Current status of precision medicine in pediatric oncology in Spain: a consensus report by the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

The study analyzes the current status of personalized medicine in pediatric oncology in Spain. It gathers national data on the tumor molecular studies and genomic sequencing carried out at diagnosis and at relapse, the centers that perform these studies, the technology used and the interpretation and clinical applicability of the results. Current challenges and future directions to achieve a coordinated national personalized medicine strategy in pediatric oncology are also discussed. Next generation sequencing-based (NGS) gene panels are the technology used in the majority of centers and financial limitations are the main reason for not incorporating these studies into routine care. Nowadays, the application of precision medicine in pediatric oncology is a reality in a great number of Spanish centers. However, its implementation is uneven and lacks standardization of protocols; therefore, national coordination to overcome the inequalities is required. Collaborative work within the Personalized Medicine Group of SEHOP is an adequate framework for encouraging a step forward in the effort to move precision medicine into the national healthcare system.

The paediatric cancer clinical research landscape in Spain: a 13-year multicentre experience of the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

PURPOSE: Early phase trials are crucial in developing innovative effective agents for childhood malignancies. We report the activity in early phase paediatric oncology trials in Spain from its beginning to the present time and incorporate longitudinal data to evaluate the trends in trial characteristics and recruitment rates. METHODS: Members of SEHOP were contacted to obtain information about the open trials at their institutions. The study period was split into two equal periods for analysis: 2007-2013 and 2014-2020. RESULTS: Eighty-one trials and two molecular platforms have been initiated. The number of trials has increased over the time of the study for all tumour types, with a predominance of trials available for solid tumours (66%). The number of trials addressed to tumours harbouring specific molecular alterations has doubled during the second period. The proportion of industry-sponsored compared to academic trials has increased over the same years. A total of 565 children and adolescents were included, with an increasing trend over the study period. For international trials, the median time between the first country study approval and the Spanish competent authority approval was 2 months (IQR 0-6.5). Fourteen out of 81 trials were sponsored by Spanish academic institutions. CONCLUSIONS: The number of available trials, and the number of participating patients, has increased in Spain from 2007. Studies focused on molecular-specific targets are now being implemented. Barriers to accessing new drugs for all ranges of age and cancer diseases remain. Additionally, opportunities to improve academic research are still required in Spain.

Distribution of segmental chromosomal alterations in neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is a heterogeneous tumor with extremely diverse prognosis according to clinical and genetic factors such as specific combinations of chromosomal imbalances. METHODS: Molecular karyotyping data from a national neuroblastic tumor database of 155 NB samples were analyzed and related to clinical data. RESULTS: Segmental chromosomal alterations (SCA) were detected in 102 NB, whereas 45 only displayed numerical alterations. Incidence of SCA was higher in stage M (92%) and MYCN amplified (MNA) NB (96%). Presence of SCA was associated with older age, especially 1q gain and 3p deletion. 96% of the deaths were observed in the SCA group and 85% of the relapsed NB contained SCA. The alteration most commonly associated with a higher number of other segmental rearrangements was 11q deletion, followed by 4p deletion. Whole-chromosome 19 gain was associated with lower stages, absence of SCA and better outcome. CONCLUSIONS: SCA are not randomly distributed and are concentrated on recurrent chromosomes. The most frequently affected chromosomes identify prognostic factors in specific risk groups. SCA are associated with older age and MNA. We have identified a small subset of patients with better outcome that share whole-chromosome 19 numeric gain, suggesting its use as a prognostic biomarker in NB.

Challenges in early phase clinical trials for childhood cancer during the COVID-19 pandemic: a report from the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP).

PURPOSE: The COVID-19 pandemic has forced healthcare stakeholders towards challenging decisions. We analyse the impact of the pandemic on the conduct of phase I-II trials for paediatric cancer during the first month of state of alarm in Spain. METHODS: A questionnaire was sent to all five ITCC-accredited Spanish Paediatric Oncology Early Phase Clinical Trial Units, including questions about impact on staff activities, recruitment, patient care, supply of investigational products, and legal aspects. RESULTS: All units suffered personnel shortages and difficulties in enrolling patients, treatment continuity, or performing trial assessments. Monitoring activity was frequently postponed (73%), and 49% of on-going trials interrupted recruitment. Only two patients could be recruited during this period (75% reduction in the expected rate). CONCLUSIONS: The COVID-19 crisis has significantly impacted clinical research practice and access to innovation for children with cancer. Structural and functional changes are under way to better cope with the expected future restrictions.

Precision medicine in Ewing sarcoma: a translational point of view.

Ewing sarcoma is a rare tumor that arises in bones of children and teenagers but, in 15% of the patients it is presented as a primary soft tissue tumor. Balanced reciprocal chimeric translocation t(11;22)(q24;q12), which encodes an oncogenic protein fusion (EWSR1/FLI1), is the most generalized and characteristic molecular event. Using conventional treatments, (chemotherapy, surgery and radiotherapy) long-term overall survival rate is 30% for patients with disseminated disease and 65-75% for patients with localized tumors. Urgent new effective drug development is a challenge. This review summarizes the preclinical and clinical investigational knowledge about prognostic and targetable biomarkers in Ewing sarcoma, finally suggesting a workflow for precision medicine committees.

Li-Fraumeni syndrome heterogeneity.

Clinical variability is commonly seen in Li-Fraumeni syndrome. Phenotypic heterogeneity is present among different families affected by the same pathogenic variant in TP53 gene and among members of the same family. However, causes of this huge clinical spectrum have not been studied in depth. TP53 type mutation, polymorphic variants in TP53 gene or in TP53-related genes, copy number variations in particular regions, and/or epigenetic deregulation of TP53 expression might be responsible for clinical heterogeneity. In this review, recent advances in the understanding of genetic and epigenetic aspects influencing Li-Fraumeni phenotype are discussed.

ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain.

INTRODUCTION: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. METHODS: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. RESULTS: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. CONCLUSIONS: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.

Spectroscopic, photochromic and kinetic behavior of photo conversion of Aberchrome 540™ in an ionic liquid media.

The photo-bleaching reaction of the chemical actinometer, Aberchrome 540™, is reported for the first time in a series of ionic liquids (ILs). This fulgide in its C-form undergoes an opening reaction to yield its E-form, when it is irradiated with UV light at wavelengths >400 nm. The magnitude of bleaching was monitored spectrophotometrically and their kinetics evaluated, obtaining first-order rate constants (kobs). The results obtained in different ILs suggest that changes in the rate constants (kobs) of the opening reaction of Aberchrome 540™ are mainly governed by weaker interactions such as coulombic (π* parameter) and Van der Waals interactions (δH2, parameter). In addition, the photochemical fatigue resistance was also studied in ILs media and compared with conventional solvents (benzene, toluene, etc.). In particular, we found that three different tendencies dependent on the ILs used exist. The first group of ILs where the reversibility of the fulgide is favored (for example, [Bmim][BF4], [Bmim][PF6] and [Bmim][OTf]), behaviour similar to conventional solvents. The second group corresponds to ILs where photo reversibility is partial; and finally, other group of ILs that prevented photo reversibility. It is proposed that depending on the ILs used, the stabilization of different forms of the fulgide can be controlled, thus resulting important in terms of choosing the appropriate ILs for a specific photochemical reaction.

Survey on paediatric tumour boards in Europe: current situation and results from the ExPo-r-Net project.

BACKGROUND: Under the ExPO-r-NeT project (European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment), we aimed to identify paediatric oncology tumour boards in Europe to investigate the kind of technologies and logistics that are in place in different countries and to explore current differences between regions. METHODS: A 20-question survey regarding several features of tumor boards was designed. Data collected included infrastructure, organization, and clinical decision-making information from the centres. The survey was distributed to the National Paediatric Haematology and Oncology Societies that forwarded the survey to the sites. For comparative analysis, respondents were grouped into four geographical regions. RESULTS: The questionnaire was distributed amongst 30 countries. Response was obtained from 23 (77%) that altogether have 212 paediatric oncology treating centres. A total of 121 institutions answered (57%). Ninety-one percent of the centres hold multidisciplinary boards; however, international second consultations are performed in 36% and only 15% participate on virtual tumor boards. Videoconferencing facilities and standard operational procedures (SOPs) are available in 49 and 43% of the centres, respectively. There were statistically significant differences between European regions concerning meeting infrastructure and organization/logistics: specific room, projecting equipment, access to medical records, videoconferencing facilities, and existence of SOPs. CONCLUSION: Paediatric tumor boards are a common feature in Europe. To reduce inequalities and have equal access to healthcare, a virtual network is needed. Important differences on the functioning and access to technology between regions in Europe have been observed and need to be addressed.

Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

Cancer in children and adolescents in Spain: incidence, treatment setting and provider specialty.

PURPOSE: To analyze cancer incidence, distribution of malignancy, treatment setting and provider specialty of cancer patients, 0-19 years old, in the Comunitat Valenciana, Spain. METHODS/PATIENTS: All incident childhood and adolescent (0-19 years) cancer cases registered in the population-based Comunitat Valenciana Childhood Cancer Registry (RTICV) from 2007 to 2010 were included. Pathological and hematological diagnoses were recoded using the International Classification of Childhood Cancer Third Edition (ICCC-3). Treatment setting and provider specialty were analyzed. RESULTS: 696 patients <20 years were diagnosed with cancer: 513 cases were children (0-14 years) and 183 were adolescents (15-19 years). Overall age-adjusted incidence for 2007-2010 was 176.0 cases per million (95 % CI 162.8-189.2), with incidence being the highest among infants (287.4), followed by 1-4 years (205.5), adolescents (179.9), 10-14 years (150.2) and 5-9 years (140.6). Among adolescents aged 14-19 years, the treatment setting differed by cancer type; 87 % of them were never seen at pediatric oncology units, while 40 % were treated in up to 20 different medical oncology departments in institutions without pediatric oncology expertise. CONCLUSIONS: This is the first population-based epidemiological study carried out in Spain on children and adolescents with cancer. Centralization of care to a small number of specialized centers and thorough pediatric and oncology team collaboration are needed to improve care and survival for adolescents with cancer in our country. We suggest the creation of specific adolescent tumor boards in main tertiary care hospitals, in which adolescents with cancer can benefit from the shared expertise of medical and pediatric specialists.

Landscape of early clinical trials for childhood and adolescence cancer in Spain.

PURPOSE: Despite numerous advances, survival remains dismal for children and adolescents with poor prognosis cancers or those who relapse or are refractory to first line treatment. There is, therefore, a major unmet need for new drugs. Recent advances in the knowledge of molecular tumor biology open the door to more adapted therapies according to individual alterations. Promising results in the adult anticancer drug development have not yet been translated into clinical practice. We report the activity in early pediatric oncology trials in Spain. METHODS: All members of the Spanish Society of Pediatric Hematology Oncology (SEHOP) were contacted to obtain information about early trials open in each center. RESULTS: 22 phase I and II trials were open as of May 2015: 15 for solid tumors (68 %) and 7 for hematological malignancies (32 %). Fourteen (64 %) were industry sponsored. Since 2010, four centers have joined the Innovative Therapies For Children With Cancer, an international consortium whose aim is developing novel therapies for pediatric cancers. A substantial number of studies have opened in these 5 years, improving the portfolio of trials for children. Results of recently closed trials show the contribution of Spanish investigators, the introduction of molecularly targeted agents and their benefits. CONCLUSIONS: Clinical trials are the way to evaluate new drugs, avoiding the use of off-label drugs that carry significant risks. The Spanish pediatric oncology community through the SEHOP is committed to develop and participate in collaborative academic trials, to favor the advancement and optimization of existing therapies in pediatric cancer.

Paediatric tumour boards in Spain: a national survey.

PURPOSE: Multidisciplinary tumour boards (MDTs) are conducted worldwide for the management of patients with cancer, and they deliver a higher standard of care by simultaneously involving different specialists in diagnosis and treatment planning. However, information of paediatric MDTs functioning is scarce. A pilot study was conducted in Spain in the frame of the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment (ExPO-r-Net). METHODS: A specific questionnaire was designed regarding various features of MDT practice. Data collected included information on the centres and the team, infrastructure for meetings, MDT organization/logistics and clinical decision-making. The survey was distributed to all Paediatric Oncology Units that register patients in the Spanish Registry of Childhood Tumours (RETI-SEHOP). RESULTS: 32 out of 43 contacted centres responded the questionnaire (74 % response rate; 88 % response rate for centres with >25 new patients/year). All units with >25 new patients/year have a dedicated Paediatric MDT compared to 76 % of units with ≤25 new patients/year. MDTs should be improved at institutional level by clear protected time in service planning for all specialists involved, incentives for attendance and attendance registration. Clinical decision-making process and follow-up of recommendation adherence should be assessed and potential legal responsibilities for physicians participating in Tumour Board defined. Network collaboration through virtual MDTs, using available videoconferencing tools, is an opportunity to share expertise among centres.

Solid ovarian tumours in childhood: a 35-year review in a single institution.

PURPOSE: Solid ovarian tumours are uncommon in childhood. Our aim is to evaluate the outcomes in a single institution over 35 years. METHODS: We reviewed their clinical presentation, management, pathology and outcomes from 1972 to 2007. RESULTS: Fifty-three patients, with a median age of 9.2 years (range 0.9-14.2), were registered. Common symptoms at presentation were abdominal pain (75.8%) and abdominal mass (57.4%). Histopathological diagnoses were: 26 mature teratoma, 10 immature teratoma, 8 dysgerminoma, 5 granulosa cell tumours, 2 yolk sac tumours, 1 gonadoblastoma and 1 embryonal carcinoma. Staging (FIGO) for malignant/borderline tumours was: 17 stage I, 1 stage II, 8 stage III and 1 stage IV. Unilateral salpingo-oophorectomy was performed in 47 cases. Sixteen patients underwent chemotherapy after surgery (15 with platinum-based regimen) and postoperative radiotherapy was given in 5 cases. Recurrence was observed in 2 patients and one died (stage III immature teratoma) after a second relapse despite multiple chemotherapy, surgery and radiotherapy. Five-year OS and 5-year EFS were 97% and 94% respectively. CONCLUSIONS: Although rare, ovarian tumours must be included in the differential diagnosis of abdominal pain in childhood. Our results confirm their excellent prognosis using conservative surgery and platinum-based chemotherapy. The key point is to maintain excellent outcome while reducing associated morbidity and preserving fertility.

Síndrome de Lynch. Prevalencia, características clínicas y tratamiento / Lynch syndrome. Prevalence. Clinical characteristics and treatment

El cáncer colorrectal hereditario no polipósico (HNPCC) o síndrome de Lynch es de transmisiónautosómica dominante con una penetrancia del 85 por ciento y representa alrededor del 5 por ciento de todos loscánceres colorrectales. El presente trabajo se realizó para establecer la prevalencia del síndrome deLynch y comparar, sus características clínicas y tipos de tratamientos empleados, con los pacientescon cáncer colorrectal esporádico. Es un estudio observacional descriptivo con componente analíticodonde se incluyeron todos los pacientes con cáncer colorrectal demostrado por estudiohistopatológico que concurrieron entre junio del 1999 a abril del 2005 a los servicios de cirugíageneral del Hospital de Clínicas e Instituto de Previsión Social. Se contactó en forma personal con elpaciente o familiar de primer grado para evaluar los antecedentes familiares de otras neoplasias yasí reunir información para el diagnóstico del síndrome de Lynch utilizando los criterios deAmsterdam II. Fueron estudiados 324 pacientes con cáncer colorrectal y la prevalencia delsíndrome de Lynch fue de 2,7 por ciento (IC 95 por ciento 0,9-4,5). La mediana de edad fue significativamente másbaja, mientras que, la presencia de tumores sincrónicos y metacrónicos fueron significativamentemás alta en los sujetos con síndrome de Lynch que en los pacientes con cáncer colorrectalesporádico. No se encontró diferencia significativa en el estadío evolutivo de los tumores y ningunadiferencia en el tipo de resecciones quirúrgicas en ambos grupos de pacientes. La prevalencia delsíndrome de Lynch en pacientes con cáncer colorrectal fue baja, sus características clínicas fueronsignificativamente diferentes al de cáncer colorrectal esporádico, mientras que el tipo deresecciones quirúrgicas no difiere en ambos grupos de pacientes.

Tumour banks in pediatric oncology.

INTRODUCTION: The information offered by the new genomic and proteomic techniques will play a central role in our knowledge of cancer; but it is limited by the lack of available tissue samples. Cancer in children is a sum of infrequent diseases, so tumor banks are support tools for translational research, providing access to a sufficiently large series of samples, which would minimize the asymmetric effect of the diverse origin. MATERIAL AND METHODS: From 2003 a Molecular Pathology Network in Pediatric Solid Tumors Netwoks exists in Spain, and we are a part of it. Our aim was to create a pediatric tumor bank program and consensus documents about its use. RESULTS: Standard Operating Procedures for collection and transport of samples have been created. CONCLUSIONS: Thinking about the fast progress in Molecular Biology and the low frequency in pediatric tumors, it is vital to consider the importance of a bio bank.

Formal hydride transfer mechanism for photoreduction of 3-phenylquinoxalin-2-ones by amines. Association Of 3-phenylquinoxalin-2-one with aliphatic amines

The photophysical and photochemical behavior of 1-methyl-3-phenylquinoxalin-2-one (MeNQ) and 3-phenylquinoxalin-2-one (HNQ) in the presence of amines is reported. While HNQ fluorescence shows an auxochromic effect and a bathochromic shift with added amines, explained by association of HNQ with amine in the ground state and emission from both excited species HNQ and [HNQ-amine], both MeNQ and HNQ are photoreduced efficiently on irradiation in the presence of amines, leading to the semireduced quinoxalin-2-ones, MeNQH(-) and HNQH(-), respectively, via an electron-proton-electron transfer, with unit quantum yields at high amine concentrations. The semireduced quinoxalin-2-ones XNQH(-) (X = H, Me) revert almost quantitatively to the parent XNQ in a dark thermal reaction with an activation free energy for MeNQH(-) of 17.4 and 25.9 kcal/mol in acetonitrile and benzene, respectively. Kinetic and spectroscopic (UV and NMR) evidence supports the proposed reaction mechanism for the reversible photoreduction.