Use of Eculizumab in Pediatric Patients with High-Risk Transplantation-Associated Thrombotic Microangiopathy: Outcomes and Risk Factors Associated with Response and Survival. A Retrospective Study on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC).

Transplantation-associated thrombotic microangiopathy (TA-TMA) is associated with high morbidity and mortality. Although survival has improved significantly with the introduction of eculizumab, the need for improvement remains, especially in high-risk patients. This study aimed to describe the results obtained with eculizumab in a pediatric cohort with the attempt to define which risk factors could determine the response to treatment. We designed a national multicenter retrospective study of children treated with eculizumab for high-risk TA-TMA. The study cohort comprised 29 patients who had undergone a first (n = 28) or second (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for malignant (n = 17) or nonmalignant (n = 12) disease. The median time from HSCT to TA-TMA diagnosis was 154 days (interquartile range [IQR], 103 to 263 days). Eleven patients (38%) who were initially diagnosed with low- to intermediate-risk TA-TMA progressed to high-risk TA-TMA (hrTA-TMA), within a median time of 4 days (IQR, 1 to 33 days). SC5b-9 was increased in 90% of 20 patients in whom it was measured. Renal (n = 12), pulmonary (n = 1), and intestinal (n = 1) biopsy confirmed the diagnosis in 12 of 14 patients (85%). Seventeen patients (58%) had extrarenal involvement with serositis (n = 13; 44,8%), pulmonary (n = 12; 41,4%), gastrointestinal (n = 8; 27.6%), cardiovascular (n = 7; 24.1%), or central nervous system (CNS) (n = 2; 6.9%) involvement. The median time from hrTA-TMA diagnosis to the initiation of eculizumab was 7 days (IQR, 1 to 8 days). Overall, 19 patients (65.5%) responded to eculizumab, of whom 17 (58.6%) achieved a complete response and 2 (6.9%) achieved a partial response. The remaining 10 patients (34.5%) did not show any of response. The overall response rate to eculizumab for TA-TMA was 27.59% (95% confidence interval [CI], 14.87% to 47.66%) at 1 month, 55.17% (95% CI, 38.43% to 73.48%) at 3 months, and 62.07% (95% CI, 45.10% to 79.13%) at 6 months after eculizumab initiation. In multivariate analysis, the pulmonary involvement decreased the probability of response (hazard ratio [HR], .18; P = .0298). The 1-year overall survival (OS) was 55.2% (95% CI, 35.6% to 71.0%) for the whole cohort and 83.3% (95% CI, 56.7% to 94.3%) for patients who responded to eculizumab. Pulmonary involvement (HR, 14.93; P = .0043) and CNS involvement (HR, 8.63; P = .0497) were associated with a statistically significant decrease in survival. We found that patients diagnosed with hrTA-TMA with pulmonary involvement had a poor response to eculizumab, and that patients with pulmonary and CNS involvement had significantly decreased survival. Given these results, we hypothesize that providing eculizumab therapy at an early stage of the disease before organ damage is established might significantly improve the response and, consequently, survival.

Utilidad de los índices celulares y el índice neutrófilo/linfocito derivado en el diagnóstico de la apendicitis aguda pediátrica / Usefulness of cell ratios and the derived neutrophil- to-lymphocyte ratio in the diagnosis of pediatric acute appendicitis

Objetivo: Analizar la precisión de los índices celulares en el diagnóstico de la apendicitis aguda pediátrica, introduciendo uno nuevo, el índice neutrófilo/linfocito derivado (INLd). Material y métodos: Estudio retrospectivo observacional de los pacientes de 0-15 años diagnosticados de apendicitis aguda (AA) y con dolor abdominal no quirúrgico (DA) tratados en nuestro centro entre 2021-2022. Se comparó el índice neutrófilo/linfocito (INL), índice monocito/linfocito (IML), índice plaqueta/linfocito (IPL) y el INLd entre los grupos. Resultados: Se incluyeron 98 casos con AA (30% mujeres, edad 10 ± 3,3 años) y 97 pacientes con DA (53% hombres, edad 9,3 ± 3,7 años). Los valores de INL, IML, IPL e INLd fueron mayores en pacientes con AA respecto a niños con DA: 9,6 rango intercuartil (RIC) 9,5 vs. 3,3 RIC 5,3: p = < 0,0001; 0,7 RIC 0,6 vs. 0,46 RIC 0,7: p = < 0,023; 199,8 RIC 163,9 vs. 134,0 RIC 129,2: p = < 0,0001; y 5,29 RIC 3,9 vs. 2,39 RIC 2,7: p = < 0,0001; respectivamente. La sensibilidad, especificidad, valor predictivo positivo-negativo, área bajo la curva ROC y el punto de corte del INLd para el diagnóstico de AA fue de 70%, 78%, 77-72%, 0,811 y 3,98; respectivamente. Conclusiones. Los índices celulares son parámetros inflamatorios útiles y coste-efectivos que pueden contribuir al diagnóstico de la apendicitis aguda pediátrica. Los resultados de este estudio sugieren que el INLd es el de mayor precisión clínica.(AU)

Objective: To analyze the accuracy of cell ratios in the diagnosis of pediatric acute appendicitis while introducing a new one – the derived neutrophil-to-lymphocyte ratio (dNLR). Materials and methods: An observational, retrospective study of patients aged 0-15 years old diagnosed with acute appendicitis (AA) and with non-surgical abdominal pain (AP) treated in our institution from 2021 to 2022 was carried out. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and dNLR were compared between groups. Results. 98 AA patients (30% of whom were female; age: 10 ± 3.3 years) and 97 AP patients (53% of whom were male; age: 9.3 ± 3.7 years) were included. NLR, MLR, PLR, and dNLR values were higher in AA patients than in AP patients: 9.6 IQR (interquartile range) 9.5 vs. 3.3 IQR 5.3: p < 0.0001; 0.7 IQR 0.6 vs. 0.46 IQR 0.7: p < 0.023; 199.8 IQR 163.9 vs. 134.0 IQR 129.2: p < 0.0001; and 5.29 IQR 3.9 vs. 2.39 IQR 2.7; p < 0.0001, respectively. Sensitivity, specificity, positive-negative predictive value, area under the ROC curve, and dNLR cut-off point for AA diagnosis were 70%, 78%, 77-72%, 0.811, and 3.98, respectively. Conclusions. Cell ratios are useful and cost-effective inflammatory parameters in the diagnosis of pediatric acute appendicitis. The results of this study suggest dNLR has the greatest clinical accuracy.(AU)

Asociaciones infrecuentes de la cutis marmorata telangiectásica congénita: reporte de dos casos / Infrequent associations of cutis marmorata telangiectatica congenita: a two-case report

Introducción: La cutis marmorata telangiectásica congénita (CMTC) es una rara malformación capilar caracterizada por eritema reticular y violáceo persistente. Presentamos dos casos de CMTC. Observación clínica: Un varón de 13 meses presentaba una mácula violácea reticular en glúteo izquierdo y una pápula parduzca con signo de Darier en el maléolo interno del pie izquierdo, que fue biopsiada identificando > 15 mastocitos/campo, con lo cual se diagnosticó de CMTC y mastocitoma cutáneo solitario. El segundo caso, una recién nacida con una lesión característica de CMTC sin otras malformaciones al nacer, que durante el seguimiento desarrolló dos tumoraciones cutáneas compatibles con hemangiomas infantiles. Comentarios. La CMTC es una condición benigna, sin embargo, aproximadamente el 50% de los casos presentan anomalías asociadas. Ante la sospecha de CMTC se deben descartar malformaciones musculoesqueléticas, oftalmológicas y cutáneas. Hasta donde tenemos conocimiento, este es el primer reporte de CMTC asociada con mastocitoma y uno de los pocos con hemangioma infantil.(AU)

Introduction: Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterized by persistent reticular and violaceous erythema. We present two cases of CMTC. Clinical observation: The first case involved a 13-month-old male with a reticular violaceous macule on the left gluteal region and a brownish papule with Darier’s sign on the inner malleolus of the left foot, which was biopsied, revealing > 15 mast cells per field, leading to a diagnosis of CMTC and solitary cutaneous mastocytoma. The secondcase involved a newborn with a characteristic CMTC lesion without other malformations at birth, who subsequently developed two cutaneous tumors consistent with infantile hemangiomas during follow-up. Discussion. CMTC is a benign condition. However, approximately 50% of cases exhibit associated anomalies. When CMTC is suspected, musculoskeletal, ophthalmological, and cutaneous malformations should be ruled out. To the best of our knowledge, this is the first report of CMTC associated with mastocytoma and one of the few cases associated with infantile hemangioma.(AU)

Usefulness of cell ratios and the derived neutrophil-to-lymphocyte ratio in the diagnosis of pediatric acute appendicitis. / Utilidad de los índices celulares y el índice neutrófilo/linfocito derivado en el diagnóstico de la apendicitis aguda pediátrica.

OBJECTIVE: To analyze the accuracy of cell ratios in the diagnosis of pediatric acute appendicitis while introducing a new one -the derived neutrophil-to-lymphocyte ratio (dNLR). MATERIALS AND METHODS: An observational, retrospective study of patients aged 0-15 years old diagnosed with acute appendicitis (AA) and with non-surgical abdominal pain (AP) treated in our institution from 2021 to 2022 was carried out. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and dNLR were compared between groups. RESULTS: 98 AA patients (30% of whom were female; age: 10 ± 3.3 years) and 97 AP patients (53% of whom were male; age: 9.3 ± 3.7 years) were included. NLR, MLR, PLR, and dNLR values were higher in AA patients than in AP patients: 9.6 IQR (interquartile range) 9.5 vs. 3.3 IQR 5.3: p< 0.0001; 0.7 IQR 0.6 vs. 0.46 IQR 0.7: p< 0.023; 199.8 IQR 163.9 vs. 134.0 IQR 129.2: p< 0.0001; and 5.29 IQR 3.9 vs. 2.39 IQR 2.7; p< 0.0001, respectively. Sensitivity, specificity, positive-negative predictive value, area under the ROC curve, and dNLR cut-off point for AA diagnosis were 70%, 78%, 77-72%, 0.811, and 3.98, respectively. CONCLUSIONS: Cell ratios are useful and cost-effective inflammatory parameters in the diagnosis of pediatric acute appendicitis. The results of this study suggest dNLR has the greatest clinical accuracy.

OBJETIVOS: Analizar la precisión de los índices celulares en el diagnóstico de la apendicitis aguda pediátrica, introduciendo uno nuevo, el índice neutrófilo/linfocito derivado (INLd). MATERIAL Y METODOS: Estudio retrospectivo observacional de los pacientes de 0-15 años diagnosticados de apendicitis aguda (AA) y con dolor abdominal no quirúrgico (DA) tratados en nuestro centro entre 2021-2022. Se comparó el índice neutrófilo/linfocito (INL), índice monocito/linfocito (IML), índice plaqueta/linfocito (IPL) y el INLd entre los grupos. RESULTADOS: Se incluyeron 98 casos con AA (30% mujeres, edad 10 ± 3,3 años) y 97 pacientes con DA (53% hombres, edad 9,3 ± 3,7 años). Los valores de INL, IML, IPL e INLd fueron mayores en pacientes con AA respecto a niños con DA: 9,6 rango intercuartil (RIC) 9,5 vs. 3,3 RIC 5,3: p< 0,0001; 0,7 RIC 0,6 vs. 0,46 RIC 0,7: p< 0,023; 199,8 RIC 163,9 vs. 134,0 RIC 129,2: p< 0,0001; y 5,29 RIC 3,9 vs. 2,39 RIC 2,7: p< 0,0001; respectivamente. La sensibilidad, especificidad, valor predictivo positivo-negativo, área bajo la curva ROC y el punto de corte del INLd para el diagnóstico de AA fue de 70%, 78%, 77-72%, 0,811 y 3,98; respectivamente. CONCLUSIONES: Los índices celulares son parámetros inflamatorios útiles y coste-efectivos que pueden contribuir al diagnóstico de la apendicitis aguda pediátrica. Los resultados de este estudio sugieren que el INLd es el de mayor precisión clínica.

Infrequent associations of cutis marmorata telangiectatica congenita: a two-case report. / Asociaciones infrecuentes de la cutis marmorata telangiectásica congénita: reporte de dos casos.

INTRODUCTION: Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterized by persistent reticular and violaceous erythema. We present two cases of CMTC. CLINICAL OBSERVATION: The first case involved a 13-month-old male with a reticular violaceous macule on the left gluteal region and a brownish papule with Darier's sign on the inner malleolus of the left foot, which was biopsied, revealing > 15 mast cells per field, leading to a diagnosis of CMTC and solitary cutaneous mastocytoma. The second case involved a newborn with a characteristic CMTC lesion without other malformations at birth, who subsequently developed two cutaneous tumors consistent with infantile hemangiomas during follow-up. DISCUSSION: CMTC is a benign condition. However, approximately 50% of cases exhibit associated anomalies. When CMTC is suspected, musculoskeletal, ophthalmological, and cutaneous malformations should be ruled out. To the best of our knowledge, this is the first report of CMTC associated with mastocytoma and one of the few cases associated with infantile hemangioma.

INTRODUCCION: La cutis marmorata telangiectásica congénita (CMTC) es una rara malformación capilar caracterizada por eritema reticular y violáceo persistente. Presentamos dos casos de CMTC. OBSERVACION CLINICA: Un varón de 13 meses presentaba una mácula violácea reticular en glúteo izquierdo y una pápula parduzca con signo de Darier en el maléolo interno del pie izquierdo, que fue biopsiada identificando > 15 mastocitos/campo, con lo cual se diagnosticó de CMTC y mastocitoma cutáneo solitario. El segundo caso, una recién nacida con una lesión característica de CMTC sin otras malformaciones al nacer, que durante el seguimiento desarrolló dos tumoraciones cutáneas compatibles con hemangiomas infantiles. COMENTARIOS: La CMTC es una condición benigna, sin embargo, aproximadamente el 50% de los casos presentan anomalías asociadas. Ante la sospecha de CMTC se deben descartar malformaciones musculoesqueléticas, oftalmológicas y cutáneas. Hasta donde tenemos conocimiento, este es el primer reporte de CMTC asociada con mastocitoma y uno de los pocos con hemangioma infantil.

Single-port transumbilical pediatric cholecystectomy: any benefits for the patient? / Colecistectomía pediátrica por puerto único transumbilical: ¿aporta algo al paciente?

OBJECTIVE: To compare the perioperative results of single-port laparoscopic cholecystectomy (SPLC) with those of laparoscopic cholecystectomy (LC), and to analyze whether there were any differences between both techniques in our patients. MATERIALS AND METHODS: A retrospective, observational analysis was carried out in non-homogeneous groups of patients under 15 years of age undergoing LC and SPLC over a 6-year period. LC was conducted using four ports, while SPLC was performed through an umbilical incision using a wound retractor to which a surgical glove was coupled for the insertion of 3 ports and instruments curved as required. 15 clinical, surgical, and economic variables were compared by means of a univariate and bivariate analysis. RESULTS: 11 patients underwent surgery - 5 through SPLC and 6 through LC. No significant differences were found in terms of mean operating time (SPLC: 144 minutes vs. LC: 139, P= 0.855) or hospital stay, but a slight increase in hospital cost was noted (SPLC: 1,160 € vs. LC: 1,177 €). The cost of LC was 1,322 € vs. 1,367 € for SPLC, with a premium of 44.30 € owing to the use of the wound retractor. None of the patients had perioperative complications, and all of them felt the cosmetic result was excellent. CONCLUSIONS: In our limited experience, the differences between SPLC and LC do not clearly support one or the other. SPLC could provide patients with a better cosmetic result and allow surgeons to improve their skills. However, we believe cholecystectomy is not the most adequate procedure to start a career in single-port laparoscopy because potential complications may be severe.

OBJETIVO: Comparar los resultados perioperatorios de la colecistectomía laparoscópica por puerto único (CLPU) respecto a la colecistectomía laparoscópica (CL) y analizar si, en nuestra casuistica, existen diferencias entre estas tecnicas. MATERIAL Y METODO: Análisis retrospectivo y observacional en grupos no homogeneos de pacientes menores de 15 años sometidos a CL y CLPU durante un periodo de 6 años. La CL se realizó con cuatro puertos y la CLPU mediante una incisión umbilical y colocación de un retractor de heridas al que se acopló un guante quirúrgico, a través del cual se insertaron 3 trócares para el instrumental convenientemente curvado. Se compararon 15 variables clínicas, quirúrgicas y económicas mediante análisis univariado y bivariado. RESULTADOS: Fueron intervenidos 11 pacientes, cinco mediante CLPU y 6 por CL. No hubo diferencias significativas en el tiempo operatorio medio (CLPU: 144 minutos vs. CL: 139, P= 0,855) ni en estancia hospitalaria, aunque sí un ligero aumento del coste hospitalario (CLPU:1.160 €, CL:1.177 €). El coste de la CL fue de 1.322 € frente a 1.367 de la CLPU, con un sobreprecio de +44,30 € debido al uso del retractor de heridas. Ningún paciente presentó complicaciones perioperatorias y todos percibían un resultado cosmético excelente. CONCLUSIONES: Las diferencias entre CLPU y CL, en nuestra reducida experiencia, no justifican decidirse claramente por una u otra técnica. La CLPU podría aportar al paciente un mejor resultado cosmético y al cirujano una mejora de sus habilidades, aunque creemos que la colecistectomía no es la intervención adecuada para iniciarse en laparoscopia por puerto único debido a la gravedad de las posibles complicaciones.

Colecistectomía pediátrica por puerto único transumbilical: ¿aporta algo al paciente? / Single-port transumbilical pediatric cholecystectomy: any benefits for the patient?

Objetivo: Comparar los resultados perioperatorios de la colecistectomía laparoscópica por puerto único (CLPU) respecto a la colecistectomía laparoscópica (CL) y analizar si, en nuestra casuistica, existendiferencias entre estas tecnicas. Material y métodos: Análisis retrospectivo y observacional engrupos no homogeneos de pacientes menores de 15 años sometidos aCL y CLPU durante un periodo de 6 años. La CL se realizó con cuatropuertos y la CLPU mediante una incisión umbilical y colocación deun retractor de heridas al que se acopló un guante quirúrgico, a travésdel cual se insertaron 3 trócares para el instrumental convenientementecurvado. Se compararon 15 variables clínicas, quirúrgicas y económicasmediante análisis univariado y bivariado. Resultados: Fueron intervenidos 11 pacientes, cinco medianteCLPU y 6 por CL. No hubo diferencias significativas en el tiempooperatorio medio (CLPU: 144 minutos vs. CL: 139, P= 0,855) ni enestancia hospitalaria, aunque sí un ligero aumento del coste hospitalario(CLPU:1.160 €, CL:1.177 €). El coste de la CL fue de 1.322 € frentea 1.367 de la CLPU, con un sobreprecio de +44,30 € debido al uso delretractor de heridas. Ningún paciente presentó complicaciones perioperatorias y todos percibían un resultado cosmético excelente. Conclusiones: Las diferencias entre CLPU y CL, en nuestra reduci-da experiencia, no justifican decidirse claramente por una u otra técnica.La CLPU podría aportar al paciente un mejor resultado cosmético y alcirujano una mejora de sus habilidades, aunque creemos que la colecistectomía no es la intervención adecuada para iniciarse en laparoscopiapor puerto único debido a la gravedad de las posibles complicaciones.(AU)

Objective: To compare the perioperative results of single-portlaparoscopic cholecystectomy (SPLC) with those of laparoscopic cholecystectomy (LC), and to analyze whether there were any differencesbetween both techniques in our patients. Materials and methods: A retrospective, observational analysis wascarried out in non-homogeneous groups of patients under 15 years ofage undergoing LC and SPLC over a 6-year period. LC was conductedusing four ports, while SPLC was performed through an umbilical incision using a wound retractor to which a surgical glove was coupled forthe insertion of 3 ports and instruments curved as required. 15 clinical,surgical, and economic variables were compared by means of a univariate and bivariate analysis. Results: 11 patients underwent surgery – 5 through SPLC and 6through LC. No significant differences were found in terms of meanoperating time (SPLC: 144 minutes vs. LC: 139, P= 0.855) or hospitalstay, but a slight increase in hospital cost was noted (SPLC: 1,160 € vs.LC: 1,177 €). The cost of LC was 1,322 € vs. 1,367 € for SPLC, witha premium of 44.30 € owing to the use of the wound retractor. Noneof the patients had perioperative complications, and all of them felt thecosmetic result was excellent. Conclusions: In our limited experience, the differences betweenSPLC and LC do not clearly support one or the other. SPLC couldprovide patients with a better cosmetic result and allow surgeons toimprove their skills. However, we believe cholecystectomy is not themost adequate procedure to start a career in single-port laparoscopybecause potential complications may be severe.(AU)

First Reported Case of Malignant Ectomesenchymoma with p.Leu122Arg Mutation in MYOD1 Gene: Extensive Intra- and Extracranial Tumor in a 15-Year-Old Female.

BACKGROUND: Ectomesenchymomas (EMs) are extremely rare neoplasms composed of malignant mesenchymal components and neuroectodermal derivatives. They are described in a wide variety of locations, with the head and neck region being one of the most frequently involved areas. EMs are usually managed as high-risk rhabdomyosarcomas and have similar outcomes. METHODS: We present the case of a 15-year-old female with an EM that arose in the parapharyngeal space and extended into the intracranial space. RESULTS: Histologically, the tumor presented an embryonal rhabdomyosarcomatous mesenchymal component and the neuroectodermal component was constituted by isolated ganglion cells. Next-generation sequencing (NGS) revealed a p.Leu122Arg (c.365 T > G) mutation in the MYOD1 gene, a p.Ala34Gly mutation in the CDKN2A gene, and CDK4 gene amplification. The patient was treated with chemotherapy. She died 17 months after the debut of symptoms. CONCLUSION(S): To our knowledge, this is the first reported case in English literature of an EM with this MYOD1 mutation. We suggest combining PI3K/ATK pathway inhibitors in these cases. NGS should be performed in EMs cases to detect mutations with potential treatment options.

Pediatric thyroidectomy in a "low volume" institution without protocolization: results and future horizons. / Tiroidectomía pediátrica en un centro de "bajo volumen" y sin protocolización: resultados y horizontes.

OBJECTIVE: Pediatric thyroidectomy is an infrequent, complex surgery, with high risk of complications. Complication rates and oncological results of non-protocolized thyroidectomy in a secondary pediatric hospital were compared with those from reference institutions. MATERIALS AND METHODS: A retrospective study of patients under 15 years old undergoing thyroidectomy ± cervical lymphadenectomy by low volume pediatric surgeons (<30 cervical endocrine surgeries annually) in a pediatric hospital from January 2010 to January 2020 was carried out. RESULTS: 11 patients undergoing 12 surgeries (mean age: 9.8 years; 63% female) were analyzed. Thyroid nodules were the main surgical indication (50%), and prevalence of genetic mutations was 45%. 1 patient had transient hypocalcemia, and there were 2 cases of transient recurrent laryngeal nerve neuropraxia (16.6%). No permanent complications were noted. 66.6% of pathological reports showed malignancy. Mean hospital stay was 2.35 days (range: 1.25-5), with an overall complication rate of 25%, similar to that reported by high-volume institutions. After a mean follow-up of 4 years, tumor recurrence has not been observed in any patient. CONCLUSIONS: In our view, an experienced pediatric surgeon specialized in pediatric and neonatal general surgery - even if below the high volume threshold - acquires the skills required in pediatric thyroid surgery without an increase in morbidity and mortality. Perioperative management should be agreed and protocolized by the various specialists involved to improve results.

OBJETIVOS: La tiroidectomía pediátrica es una intervención infrecuente, compleja y con un riesgo elevado de complicaciones. Se evalúa la tasa de complicaciones y resultados oncológicos de la tiroidectomía no protocolizada en un hospital infantil de segundo nivel en comparación con los centros de referencia. MATERIAL Y METODOS: Estudio retrospectivo de los pacientes menores de 15 años sometidos a tiroidectomía ± disección ganglionar cervical por cirujanos pediátricos de bajo volumen (< 30 cirugías endocrinas cervicales/año) entre enero de 2010 y enero de 2020 en un hospital infantil. RESULTADOS: Se analizaron once pacientes sometidos a 12 procedimientos quirúrgicos (edad media 9,8 años, 63% niñas). Los nódulos tiroideos fueron la principal indicación quirúrgica (50%) y la prevalencia de mutaciones genéticas en la serie fue del 45%. Un paciente presentó hipocalcemia transitoria y hubo 2 casos de neuropraxia transitoria del nervio laríngeo recurrente (16,6%). No hubo complicaciones permanentes. El 66,6% de los informes anatomopatológicos mostraron malignidad. La estancia hospitalaria media fue de 2,35 días (rango 1,25-5) con una tasa global de complicaciones del 25%, similar a la reportada por centros de alto volumen. Después de un seguimiento medio de 4 años, ningún paciente ha presentado recidiva tumoral. CONCLUSIONES: Sugerimos que un cirujano infantil con experiencia en cirugía pediátrica general y neonatal, a pesar de no superar el umbral de alto volumen, adquiere las facultades para realizar la cirugía tiroidea pediátrica sin aumento de morbilidad y mortalidad. El manejo perioperatorio debe ser consensuado entre los diversos especialistas involucrados y protocolizado para mejorar los resultados.

Tiroidectomía pediátrica en un centro de “bajo volumen” y sin protocolización: resultados y horizontes / Pediatric thyroidectomy in a “low volume” institution without protocolization: results and future horizons

Objetivos: La tiroidectomía pediátrica es una intervención infre-cuente, compleja y con un riesgo elevado de complicaciones. Se evalúala tasa de complicaciones y resultados oncológicos de la tiroidectomía noprotocolizada en un hospital infantil de segundo nivel en comparacióncon los centros de referencia. Material y métodos: Estudio retrospectivo de los pacientes menoresde 15 años sometidos a tiroidectomía ± disección ganglionar cervical porcirujanos pediátricos de bajo volumen (< 30 cirugías endocrinas cervi-cales/año) entre enero de 2010 y enero de 2020 en un hospital infantil. Resultados: Se analizaron once pacientes sometidos a 12 proce-dimientos quirúrgicos (edad media 9,8 años, 63% niñas). Los nódulostiroideos fueron la principal indicación quirúrgica (50%) y la prevalenciade mutaciones genéticas en la serie fue del 45%. Un paciente presentóhipocalcemia transitoria y hubo 2 casos de neuropraxia transitoria delnervio laríngeo recurrente (16,6%). No hubo complicaciones permanen-tes. El 66,6% de los informes anatomopatológicos mostraron malignidad.La estancia hospitalaria media fue de 2,35 días (rango 1,25-5) con unatasa global de complicaciones del 25%, similar a la reportada por centrosde alto volumen. Después de un seguimiento medio de 4 años, ningúnpaciente ha presentado recidiva tumoral. Conclusiones: Sugerimos que un cirujano infantil con experienciaen cirugía pediátrica general y neonatal, a pesar de no superar el umbralde alto volumen, adquiere las facultades para realizar la cirugía tiroideapediátrica sin aumento de morbilidad y mortalidad. El manejo periopera-torio debe ser consensuado entre los diversos especialistas involucradosy protocolizado para mejorar los resultados.(AU)

Objective: Pediatric thyroidectomy is an infrequent, complex sur-gery, with high risk of complications. Complication rates and oncolog-ical results of non-protocolized thyroidectomy in a secondary pediatrichospital were compared with those from reference institutions. Materials and methods: A retrospective study of patients under15 years old undergoing thyroidectomy ± cervical lymphadenectomyby low volume pediatric surgeons (<30 cervical endocrine surgeriesannually) in a pediatric hospital from January 2010 to January 2020was carried out. Results: 11 patients undergoing 12 surgeries (mean age: 9.8 years;63% female) were analyzed. Thyroid nodules were the main surgical in-dication (50%), and prevalence of genetic mutations was 45%. 1 patienthad transient hypocalcemia, and there were 2 cases of transient recurrentlaryngeal nerve neuropraxia (16.6%). No permanent complications werenoted. 66.6% of pathological reports showed malignancy. Mean hospitalstay was 2.35 days (range: 1.25-5), with an overall complication rateof 25%, similar to that reported by high-volume institutions. After amean follow-up of 4 years, tumor recurrence has not been observedin any patient. Conclusions: In our view, an experienced pediatric surgeon spe-cialized in pediatric and neonatal general surgery – even if below thehigh volume threshold – acquires the skills required in pediatric thyroidsurgery without an increase in morbidity and mortality. Perioperative management should be agreed and protocolized by the various specialistsinvolved to improve results.(AU)

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.

A phase I/II dose-escalation multi-center study to evaluate the safety of infusion of natural killer cells or memory T cells as adoptive therapy in coronavirus pneumonia and/or lymphopenia: RELEASE study protocol.

BACKGROUND: Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state. This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19. METHODS: In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC. In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC. DISCUSSION: We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578210 . First Posted : October 8, 2020.

Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE).

BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Abdominal hernia repair using the Rives-Stoppa technique: an abdominal reconstruction. / Eventroplastia abdominal con técnica de Rives-Stoppa: reconstruyendo un abdomen.

INTRODUCTION: Retromuscular mesh hernia repair using Rives-Stoppa technique has demonstrated the best results when it comes to repairing large midline hernias. We present the first pediatric case successfully treated with this technique. CLINICAL CASE: This is the case of a 9-year-old male patient with hernia following urgent midline laparotomy. Basic repair principles included opening of the hernia sac and adhesiolysis, longitudinal incision on the posterior sheath of the rectus muscle and division of the retromuscular space, closure of the posterior sheath, placement of a mesh on this plane in the brand-new retromuscular space, and tension-free closure of the anterior musculo-aponeurotic flap, thus reconstructing the midline. No recurrences have been noted after a 2-year follow-up. DISCUSSION: Rives-Stoppa technique allows for a more anatomical layered reconstruction, which helps restore the anatomical and physiological properties of the abdominal wall. In our view, this could be a useful alternative for pediatric hernia treatment.

INTRODUCCION: La eventroplastia con malla retromuscular de Rives-Stoppa ha demostrado en adultos tener los mejores resultados en la reparación de las grandes eventraciones de la línea media. Presentamos el primer caso pediátrico tratado exitosamente con esta técnica. CASO CLINICO: Varón de 9 años con eventración tras laparotomía media urgente. Los principios básicos de la corrección fueron: apertura del saco herniario y adhesiolisis, incisión longitudinal sobre la vaina posterior del músculo recto y tallado del espacio retromuscular, cierre de la vaina posterior, colocación de una malla sobre este plano alojándola en el espacio retromuscular creado y cierre sin tensión del colgajo musculo-aponeurótico anterior, reconstruyendo así la línea media. No recidiva tras 2 años de seguimiento. COMENTARIOS: La técnica de Rives-Stoppa implica una reconstrucción por planos más anatómica que restaura las propiedades anatomofisiológicas de la pared abdominal. Consideramos que puede ser una alternativa útil en el tratamiento de las eventraciones pediátricas.

Eventroplastia abdominal con técnica de Rives-Stoppa: reconstruyendo un abdomen / Abdominal hernia repair using the Rives-Stoppa technique: an abdominal reconstruction

Introducción: La eventroplastia con malla retromuscular de Rives-Stoppa ha demostrado en adultos tener los mejores resultados en lareparación de las grandes eventraciones de la línea media. Presentamosel primer caso pediátrico tratado exitosamente con esta técnica. Caso clínico: Varón de 9 años con eventración tras laparotomíamedia urgente. Los principios básicos de la corrección fueron: aperturadel saco herniario y adhesiolisis, incisión longitudinal sobre la vainaposterior del músculo recto y tallado del espacio retromuscular, cierrede la vaina posterior, colocación de una malla sobre este plano aloján-dola en el espacio retromuscular creado y cierre sin tensión del colgajomusculo-aponeurótico anterior, reconstruyendo así la línea media. Norecidiva tras 2 años de seguimiento. Comentarios: La técnica de Rives-Stoppa implica una reconstruc-ción por planos más anatómica que restaura las propiedades anatomo-fisiológicas de la pared abdominal. Consideramos que puede ser unaalternativa útil en el tratamiento de las eventraciones pediátricas.(AU)

Introduction: Retromuscular mesh hernia repair using Rives-Stoppatechnique has demonstrated the best results when it comes to repairinglarge midline hernias. We present the first pediatric case successfullytreated with this technique. Clinical case: This is the case of a 9-year-old male patient with her-nia following urgent midline laparotomy. Basic repair principles includedopening of the hernia sac and adhesiolysis, longitudinal incision on the posterior sheath of the rectus muscle and division of the retromuscularspace, closure of the posterior sheath, placement of a mesh on this planein the brand-new retromuscular space, and tension-free closure of theanterior musculo-aponeurotic flap, thus reconstructing the midline. Norecurrences have been noted after a 2-year follow-up. Discussion: Rives-Stoppa technique allows for a more anatomicallayered reconstruction, which helps restore the anatomical and physi-ological properties of the abdominal wall. In our view, this could be auseful alternative for pediatric hernia treatment.(AU)

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.

Genetic predisposition to fetal and neonatal cancer

Background Neonatal tumors represent an extremely rare and heterogeneous disease with an unknown etiology. Due to its early onset, it has been proposed that genetic factors could play a critical role; however, germline genetic analysis is not usually performed in neonatal cancer patients Patients and methods To improve the identification of cancer genetic predisposition syndromes, we retrospectively review clinical characteristics in 45 patients with confirmed tumor diagnosis before 28 days of age, and we carried out germline genetic analysis in 20 patients using next-generation sequencing and directed sequencing. Results The genetic studies did not find any germline mutation except patients diagnosed with bilateral retinoblastoma who harbored RB1 germline mutations. Conclusions Our results suggest that genetic factors have almost no higher impact in most neonatal tumors. However, since the heterogeneity of the tumors and the small sample size analyzed, we recommend complementary and centralized germline studies to discard the early onset as an additional criterion to take into account to improve the identification of cancer genetic predisposition syndromes in neonates (AU)

[Cranio-facial-cervical and subglottic hemangioma with respiratory symptoms. A therapeutic emergency].

We describe the case of a 41-day-old infant with a left craniofacial cervical and subglottic hemangioma with respira-tory symptoms. Although infantile hemangiomas are occasional benign vascular tumors that appear predominantly on the skin, 1-2% of patients may have airway lesions that can sometimes cause potentially life-threatening respiratory condi-tions. The decision was made to immediately commence treatment with propranolol, without waiting to complete the exten-sion and syndromic diagnoses. There was a positive clinical response and respiratory symptoms dissipated in twelve hours. Early treatment with beta-blockers is essential for children with hemangiomas whose location causes symptoms or significant functional changes: in some cases it may be a matter of urgency.

Hemangioma cráneo-facio-cervical y subglótico con clínica respiratoria. Una urgencia terapéutica / Cranio-facial-cervical and subglottic hemangioma with respiratory symptoms. A therapeutic emergency

Se describe el caso de una lactante de 41 días de vida con un hemangioma cráneo-facio-cervical izquierdo y subglótico con repercusión respiratoria. Aunque los hemangiomas infantiles son tumores vasculares benignos que se presentan predominantemente en piel y de forma aislada, un 1-2% de los pacientes pueden tener lesiones en la vía aérea que ocasionalmente provocan cuadros respiratorios potencialmente mortales. Se decidió iniciar inmediatamente el tratamiento con propranolol, sin esperar a completar el diagnóstico de extensión y sindrómico, con buena respuesta clínica y desaparición de la sintomatología respiratoria en las siguientes doce horas. En los niños con hemangiomas que por su localización produzcan síntomas o alteración funcional importante, es imprescindible iniciar el tratamiento betabloqueante de forma precoz y en algunos casos, urgentemente

We describe the case of a 41-day-old infant with a left craniofacial cervical and subglottic hemangioma with respiratory symptoms. Although infantile hemangiomas are occasional benign vascular tumors that appear predominantly on the skin, 1-2% of patients may have airway lesions that can sometimes cause potentially life-threatening respiratory conditions. The decision was made to immediately commence treatment with propranolol, without waiting to complete the extension and syndromic diagnoses. There was a positive clinical response and respiratory symptoms dissipated in twelve hours. Early treatment with beta-blockers is essential for children with hemangiomas whose location causes symptoms or significant functional changes: in some cases it may be a matter of urgency

SARS-CoV-2-Specific Memory T Lymphocytes From COVID-19 Convalescent Donors: Identification, Biobanking, and Large-Scale Production for Adoptive Cell Therapy.

Syndrome coronavirus 2 (SARS-CoV-2) pandemic is causing a second outbreak significantly delaying the hope for the virus' complete eradication. In the absence of effective vaccines, we need effective treatments with low adverse effects that can treat hospitalized patients with COVID-19 disease. In this study, we determined the existence of SARS-CoV-2-specific T cells within CD45RA- memory T cells in the blood of convalescent donors. Memory T cells can respond quickly to infection and provide long-term immune protection to reduce the severity of COVID-19 symptoms. Also, CD45RA- memory T cells confer protection from other pathogens encountered by the donors throughout their life. It is of vital importance to resolve other secondary infections that usually develop in patients hospitalized with COVID-19. We found SARS-CoV-2-specific memory T cells in all of the CD45RA- subsets (CD3+, CD4+, and CD8+) and in the central memory and effector memory subpopulations. The procedure for obtaining these cells is feasible, easy to implement for small-scale manufacture, quick and cost-effective, involves minimal manipulation, and has no GMP requirements. This biobank of specific SARS-CoV-2 memory T cells would be immediately available "off-the-shelf" to treat moderate/severe cases of COVID-19, thereby increasing the therapeutic options available for these patients.