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.

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.

Improving the quality of care in the molecular era for children and adolescents with medulloblastoma.

PURPOSE: Elevated mortality and morbidity rates persist in pediatric patients with medulloblastoma. We present a clinical audit of a real-world cohort of patients in search for pragmatic measures to improve their management and outcome. METHODS/PATIENTS: All pediatric patients with medulloblastoma treated between 2003 and 2016 at a Spanish reference center were reviewed. In the absence of internationally accepted quality indicators (QIs) for pediatric CNS tumors, diagnostic, therapeutic, survival, and time QIs were defined and assessed. RESULTS: Fifty-eight patients were included, 24% were younger children (< 3 years), 36% high risk (anaplastic, metastasis, or surgical residue > 1.5 cm2), and 40% standard risk. Five-year OS was 59.2% (95% CI 47-75); 5-year PFS 36.4% (95% CI 25-53). Five main areas of quality assurance were identified: diagnosis, global strategy, frontline treatment modalities, outcomes, and long-term and end-of-life care. A set of 34 QIs was developed and applied. Lack of central pathology review, delay in the incorporation of novel molecular markers, and absence of a neurocognitive and quality-of-life evaluation program were some of the audit findings. CONCLUSIONS: This real-world research study resulted in the development of a pragmatic set of QIs, aimed to improve clinical audits and quality of care given to children and adolescents with medulloblastoma. We hope that our findings will serve as a reference to further develop a quality assurance system with specific QIs for pediatric CNS tumors in the future and that this will ultimately improve the survival and quality of life of these patients.

Outcome of childhood leukaemia survivors and necrosis of the femoral head treated with autologous mesenchymal stem cells.

PURPOSE: Corticoid-induced osteonecrosis (ON) of femoral head can lead to severe hip joint impairment and hip replacement, with negative impact in young survivors of acute lymphoblastic leukaemia (ALL) with long life expectancy. We aim to improve quality of life in these patients with a novel approach. METHODS/PATIENTS: Based on the regenerative capacities of mesenchymal stem cells (MSCs), we performed locally implanted autologous cell therapy in two adolescents suffering of bilateral femoral ON. This required a simple, minimally invasive surgical procedure. RESULTS: Both patients experienced significant pain relief and restoration of gait kinematic values. Radiographic evaluation showed cessation of hip collapse. No toxicities/complications were observed after a 4-year follow-up. CONCLUSIONS: Our preliminary results suggest that autologous MSCs can be considered as a novel treatment for children and young adults with ON after overcoming ALL. It may avoid hip replacement and improve quality of life of leukaemia survivors.

Management and outcome of children with neuroendocrine tumors of the appendix in Spain: Is there room for improvement?

PURPOSE: Neuroendocrine tumors (NETs) are, after lymphomas, the most frequent gastrointestinal tumors in children, mainly located in the appendix. Best management remains unclear, given the absence of pediatric guidelines. We present the first Spanish series of pediatric patients with NETs. PATIENTS AND METHODS: Retrospective study of all pediatric patients (<18 years) with NET treated in four oncology reference institutions in Spain between 1994 and 2015. RESULTS: Seventeen patients were included. All patients presented with acute abdomen. TNM stage was T1a (82%) and T1b (12%). Extension study was heterogenous, with only 4 patients undergoing an OctreoScan. Four patients met criteria for second surgery (affected surgical margins or mesoappendix invasion), but it was only performed in two. Despite the diverse management, none of the patients relapsed during follow-up. CONCLUSIONS: The disparity in diagnostic tests, second surgery criteria and follow-up shown in this study highlights the need for specific pediatric guidelines.

Lack of evidence for the size principle of selective vulnerability of axons in toxic neuropathies. I. The effects of subcutaneous injections of 2,5-hexanedione on behavior and muscle spindle function.

2,5-Hexanedione (HD) produces a central-peripheral distal axonopathy. It has been suggested that agents which produce this type of axonopathy show a predilection to the largest diameter fibers. This has been based primarily on morphological data. However, electrophysiological evidence and some clinical and morphological data suggest that this may not be the case. In particular, in acrylamide neuropathy, muscle spindle primary afferents do not show this selectivity, as well as autonomic fibers. This study was carried out to determine whether the largest diameter axons were selectively vulnerable to HD. We found that subcutaneous injections of HD in cats produced a dose-dependent increase in behavioral deficits such as contact placing, stepping, and locomotion. There was also a dose-dependent decrease in the position sensitivity of muscle spindle primary and secondary endings. However, the secondary endings, which are innervated by smaller axons, were affected prior to the primary endings. Also, the velocity sensitivity of the primary endings was depressed at a similar time frame as the position sensitivity of these same endings. These data are consistent with the hypothesis that the caliber of the axon is not the only determinant of the selective vulnerability of axons in distal axonopathy.

Effects of 2,5-hexanedione on deefferented muscle spindle position sensitivity.

2,5-Hexanedione (HD) produces a neurofilamentous axonpathy in humans and experimental animals. The present study was carried out to determine the time course of the effects of HD on muscle spindle position sensitivity to permit comparisons with similar effects of other toxicants which produce a neurofilamentous axonopathy. Cats were administered HD either via their drinking water or via osmotic minipumps. Muscle spindle position sensitivity was tested after a total HD dose of 2.43 or 4.85 g/kg via the drinking water or 0.96, 1.91, or 4.78 g/kg via an osmotic minipump. The position sensitivities of both primary and secondary endings were depressed regardless of the route of administration. However, secondary muscle spindle afferents in the animals intoxicated with HD via the minipumps were affected to a greater extent than primary muscle spindle afferents at all doses studied. These data show that HD alters muscle spindle function and lends support to the suggestion that the largest diameter fibers are not the most vulnerable to HD.

Primary afferent terminal function following acrylamide: alterations in the dorsal root potential and reflex.

The dorsal root potential (DRP) and the dorsal root reflex (DRR) were studied in acrylamide (ACR)-induced axonopathy to determine the nature and extent of primary afferent terminal (PAT) dysfunction. Cats were administered 30 mg/kg/day ACR for either 5 (ACR 5D) or 10 (ACR 10D) days. The day after the last injection, the spinal cord as isolated in situ and the DRP and DRR were elicited. It was found that only 21% of the ACR 10D animals exhibited a DRP. Furthermore, in that 21%, the DRP appeared to degrade over distance differently from the control group. There was no change in the DRP evoked in the ACR 5D group. ACR affected the DRR when evoked from the cutaneous sural nerve (SU) to a greater extent than when evoked from the medial gastrocnemius (MG) nerve. A SU-evoked DRR could not be elicited in any of the animals in the ACR 10D group and in only 20% of the ACR 5D group. There was no difference in the ability to elicit a MG-evoked DDR in either ACR-treated group when compared to control. However, the maximum-evoked area under the DRR elicited from the MG nerve was significantly smaller in the ACR-treated groups than in control. These data show that ACR does indeed impair PAT function. ACR preferentially affects the PAT processing of the SU when compared to the MG nerve, which may indicate that the selective vulnerability of the largest diameter fibers to ACR is not necessarily true.