Perovskite Solar Cell Photoelectrodes.

The ability to control the porosity of thin oxide films is a key factor determining their properties. Despite the abundance of dry processes for synthesizing oxide porous layers, a high porosity range is typically achieved by spin-coating-based wet chemical methods. Besides, special techniques such as supercritical drying are required to replace the pore liquid with air while maintaining the porous network. In this study, we propose a new method for the fabrication of ultraporous titanium dioxide thin films at room or mild temperatures (T ≤ 120 °C) by a sequential process involving plasma deposition and etching. These films are conformal to the substrate topography even for high-aspect-ratio substrates and show percolated porosity values above 85% that are comparable to those of advanced aerogels. The films deposited at room temperature are amorphous. However, they become partly crystalline at slightly higher temperatures, presenting a distribution of anatase clusters embedded in the sponge-like open porous structure. Surprisingly, the porous structure remains after annealing the films at 450 °C in air, which increases the fraction of embedded anatase nanocrystals. The films are antireflective, omniphobic, and photoactive, becoming superhydrophilic when subjected to ultraviolet light irradiation. The supported, percolated, and nanoporous structure can be used as an electron-conducting electrode in perovskite solar cells. The properties of the cells depend on the aerogel-like film thickness, which reaches efficiencies close to those of commercial mesoporous anatase electrodes. This generic solvent-free synthesis is scalable and applicable to ultrahigh porous conformal oxides of different compositions, with potential applications in photonics, optoelectronics, energy storage, and controlled wetting.