Rhabdoid tumors in patients conceived following ART: is there an association?

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Hematuria asintomática como manifestación del tumor de Wilms botrioide / Asymptomatic haematuria as a sign of a botyroid Wilms tumour

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Tumor de Wilms: revisión de nuestra experiencia en los últimos 15 años / Wilms' tumour: A review of 15 years recent experience

Introducción: El tumor de Wilms es el tumor renal más frecuente en la edad pediátrica. Su tratamiento es multimodal: incluye quimioterapia y cirugía, con o sin radioterapia. La supervivencia de estos pacientes es excelente, superando el 90%. Presentamos la experiencia de nuestro centro en el tratamiento del tumor de Wilms durante los últimos 15 años. Pacientes y métodos: Se ha realizado un estudio retrospectivo de 40 pacientes pediátricos diagnosticados de forma consecutiva de nefroblastoma entre 2002 y 2016 en el Servicio de Hemato-Oncología pediátrica del Hospital Niño Jesús de Madrid. Se analizaron las características clínicas, los métodos diagnósticos, el tratamiento realizado y la evolución posterior. Resultados: De los 40 pacientes, 23 eran niños con una mediana de edad al diagnóstico de 2,5 años (rango, 4 meses-15 años). A 3 pacientes se les realizó nefrectomía inicial, 3 recibieron una punción aspiración con agua fina, seguida de quimioterapia y 34 pacientes recibieron quimioterapia preoperatoria directamente. La mediana de seguimiento de los pacientes fue de 6,75 años (rango, 10 meses-13,92 años). Dos pacientes fallecieron de progresión de su enfermedad. Ningún paciente falleció de toxicidad en relación con el tratamiento. La supervivencia global y la supervivencia libre de evento a los 5 años fue del 94,6 ± 3,7% y 89,4 ± 5%, respectivamente. Conclusión: El tratamiento del tumor de Wilms es un éxito de la medicina moderna, consiguiendo en la actualidad una supervivencia que en nuestra serie alcanza el 95% (AU)

Introduction: Wilms' tumour is the most frequent renal tumour in children. Multi-modal treatment includes chemotherapy and surgery, with or without radiotherapy. The survival is excellent, with rates exceeding 90%. A review is presented on our experience over the last 15 years of treating Wilms' tumour in Hospital Niño Jesús, Madrid. Patients and methods: A retrospective study was conducted on 40 consecutive paediatric patients diagnosed with nephroblastoma between 2002 and 2016 in the Hospital Niño Jesús in Madrid. The clinical characteristics, diagnostic methods, treatment, and follow-up were analysed. Results: Of the 40 patients, 23 were boys, with a median age at diagnosis of 2.5 years (range, 4 months-15 years). Three patients underwent initial nephrectomy, three received a fine needle aspiration biopsy, followed by chemotherapy, and 34 patients started pre-operative chemotherapy directly. The median follow-up of the patients was 6.75 years (range, 10 months - 13.92 years). Two patients died from disease progression. There were no treatment-related deaths. Overall survival and event-free survival at 5 years was 94.6 ± 3.7% and 89.4 ± 5%, respectively. Conclusion: Wilms' tumour treatment is a success of modern medicine, currently achieving a survival rate of 95% in our series (AU)

[Wilms' tumour: A review of 15 years recent experience]. / Tumor de Wilms: revisión de nuestra experiencia en los últimos 15 años.

INTRODUCTION: Wilms' tumour is the most frequent renal tumour in children. Multi-modal treatment includes chemotherapy and surgery, with or without radiotherapy. The survival is excellent, with rates exceeding 90%. A review is presented on our experience over the last 15 years of treating Wilms' tumour in Hospital Niño Jesús, Madrid. PATIENTS AND METHODS: A retrospective study was conducted on 40 consecutive paediatric patients diagnosed with nephroblastoma between 2002 and 2016 in the Hospital Niño Jesús in Madrid. The clinical characteristics, diagnostic methods, treatment, and follow-up were analysed. RESULTS: Of the 40 patients, 23 were boys, with a median age at diagnosis of 2.5 years (range, 4 months-15 years). Three patients underwent initial nephrectomy, three received a fine needle aspiration biopsy, followed by chemotherapy, and 34 patients started pre-operative chemotherapy directly. The median follow-up of the patients was 6.75 years (range, 10 months - 13.92 years). Two patients died from disease progression. There were no treatment-related deaths. Overall survival and event-free survival at 5 years was 94.6±3.7% and 89.4±5%, respectively. CONCLUSION: Wilms' tumour treatment is a success of modern medicine, currently achieving a survival rate of 95% in our series.

Dicentric translocation (9;12) in acute lymphoblastic leukemia: a chromosomal abnormality with an excellent prognosis?

PURPOSE: Recurrent chromosomal abnormalities present in the leukemic cells of pediatric patients with acute lymphoblastic leukemia (ALL) often allow us to classify patients according to their prognosis, in order to establish further treatment. The dicentric translocation (9;12) consists of the rearrangement of the short arms of chromosomes 9 and 12 generating a dicentric chromosome (9;12). Patients with this alteration present a very good response to treatment and an excellent prognosis. METHODS: We present the case of an adolescent with ALL in which the dicentric translocation (9;12) was observed in the karyotype of the blasts at diagnosis. RESULTS AND CONCLUSION: Given the excellent results of our patient and most of the series published to date, an international study is necessary to determine the true prognostic significance of this molecular alteration.

Tumores germinales intracraneales: revisión de 21 años / Intracranial germ cell tumours: A 21-year review

INTRODUCCIÓN: Los tumores de células germinales intracraneales son un grupo poco frecuente de tumores en niños. Comprenden un grupo heterogéneo de neoplasias, que aunque comparten un origen común, presentan comportamientos clínicos muy diferentes. PACIENTES Y MÉTODOS: Análisis retrospectivo de las características epidemiológicas e histológicas, las manifestaciones clínicas y la evolución de 20 pacientes diagnosticados de tumor de células germinales intracraneal en el Hospital Infantil Universitario Niño Jesús de Madrid durante los años 1994-2014. RESULTADOS: Se obtuvieron 20 pacientes: 14 niños y 6 niñas. La edad media fue de 11,1 años (rango 2-18 años). Se realizó confirmación histológica en el 95% de los pacientes. De los 20 pacientes, 14 fueron germinomas puros (70%) y 6 tumores de células germinales no germinomas (30%). Las localizaciones más frecuentes fueron pineal (45%) y supraselar (45%). Los síntomas más frecuentes en el momento del diagnóstico en los tumores de localización pineal fueron cefalea y vómitos (77,77%), seguido de alteraciones visuales (44,4%), y en los tumores de localización supraselar, polidipsia y poliuria (100%). En el momento del diagnóstico recibieron radioterapia el 90% de los pacientes y quimioterapia asociada a la radioterapia el 55%. Presentaron recaída tumoral 4 pacientes (20%), de los cuales 3 fallecieron. La supervivencia global fue del 80%, siendo un 85,7% para los germinomas y un 60% para los no germinomas. CONCLUSIÓN: El tipo histológico más frecuente fue el germinoma. Los tumores de células germinales son un grupo heterogéneo de tumores que conllevan un pronóstico diferente, por lo que un adecuado diagnóstico y estadificación es fundamental para planear el tratamiento

INTRODUCTION: Intracranial germ cell tumours are rare in children. They are a heterogeneous group of neoplasms that show different clinical manifestations despite having a common origin. PATIENTS AND METHODS: A retrospective analysis was carried out on the epidemiological and histological characteristics, clinical manifestations, and outcomes of 20 patients diagnosed with intracranial germ cell tumours in the Ni˜no Jesús Children's Hospital of Madrid from 1994-2014. RESULTS: A total of 20 patients were identified: 14 boys and 6 girls. The mean age was 11.1 years (range 2-18 years). Histological confirmation of the diagnosis was obtained in 95% of the patients. Of the 20 patients, 14 were pure germinoma (70%) and 6 non-seminomatous germ cell tumours (30%). The most frequent locations were pineal (45%) and suprasellar (45%). The most frequent clinical symptoms in pineal tumours at diagnosis were headache and vomiting (77.77%), followed by visual disturbances (44.4%). In suprasellar tumours it was polydipsia and polyuria (100%). At diagnosis, 90% of the patients received radiotherapy, and 55% received chemotherapy combined with radiotherapy. There was a relapse in 4 patients (20%), and 3 of them died. Overall survival was 80%; 85.7% for pure germinomas and 60% for non-seminomatous germ cell tumours. CONCLUSIONS: The most common histological subtype was pure germinoma. Germ cell tumours include heterogeneous disease entities that have a variable prognosis. Thus, an accurate diagnosis is vital for patient counselling and treatment planning

[Intracranial germ cell tumours: A 21-year review]. / Tumores germinales intracraneales: revisión de 21 años.

INTRODUCTION: Intracranial germ cell tumours are rare in children. They are a heterogeneous group of neoplasms that show different clinical manifestations despite having a common origin. PATIENTS AND METHODS: A retrospective analysis was carried out on the epidemiological and histological characteristics, clinical manifestations, and outcomes of 20 patients diagnosed with intracranial germ cell tumours in the Niño Jesús Children's Hospital of Madrid from 1994-2014. RESULTS: A total of 20 patients were identified: 14 boys and 6 girls. The mean age was 11.1 years (range 2-18 years). Histological confirmation of the diagnosis was obtained in 95% of the patients. Of the 20 patients, 14 were pure germinoma (70%) and 6 non-seminomatous germ cell tumours (30%). The most frequent locations were pineal (45%) and suprasellar (45%). The most frequent clinical symptoms in pineal tumours at diagnosis were headache and vomiting (77.77%), followed by visual disturbances (44.4%). In suprasellar tumours it was polydipsia and polyuria (100%). At diagnosis, 90% of the patients received radiotherapy, and 55% received chemotherapy combined with radiotherapy. There was a relapse in 4 patients (20%), and 3 of them died. Overall survival was 80%; 85.7% for pure germinomas and 60% for non-seminomatous germ cell tumours. CONCLUSIONS: The most common histological subtype was pure germinoma. Germ cell tumours include heterogeneous disease entities that have a variable prognosis. Thus, an accurate diagnosis is vital for patient counselling and treatment planning.

Rituximab in lymphomatoid granulomatosis.

BACKGROUND: Lymphomatoid granulomatosis (LG) is an Epstein-Barr virus-associated, multisystemic disease that combines a granulomatous inflammatory process with lymphoproliferative potential. It is a rare disorder with a variable clinical presentation ranging from an indolent process to an aggressive B-cell lymphoma. Outcome is unpredictable, and a standard treatment has not yet been established. Cases treated with rituximab, an anti-CD20 monoclonal antibody, have been reported with variable results. OBSERVATION: We report on 2 children with LG treated with rituximab and review the literature. The first patient had good response but the second did not. CONCLUSIONS: Rituximab is a treatment option for LG.

Gorham-Stout disease and cerebrospinal fluid otorrhea.

OBJECTIVE AND IMPORTANCE: Gorham-Stout disease is a rare entity characterized by vascular proliferation causing local destruction of bone tissue. Owing to its low incidence and variable clinical presentation, the diagnosis requires a high degree of awareness by the clinician. CLINICAL PRESENTATION: We present the case of a 2-year-old boy diagnosed of Gorham-Stout syndrome with involvement of the temporal bone and secondary cerebrospinal fluid (CSF) leakage. INTERVENTION: Because of the CSF leakage, the patient required two surgical interventions. The second intervention included mastectomy and placement of a patch and a lumbar drainage device during 50 days, after which the leakage ceased. CONCLUSION: Gorham-Stout disease is a rare condition that can affect the skull base and even present with CSF leakage.