Analysis of germline variants in pediatric patients diagnosed with desmoid tumors and nuchal-type fibromas.

Desmoid tumor (DT) is a fibroblastic proliferation arising in soft tissue characterized by localized infiltrative growth with an inability to metastasize but with a tendency to recurrence. Nuchal-type fibromas are benign soft tissue lesions that are usually developed in the posterior neck. The development of these neoplasms can be associated with a hereditary cancer predisposition syndrome, mainly familial adenomatous polyposis (FAP) syndrome caused by APC germline mutations. Gardner syndrome is a variant of FAP characterized by the presence of extracolonic manifestations including soft tissue tumors as DTs and nuchal-type fibromas. However, the development of these tumors could be associated with germline alterations in other genes related to colorectal cancer development. The objective of this study was to analyze germline variants in APC, MUTYH, POLD1 and POLE genes in five pediatric patients diagnosed with DTs or nuchal-type fibromas. We identified two pathogenic variants in the APC gene in two different patients diagnosed with nuchal-type fibroma and DTs and two variants of uncertain significance in POLD1 in two patients diagnosed with nuchal-type fibroma. Two patients had family history of colorectal cancer, however, only one of them showed an APC germline pathogenic variant. The analysis of germline variants and genetic counseling is essential for pediatric patients diagnosed with DTs or nuchal-type fibromas and their relatives.

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing.

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans´ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome.

Manejo clínico de las complicaciones agudas de la anemia falciforme: 11 años de experiencia en un hospital terciario / Clinical management of the acute complications of sickle cell anemia: 11 years of experience in a tertiary hospital

Introducción: La drepanocitosis es una anemia emergente en Europa que condiciona una elevada morbilidad con complicaciones agudas y crónicas. El manejo de estos pacientes es complejo y requiere atención interdisciplinar. El objetivo del estudio es analizar las características y el manejo de los pacientes con drepanocitosis que ingresan por complicaciones agudas.Métodos: Estudio descriptivo retrospectivo de los ingresos por complicaciones agudas de pacientes con drepanocitosis menores de 16 años en un hospital terciario entre 2010 y 2020. Se revisaron los datos clínicos, analíticos y radiológicos.Resultados: Se incluyeron 71 ingresos correspondientes a 25 pacientes, el 40% diagnosticados por cribado neonatal. Los ingresos se incrementaron de forma progresiva durante este periodo. Los diagnósticos más frecuentes fueron la crisis vasooclusiva (35,2%), el síndrome febril (33,8%) y el síndrome torácico agudo (32,3%). Nueve pacientes precisaron ingreso en cuidados intensivos. En 20 ingresos se obtuvo documentación microbiológica, 60% bacterias. En el 86% se administró antibioterapia y 28% precisaron analgesia con opioides. El 89% cumplían la pauta de vacunación adecuada y el 41% recibían hidroxiurea previo al ingreso.Conclusiones: Las complicaciones agudas que precisan ingreso hospitalario son frecuentes en los pacientes con drepanocitosis, siendo las más habituales la crisis vasooclusiva y el síndrome febril. Esto conlleva un uso elevado de antibioterapia y opioides. El diagnóstico precoz facilita el reconocimiento de complicaciones de riesgo vital como el síndrome torácico agudo y el secuestro esplénico. A pesar de las medidas preventivas y los tratamientos indicados en la actualidad, estas complicaciones agudas precisan manejo hospitalario. (AU)

Introduction: Sickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications.Methods: Retrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed.Results: We included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%.Conclusions: Acute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management. (AU)

Clinical management of the acute complications of sickle cell anemia: 11 years of experience in a tertiary hospital.

INTRODUCTION: Sickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications. METHODS: Retrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed. RESULTS: We included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%. CONCLUSIONS: Acute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management.

Clinical Value of NGS Genomic Studies for Clinical Management of Pediatric and Young Adult Bone Sarcomas.

Genomic techniques enable diagnosis and management of children and young adults with sarcomas by identifying high-risk patients and those who may benefit from targeted therapy or participation in clinical trials. Objective: to analyze the performance of an NGS gene panel for the clinical management of pediatric sarcoma patients. We studied 53 pediatric and young adult patients diagnosed with sarcoma, from two Spanish centers. Genomic data were obtained using the Oncomine Childhood Cancer Research Assay, and categorized according to their diagnostic, predictive, or prognostic value. In 44 (83%) of the 53 patients, at least one genetic alteration was identified. In 80% of these patients, the diagnosis was obtained (n = 11) or changed (n = 9), and thus genomic data affected therapy. The most frequent initial misdiagnosis was Ewing's sarcoma, instead of myxoid liposarcoma (FUS-DDDIT3), rhabdoid soft tissue tumor (SMARCB1), or angiomatoid fibrous histiocytoma (EWSR1-CREB1). In our series, two patients had a genetic alteration with an FDA-approved targeted therapy, and 30% had at least one potentially actionable alteration. NGS-based genomic studies are useful and feasible in diagnosis and clinical management of pediatric sarcomas. Genomic characterization of these rare and heterogeneous tumors also helps in the search for prognostic biomarkers and therapeutic opportunities.

Variants in vincristine pharmacodynamic genes involved in neurotoxicity at induction phase in the therapy of pediatric acute lymphoblastic leukemia.

Vincristine is an important drug of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. A genetic variant in CEP72, a gene involved in vincristine pharmacodynamics, was recently associated with neurotoxicity after prolonged vincristine treatment. This association was not replicated in our Spanish population during induction phase. To test the possibility that other variants in genes involved in vincristine pharmacodynamics were associated with vincristine neuropathy in early phases of the treatment, we evaluated the correlation with toxicity of 24 polymorphisms in 9 key genes in a large cohort of 152 Spanish children with B-ALL homogeneously treated. Results showed no association between any genetic variant in the TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4, MAPT, MIR146a, MIR202, and MIR411 genes and vincristine-related neurotoxicity. These results are in line with the hypothesis that there are different mechanisms causing pheripheral neurotoxicity after prolonged and short-term vincristine treatments.

Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia.

Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

Vincristine pharmacokinetics pathway and neurotoxicity during early phases of treatment in pediatric acute lymphoblastic leukemia.

AIM: Vincristine is an important component of acute lymphoblastic leukemia (ALL) treatment protocols that can cause neurotoxicity. Patients treated with LAL/SHOP protocols often suffer from vincristine-related neurotoxicity in early phases of treatment. Recently, a genome-wide association study connected a SNP in CEP72, involved in vincristine pharmacodynamics, with neurotoxicity during later phases of therapy, which was not replicated during induction phase. These results, together with previous studies indicating that polymorphisms in pharmacokinetic genes are associated with drug toxicity, suggest that changes in the activity or levels of vincristine transporters or metabolizers could work as predictors of vincristine-related neurotoxicity in early phases of treatment in pediatric ALL. PATIENTS & METHODS: We analyzed 150 SNPs in eight key genes involved in vincristine pharmacokinetics and in 13 miRNAs that regulate them. We studied their correlation with neurotoxicity during induction phase in 152 ALL patients treated with LAL/SHOP protocols. RESULTS: The strongest associations with neurotoxicity were observed for two SNPs in ABCC2. The genotypes rs3740066 GG and rs12826 GG were associated with increased neurotoxicity. CONCLUSION: Polymorphisms in ABCC2 could be novel markers for vincristine-related neurotoxicity in pediatric ALL in early phases.

Lack of association of the CEP72 rs924607 TT genotype with vincristine-related peripheral neuropathy during the early phase of pediatric acute lymphoblastic leukemia treatment in a Spanish population.

Vincristine is a component of acute lymphoblastic leukemia (ALL) treatment with the potential to induce peripheral neuropathy. Recently, the CEP72 rs924607 TT genotype was found to be associated with vincristine-induced toxicity during the continuation phase in pediatric ALL patients treated on the Total XIIIB and COG AALL0433 protocols at St Jude Children's Research Hospital and Children's Oncology Group. This finding could provide a base for safer dosing of vincristine. Nevertheless, there are variations in vincristine regimens among ALL treatment protocols and phases in different populations. Therefore, the aim of this study was to determine whether the CEP72 rs924607 TT genotype is a useful marker of vincristine neuropathy during induction therapy among Spanish children with B-ALL treated on the LAL-SHOP protocols. No association was found between neurotoxicity during the induction phase and the rs924607 TT genotype. This lack of association could be because of population differences and/or differences in neurotoxicity etiology between induction and continuation phases of treatment.

Meduloblastoma: aspectos diferenciales entre el tumor infantil y del adulto / Differential aspects in children and adult patients with medulloblastoma

Fundamento y objetivo: El meduloblastoma es el tumor cerebral maligno más frecuente en la infancia. El objetivo de este estudio es describir datos clínicos, diagnósticos, terapéuticos, pronósticos y de supervivencia de pacientes adultos y niños con meduloblastoma. Pacientes y método: Se trata de un estudio observacional de una cohorte retrospectiva formada por todos los pacientes diagnosticados de meduloblastoma cerebral en los últimos 19 años (1989–2007) en el Hospital de Cruces del municipio de Baracaldo, Vizcaya. Resultados: Se incluyó a 37 pacientes: 20 varones y 17 mujeres, con edades comprendidas entre 1 y 48 años (edad media de 13,7 años y desviación típica de 11,4). Se encontraron diferencias significativas en la localización tumoral y en la mortalidad según diseminación inicial. Presentaron metástasis al diagnóstico 2 pacientes. La resección quirúrgica tumoral fue total en el 75% de los casos. Se observó recaída en la evolución del 59,5% de los pacientes, con afectación del líquido cefalorraquídeo en el 27%. Se detectaron secuelas en la evolución del 100% de los supervivientes, entre las que destacaron las alteraciones cerebelosas y oculares. En uno de los pacientes se diagnosticó una segunda neoplasia (meningioma y sarcoma maxilar). Se puede destacar de el presente estudio la agresividad del meduloblastoma tanto en el niño como en el adulto, con una mortalidad global del 56,8% y, a los 5 años del diagnóstico, del 48,6%. Conclusiones: Se considera necesario un tratamiento multidisciplinario y un seguimiento a largo plazo de los pacientes y de las secuelas de los supervivientes, teniendo en cuenta la posibilidad de segundas neoplasias (AU)

Background and objective: Medulloblastoma is the more frequent malignant cerebral tumor in childhood. Patients and methods: This is an observational study of a retrospective cohort in which there were included all the patients diagnosed of medulloblastoma in the last 19 years (1989–2007) in Hospital de Cruces of Baracaldo, Vizcaya, Spain. Results: There were included 37 patients, 20 men and 17 women, with ages between 1 and 48 years (average age 13.7 years with standard deviation 11.4). Tumor site and mortality according to initial dissemination were variables of statistic significance. Metastases were detected at diagnosis in two patients. The surgical resection was total in 75% of the patients. A relapse was diagnosed in the follow-up in 59.5% of the patients, with a positive spinal fluid in 27%. Sequelae were detected in 100% of the survivors, mainly with cerebellar and ocular alterations. One patient developed a meningioma and a maxillary sarcoma at the long term follow-up. It is important to emphasize the aggressiveness of medulloblastoma in both children and adults, with a global mortality of 56.8% and 48,6% at 5 years. Conclusions: It is considered necessary a multidisciplinary treatment and a long term monitoring of the patients and the sequelae of the survivors, including the possibility of second tumours (AU)

[Differential aspects in children and adult patients with medulloblastoma]. / Meduloblastoma: aspectos diferenciales entre el tumor infantil y del adulto.

BACKGROUND AND OBJECTIVE: Medulloblastoma is the more frequent malignant cerebral tumor in childhood. PATIENTS AND METHODS: This is an observational study of a retrospective cohort in which there were included all the patients diagnosed of medulloblastoma in the last 19 years (1989-2007) in Hospital de Cruces of Baracaldo, Vizcaya, Spain. RESULTS: There were included 37 patients, 20 men and 17 women, with ages between 1 and 48 years (average age 13.7 years with standard deviation 11.4). Tumor site and mortality according to initial dissemination were variables of statistic significance. Metastases were detected at diagnosis in two patients. The surgical resection was total in 75% of the patients. A relapse was diagnosed in the follow-up in 59.5% of the patients, with a positive spinal fluid in 27%. Sequelae were detected in 100% of the survivors, mainly with cerebellar and ocular alterations. One patient developed a meningioma and a maxillary sarcoma at the long term follow-up. It is important to emphasize the aggressiveness of medulloblastoma in both children and adults, with a global mortality of 56.8% and 48,6% at 5 years. CONCLUSIONS: It is considered necessary a multidisciplinary treatment and a long term monitoring of the patients and the sequelae of the survivors, including the possibility of second tumours.