COVID-19 in Pediatric Cancer Patients and Hematopoietic Stem Cell Transplant Recipients in a Tertiary Care Hospital in Argentina.

The outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer pediatric patients was initially uncertain. The objective of this study was to describe the characteristics and outcome of cancer patients and hematopoietic stem cell transplant recipients from 0 to 19 years with detectable SARS-CoV-2 from April 23, 2020, to April 30, 2022, treated in a tertiary-level hospital in Argentina. A total of 348 cases were registered in 339 patients. The median age was 89.5 (3 to 224) months. The sex was predominantly male: 193 (55.5%). The most common malignant disease was leukemia (42.8%). One hundred four cases (29.9%) had comorbidities. Of the 346 cases with an available blood count, 17.6% had a lymphocyte count <300/mm 3 . Fever was the most common symptom. In most cases (93.1%) presented asymptomatic or mild disease. Twenty-one cases (6%) presented severe or critical status. Eleven of 24 admissions to the intensive care unit were due to COVID-19 (coronavirus disease 2019). Eight patients (2.3%) died. Two deaths were attributable to SARS-CoV-2 (0.6%). Being older, having fever, lymphopenia at diagnosis, and having received hematopoietic stem cell transplant were associated with a more severe disease. Around 90% of the children continued their cancer treatment without any change.

The spectrum of morphological findings in pediatric central nervous system MN1-fusion-positive neuroepithelial tumors.

PURPOSE: Central nervous system high-grade neuroepithelial tumor with MN1 alteration (CNS-HGNET-MN1) is a rare entity defined by its DNA methylation pattern and pathologically considered to be high-grade with mixed patterns, stromal hyalinization, and with astrocytic differentiation. Our aim was to present six pediatric cases to contribute to the characterization of this group of tumors. MATERIAL AND METHODS: Six female patients aged 4 to 12 years with CNS tumors with MN1 alteration identified using genome-wide methylation arrays and/or RT-PCR were included. Clinicopathological, morphological, immunohistochemical, and molecular findings were analyzed. RESULTS: Tumor location was the parietal lobe in four and the intramedullary spinal cord in two. Two were morphologically diagnosed as ependymomas, one as gliofibroma, one as a HGNET-MN1 altered and the other two were difficult to classify. All were well-defined tumors, with a cystic component in three. Only two tumors had extensive stromal hyalinization, three had pseudopapillary formations, and four had other patterns. Multinucleated, clear, and rhabdoid cells were present. Necrosis and histiocyte clusters were also observed. Proliferative index was >10 in four. GFAP, EMA, CK, and SYN were variable, while Olig2 staining was mostly positive. Four of six patients with supratentorial tumors and complete resections were alive and tumor free after 2 to 10 years of follow-up. The two cases with medullary involvement and incomplete resections were alive and undergoing treatment 2 years after surgery. CONCLUSION: Neuroepithelial-MN1 tumors are challenging and suspicion requires molecular confirmation. Our pediatric data contribute to the knowledge for accurate diagnosis. Although further studies with a larger number of cases should be conducted in order to draw more robust conclusions regarding clinico-pathological features, here we present valuable pediatric data to increase the knowledge that may lead to the accurate management of this group of tumors.

Medulloblastoma and Down Syndrome: An Extremely Rare Association.

Medulloblastoma has a reduced incidence in Down syndrome (DS). This protective characteristic has not been clarified yet. Here, we report the second case of SHH medulloblastoma and DS documented in the literature. A complete surgery was performed followed by reduced craniospinal irradiation dose and adjuvant chemotherapy. No evidence of tumor recurrence was observed. The overall survival was 9.1 years. No family history or physical stigma of other hereditary predisposition syndrome was found. In the elucidation of this extremely rare association, future case reports play an important role in defining the spectrum of brain tumors and their peculiar features in DS.

Subsequent malignant neoplasms in the pediatric age in retinoblastoma survivors in Argentina.

BACKGROUND: Retinoblastoma survivors in low- and middle-income countries are exposed to high-intensity treatments that potentially place them at higher risk of early subsequent malignant neoplasms (SMNs). METHODS: We followed 714 (403 [56.4%] nonhereditary and 311 [43.5%] hereditary) retinoblastoma survivors diagnosed from August 1987 to December 2016, up to the age of 16 years. We quantified risk of SMNs with cumulative incidence (CI) and standardized incidence ratios (SIR) analysis. Multivariate regression Cox model was used to determine the association of treatments and risk of SMNs. RESULTS: Median follow-up was of 9 years (range: 0.18-16.9) and 24 survivors (3.36%) developed 25 SMNs (n = 22 hereditary, n = 2 nonhereditary). SMNs included sarcomas (osteosarcomas, Ewing sarcomas, rhabdomyosarcomas; n = 12), leukemias (n = 5), and central nervous system tumors (CNS; n = 3). All cases of acute myeloid leukemia (AML) and most of Ewing sarcomas occurred within 5 years of retinoblastoma diagnosis. The type of SMN was the main indicator of mortality (five of five patients with leukemias, six of 12 with sarcomas, and zero of three with CNS tumors died). Compared to the general population, radiation increased the risk of Ewing sarcoma in hereditary survivors by 700-fold (95% CI = 252-2422.6) and chemotherapy increased the risk of AML by 140-fold (95% CI = 45.3-436). The CI of SMNs for hereditary survivors was 13.7% (95% CI = 8.4-22.1) at 15 years. CONCLUSION: Retinoblastoma survivors from Argentina are at higher risk of developing SMNs early in life compared to the general Argentinean population, especially those treated with radiation plus chemotherapy. AML and Ewing sarcoma presented within 5 years of retinoblastoma diagnosis are associated with chemotherapy and radiation exposure.

[Targeted therapies with BRAF inhibitors for pediatric low- and high-grade gliomas with BRAFv600e mutation. Prof. Dr. Juan P. Garrahan Hospital experience]. / Terapias dirigidas con inhibidores del BRAF en gliomas pediátricos de alto y bajo grado con la mutación BRAFV600E. Experiencia del Hospital Prof. Dr. Juan P. Garrahan.

The BRAFV600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAFV600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAFV600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAFV600E mutated low-grade gliomas treated with BRAFV600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.

La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAFV600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAFV600E mutado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAFV600E mutado tratados con inhibidores BRAFV600E. En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.

Terapias dirigidas con inhibidores del braf en gliomas pediátricos de alto y bajo grado con la mutación brafv600e. Experiencia del hospital Prof. Dr. Juan P. Garrahan / Targeted therapies with BRAF inhibitors for pediatric low- and high-grade gliomas with BRAF v600e mutation. Prof. Dr. Juan P. Garrahan Hospital experience

Resumen La mutación puntual V600E del gen BRAF juega un papel fundamental en la tumorigénesis de muchos gliomas. La inhibición de su producto forma parte de terapias innovadoras emergentes en los últimos años. Conocer el rol de estos tratamientos resulta imprescindible. El objetivo del trabajo fue describir la respuesta clínico-radiológica en niños con gliomas BRAF V600E mutado tratados con inhibidores BRAF. Para ello se realizó un estudio descriptivo y retrospectivo en pacientes menores de 16 años con gliomas BRAF V600E mu tado que recibieron vemurafenib o dabrafenib en el Hospital Garrahan. Trece pacientes tratados en los últimos 7 años fueron incluidos: 9 gliomas de bajo grado y 4 de alto grado. La mediana de edad al diagnóstico fue 8.6 años (0.89-14.04) y del comienzo del inhibidor 11.62 años (3.64-15.42). Inicialmente, todos habían realizado tratamiento quirúrgico, y 12/13 recibieron previamente otra terapia: 11 quimioterapia (eventualmente hasta 4 líneas distintas) y 4 radioterapia. Con la terapia dirigida, 10 pacientes tuvieron una disminución tumoral mayor o igual al 25%, quedando evidenciada en 7 niños la mejor respuesta dentro de los 6 meses del inicio. Hubo 4 progresados intratratamiento (todos alto grado), y 2 progresados prontamente luego de suspender el inhibidor (ambos bajo grado). Cinco presentaron efectos adversos grado 3-4, con recuperación ad-integrum. Se describe una buena y sostenida respuesta clínico-radiológica, con tolerancia aceptable, en pacientes con gliomas de bajo grado BRAF V600E mutado tratados con inhibidores BRAF V600E . En contraste, la respuesta en pacientes con gliomas de alto grado fue intermedia y de poca duración, con progresión tumoral precoz.

Abstract The BRAF V600E point mutation plays a key role in the tumorigenesis of many gliomas. Inhibiting its product is part of the innovative therapies emerging in recent years. Knowing the role of these treatments is essential. The aim of this experience was to describe the clinical-radiological response of pediatric BRAF V600E mutated gliomas treated with BRAF inhibitors. To this end, a descriptive and retrospective study was performed in patients under 16 years of age with BRAF V600E gliomas, who received vemurafenib or dabrafenib at Hospital Garrahan. Thirteen patients treated in the last 7 years were included: 9 were low-grade and 4 high-grade gliomas. The median age at diagnosis was 8.6 years (0.89-14.04) and at start of targeted therapy was 11.62 years (3.64-15.42). All patients had previously a surgical procedure, and 12/13 had received another therapy prior BRAF inhibition: 11 chemotherapy (in one case, up to 4 different protocols) and 4 radiotherapy. Under targeted therapy, tumour response was obtained in 10 patients (size reduction equal to or greater than 25%), and best response was observed in the first 6 months of treatment in 7 children. Four patients progressed under treatment (all high-grade gliomas) and 2 progressed shortly after stopping the inhibitor (both low-grade gliomas). Five patients had grade 3-4 toxicity, with subsequent full recovery. A good and sustained clinical-radiological response, with acceptable tolerance, is described in patients with BRAF V600E mutated low-grade gliomas treated with BRAF V600E inhibitors. In contrast, the response in patients with high-grade gliomas was intermediate and of short duration, with early tumour progression.

Craniospinal irradiation as part of re-irradiation for children with recurrent medulloblastoma.

BACKGROUND: Many studies have demonstrated in the last years that once medulloblastoma has recurred, the probability of regaining tumor control is poor despite salvage therapy. Although re-irradiation has an emerging role in other relapsed brain tumors, there is a lack of strong data on re-irradiation for medulloblastoma. METHODS: This is a retrospective cohort study of patients aged 18 years or under, treated at least by a second course of external beam for recurrence medulloblastoma at Garrahan Hospital between 2009 and 2020. Twenty-four patients met eligibility criteria for inclusion. All patients received upfront radiotherapy as part of the curative-intent first radiotherapy, either craniospinal irradiation (CSI) followed by posterior fossa boost in 20 patients or focal posterior fossa radiation in 4 infants. The second course of radiation consisted of CSI in 15 and focal in 9. The 3-year post first failure OS (50% vs. 0%; p = 0.0010) was significantly better for children who received re-CSI compared to children who received focal re-irradiation. Similarly, the 3-year post-re-RT PFS (31% vs. 0%; p = 0.0005) and OS (25% vs. 0%; p = 0.0003) was significantly improved for patients who received re-CSI compared to patients who received focal re-irradiation. No symptomatic intratumoral haemorrhagic events or symptomatic radionecrosis were observed. Survivors fell within mild to moderate intellectual disability range, with a median IQ at last assessment of 58 (range 43-69). CONCLUSIONS: Re-irradiation with CSI is a safe and effective treatment for children with relapsed medulloblastoma; improves disease control and survival compared with focal re-irradiation. However this approach carries a high neurocognitive cost.

Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study.

BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumors with multilayered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n = 307). Additional cases (n = 66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n = 292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58 (19%) cases as ETMR, 57 (19%) as high-grade glioma (HGG), 36 (12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63% ± 7%, OS: 85% ± 5%, n = 63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18% ± 6% and 22% ± 7%, and 5-year OS of 24% ± 6% and 25% ± 7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk CSI-based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

Intracranial germ cells tumour: a single institution experience in Argentina.

BACKGROUND: Intracranial germ cell tumor (iGCT) represents a rare and heterogeneous group, with variable incidence and diverse treatment strategies. Although multiagent chemotherapy with reduced radiotherapy strategy has been applied by several cooperative groups in North America and Western Europe, there is a paucity of data to understand if this combined regimen is suitable in low-middle income countries (LMIC). METHODS: We evaluate the outcome in a cohort of iGCT treated by SIOP-CNS-GCT-96 strategy at hospital J.P Garrahan in Argentina over the last 20 years. Radiation field and dose included focal radiotherapy (FRT) before 2009 or focal radiotherapy plus whole ventricular radiotherapy (WVRT) after 2009 for localized germinoma and FRT or FRT plus WVRT or CSI for non germinomatous germ cell tumors (NGGCT) RESULTS: Sixty iGCT were identified; 39 germinoma and 21 NGGCT. Median follow-up was 6.57 years (range 0.13-20.5). 5-year PFS and OS were 83.5% (95% CI [165.53-223.2]) and 88.7% (95% CI [169.84-223.2]) for the germinoma group, while for the NGGCT group were 75% (95% CI [133.27-219.96]) and 64.2% (95% CI [107.38-201.81]) respectively. The localized germinoma group showed poor results between 2000 and 2009 with 5-year PFS and OS of 69 and 75% respectively, and an excellent outcome between 2010 and 2019 with a 5-years PFS and OS of 92.8 and 100%. A univariable analysis identified this difference in survival as related to the field of radiotherapy, specifically whole ventricular radiotherapy. FRT increased the risk of recurrence in localized germinoma, involving not only ventricular relapses; but spinal cord and disseminated disease as well. There were no relapses of localized NGGCT after FRT and FRT plus WVRT. CONCLUSION: Herein we demonstrate that intensive chemotherapy followed by FRT plus WVRT for germinoma is a feasible and effective strategy, warranting further study in the developing world.

Treatment response of CNS high-grade neuroepithelial tumors with MN1 alteration.

Central nervous system high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) is a rare recently described entity. Fourteen CNS HGNET-MN1 patients were identified using genome-wide methylation arrays/RT-PCR across seven institutions. All patients had surgery (gross total resection: 10; subtotal resection: four) as initial management followed by observation alone in three patients, followed by radiotherapy in eight patients (focal: five; craniospinal: two; CyberKnife: one) and systemic chemotherapy in three patients. Seven patients relapsed; five local and two metastatic, despite adjuvant radiotherapy, of which three died. Treatment of CNS HGNET-MN1 remains a major treatment challenge despite aggressive surgical resections and upfront radiotherapy, warranting new approaches to this rare malignancy.

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

PURPOSE: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02). CONCLUSION: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

Bevacizumab for pediatric radiation necrosis.

BACKGROUND: Radiation necrosis is a frequent complication occurring after the treatment of pediatric brain tumors; however, treatment options remain a challenge. Bevacizumab is an anti-VEGF monoclonal antibody that has been shown in small adult cohorts to confer a benefit, specifically a reduction in steroid usage, but its use in children has not been well described. METHODS: We describe our experience with bevacizumab use for symptomatic radiation necrosis at 5 institutions including patients treated after both initial irradiation and reirradiation. RESULTS: We identified 26 patients treated with bevacizumab for symptomatic radiation necrosis, with a wide range of underlying diagnoses. The average age at diagnosis of radiation necrosis was 10.7 years, with a median time between the last dose of radiation and the presentation of radiation necrosis of 3.8 months (range, 0.6-110 months). Overall, we observed that 13 of 26 patients (50%) had an objective clinical improvement, with only 1 patient suffering from significant hypertension. Radiological improvement, defined as reduced T2/fluid-attenuated inversion recovery signal and mass effect, was observed in 50% of patients; however, this did not completely overlap with clinical response. Both early and late radiation necrosis responded equally well to bevacizumab therapy. Overall, bevacizumab was very well tolerated, permitting a reduction of corticosteroid dose and/or duration in the majority of patients. CONCLUSIONS: Bevacizumab appears to be effective and well-tolerated in children as treatment for symptomatic radiation necrosis and warrants more robust study in the context of controlled clinical trials.

Bridging the treatment gap in infant medulloblastoma: molecularly informed outcomes of a globally feasible regimen.

BACKGROUND: Infant medulloblastoma represents an enormous challenge in neuro-oncology, due to their simultaneous high-risk of recurrence and high risk of severe neurodevelopmental sequelae with craniospinal irradiation. Currently infant medulloblastoma are treated with intensified protocols, either comprising intraventricular methotrexate or autologous transplant, both of which carry significant morbidity and are not feasible in the majority of the world. We sought to evaluate the molecular predictors of outcome in a cohort of infants homogeneously treated with induction chemotherapy, focal radiation and maintenance chemotherapy. METHODS: In a retrospective analysis, 29 young children treated with a craniospinal irradiation sparing strategy from Hospital Garrahan in Buenos Aires were profiled using Illumina HumanMethylationEPIC arrays, and correlated with survival. RESULTS: Twenty-nine children (range, 0.3-4.6 y) were identified, comprising 17 sonic hedgehog (SHH), 10 Group 3/4, and 2 non-medulloblastomas. Progression-free survival (PFS) across the entire cohort was 0.704 (95% CI: 0.551-0.899). Analysis by t-distributed stochastic neighbor embedding revealed 3 predominant groups, SHHß, SHHγ, and Group 3. Survival by subtype was highly prognostic with SHHγ having an excellent 5-year PFS of 100% (95% CI: 0.633-1) and SHHß having a PFS of 0.56 (95% CI: 0.42-1). Group 3 had a PFS of 0.50 (95% CI: 0.25-1). Assessment of neurocognitive outcome was performed in 11 patients; the majority of survivors fell within the low average to mild intellectual disability, with a median IQ of 73.5. CONCLUSIONS: We report a globally feasible and effective strategy avoiding craniospinal radiation in the treatment of infant medulloblastoma, including a robust molecular correlation along with neurocognitive outcomes.

Bevacizumab for NF2-associated vestibular schwannomas of childhood and adolescence.

Seventeen children at six institutions with neurofibromatosis type 2 (NF2)-related vestibular schwannomas received bevacizumab. Eight of the 13 patients with initial hearing loss (61%) showed objective hearing improvement within six months of treatment. No patients showed hearing deterioration during therapy; however, only two patients showed objective radiological response. Seven of eight patients had tumor progression or worsening hearing loss upon cessation of treatment. Bevacizumab was well tolerated with no patients discontinuing therapy. Bevacizumab appears to postpone hearing loss in childhood NF2-associated vestibular schwannomas, but responses are not durable, suggesting that either longer maintenance therapy or new strategies are required.

Minimal disseminated disease evaluation and outcome in trilateral retinoblastoma.

Trilateral retinoblastoma (TRb) presents a management challenge, since intracranial tumours are seldom times resectable and quickly disseminate. However, there are no risk factors to predict the final outcome in each patient. OBJECTIVE: To evaluate minimal disseminated disease (MDD) in the bone marrow (BM) and the cerebrospinal fluid (CSF) at diagnosis and during follow-up and reviewing its potential impact in the outcome of patients with TRb. METHODS AND ANALYSIS: We evaluated MDD in five patients with TRb, detecting the mRNA of CRX and/or GD2, in samples from BM and CSF, obtained at diagnosis, follow-up and relapse. RESULTS: Treatment involved intensive systemic chemotherapy in four patients, one did not receive this treatment and died of progression of the disease. Two patients underwent stem cell rescue. Three patients had leptomeningeal relapse and died. One patient remains disease-free for 84 months. RB1 mutations were identified in the five patients, all of them were null mutations. At diagnosis, one patient had tumour cells in the CSF, and none had the BM involved. Only one case of four presented MDD during follow-up in the CSF, without concomitant detection in the BM. On leptomeningeal relapse, no case had MDD in the BM. In all these cases, cells in the CSF were positive for GD2 and/or CRX. CONCLUSION: CSF dissemination always concluded in the death of the patient, without concomitant systemic dissemination denoting the importance of increasing treatment directed to the CSF compartment. The MDD presence could indicate a forthcoming relapse.

Second Neoplasms in Children Following a Treatment for Acute Leukemia and/or Lymphoma: 29 Years of Experience in a Single Institution in Argentina.

INTRODUCTION: Childhood acute leukemias (AL) and lymphomas achieve good survival rates. However, second neoplasms (SN) are a devastating event. METHODS: From August 1987 to December 2016, 34 of 3321 (1%) patients with diagnosis of AL or lymphoma developed SN. SN were AL (n=16), CNS tumors (n=5), endocrinal tumors (n=3), lymphomas (n=2), schwannoma (n=2) assorted sarcomas (n=4), retinal melanoma (n=1), and Vanek tumor (n=1). Median latency was 51 (range, 10 to 110) months for hematological malignancies and 119 (range, 25 to 236) months for solid tumors (P=0.001). RESULTS: A total of 33 patients with SN were treated taking into account cumulative doses of anthracyclines and radiotherapy. Twenty-three (67.6%) patients achieved complete remission (CR), 5 died early during therapy and 5 were refractory or partial responders. Six patients presented relapses of the SN and 1 died in CR. Seventeen patients remain alive in CR, with a median follow-up of 110 (range, 4 to 276) months. CONCLUSIONS: (1) The latency period was significantly longer for patients developing solid tumors than for those developing AL. (2) AL was the most frequent SN. (3) Our results strongly encourage giving standard therapy to SN, considering cumulative doses of previous treatment, since similar probabilities of surviving as "de novo" counterparts can be achieved.

Tumores cerebrales infratentoriales y supratentoriales: comparación de perfil cognitivo y su impacto en la calidad de vida en niños en edad escolar / Infra- and supratentorial brain tumors: comparison of the cognitive profile and its impact on quality of life in school-age children

INTRODUCCION: Los avances científicos han logrado aumentar la cantidad de pacientes pediátricos que sobreviven a enfermedades oncológicas. En general, para los niños que padecen tumores del sistema nervioso central, esta sobrevida viene acompañada de efectos adversos secundarios, tales como déficits cognitivos.OBJETIVO: Evaluar las funciones cognitivas y la calidad de vida en niños con tumores cerebrales infratentoriales y supratentoriales.METODOS: Se realizó un estudio analítico observacional. La muestra total estuvo conformada por 51 sujetos. Se utilizaron los siguientes instrumentos de medición: Escala de Inteligencia de Wechsler para niños IV, Sistema de Evaluación Cognitiva; Test de Memoria y Aprendizaje; Escala Graffar y Peds Quality of Life 4.0.RESULTADOS: La comparación de los resultados no arrojó diferencias significativas entre localizaciones tumorales infratentoriales y supratentoriales. La totalidad de los pacientes evaluados en un período de post-tratamiento oncológico presentó un descenso similar y significativo en todas las áreas estudiadas, en relación con lo esperado para la población general. Las funciones cognitivas que evidenciaron mayor compromiso fueron la velocidad de procesamiento y la capacidad atencional (principalmente en tareas de planificación). Los resultados observados pusieron de manifiesto estos déficits, así como un alto compromiso de la calidad de vida escolar.CONCLUSIONES: El trabajo se presenta como un estudio preliminar. A partir de él se podría definir la tendencia general del estado neurocognitivo, analizar su impacto en la calidad de vida de la población estudiada y plantear interrogantes dirigidos a futuras investigaciones.

INTRODUCTION: Due to scientific advances, there is a growing number of pediatric patients surviving cancer. In general, for children who suffer from central nervous system tumors, this survival is associated with secondary adverse effects, such as cognitive deficits.OBJECTIVE: To assess cognitive functions and quality of life in children with infratentorial and supratentorial brain tumors.METHODS: An analytical observational study was conducted. The total sample consisted of 51 subjects. Following measurement instruments were used: Wechsler Intelligence Scale for Children, Fourth Edition (WISC IV), Cognitive Assessment System (CAS), Test of Memory and Learning (TOMAL), Graffar Scale and Peds Quality of Life 4.0.RESULTS: The comparisons of the results did not show significant differences between infratentorial and supratentorial tumor location. All patients that were evaluated in the post-cancer treatment period revealed a similar significant impairment in all the areas studied, when compared with the level expected in the general population. The most severely affected cognitive functions were processing speed and attention span, mainly on planning tasks. The findings also showed that quality of life at school is severely affected in these children.CONCLUSIONS: This is a preliminary study whose results may define a general trend of neurocognitive status, analyzing its impact on the quality of life of the study population and posing useful questions for the future research.

Tumores cerebrales infratentoriales y supratentoriales: comparación de perfil cognitivo y su impacto en la calidad de vida en niños en edad escolar / Infra- and supratentorial brain tumors: comparison of the cognitive profile and its impact on quality of life in school-age children

INTRODUCCION: Los avances científicos han logrado aumentar la cantidad de pacientes pediátricos que sobreviven a enfermedades oncológicas. En general, para los niños que padecen tumores del sistema nervioso central, esta sobrevida viene acompañada de efectos adversos secundarios, tales como déficits cognitivos.OBJETIVO: Evaluar las funciones cognitivas y la calidad de vida en niños con tumores cerebrales infratentoriales y supratentoriales.METODOS: Se realizó un estudio analítico observacional. La muestra total estuvo conformada por 51 sujetos. Se utilizaron los siguientes instrumentos de medición: Escala de Inteligencia de Wechsler para niños IV, Sistema de Evaluación Cognitiva; Test de Memoria y Aprendizaje; Escala Graffar y Peds Quality of Life 4.0.RESULTADOS: La comparación de los resultados no arrojó diferencias significativas entre localizaciones tumorales infratentoriales y supratentoriales. La totalidad de los pacientes evaluados en un período de post-tratamiento oncológico presentó un descenso similar y significativo en todas las áreas estudiadas, en relación con lo esperado para la población general. Las funciones cognitivas que evidenciaron mayor compromiso fueron la velocidad de procesamiento y la capacidad atencional (principalmente en tareas de planificación). Los resultados observados pusieron de manifiesto estos déficits, así como un alto compromiso de la calidad de vida escolar.CONCLUSIONES: El trabajo se presenta como un estudio preliminar. A partir de él se podría definir la tendencia general del estado neurocognitivo, analizar su impacto en la calidad de vida de la población estudiada y plantear interrogantes dirigidos a futuras investigaciones.

INTRODUCTION: Due to scientific advances, there is a growing number of pediatric patients surviving cancer. In general, for children who suffer from central nervous system tumors, this survival is associated with secondary adverse effects, such as cognitive deficits.OBJECTIVE: To assess cognitive functions and quality of life in children with infratentorial and supratentorial brain tumors.METHODS: An analytical observational study was conducted. The total sample consisted of 51 subjects. Following measurement instruments were used: Wechsler Intelligence Scale for Children, Fourth Edition (WISC IV), Cognitive Assessment System (CAS), Test of Memory and Learning (TOMAL), Graffar Scale and Peds Quality of Life 4.0.RESULTS: The comparisons of the results did not show significant differences between infratentorial and supratentorial tumor location. All patients that were evaluated in the post-cancer treatment period revealed a similar significant impairment in all the areas studied, when compared with the level expected in the general population. The most severely affected cognitive functions were processing speed and attention span, mainly on planning tasks. The findings also showed that quality of life at school is severely affected in these children.CONCLUSIONS: This is a preliminary study whose results may define a general trend of neurocognitive status, analyzing its impact on the quality of life of the study population and posing useful questions for the future research.

A complex karyotype in an atypical teratoid/rhabdoid tumor: case report and review of the literature.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive and uncommon neoplasm of the central nervous system that usually occurs in children less than 2 years of age. It is characterized by deletions and/or mutations of the INI1 tumor suppressor gene located in chromosome band 22q11.2. We performed cytogenetic and molecular studies of an AT/RT on a 15-month-old boy. The tumor showed a complex karyotype with one cell line showing monosomy 22 and another near-tetraploid one with additional chromosomal abnormalities, involving chromosomes 2, 3, 5, 6, and Y, which had not been previously described. Sequence analysis of the tumor did not identify mutations of the INI1 gene. The karyotypic evolution observed in this tumor suggests that INI1 has an epigenetic role in the maintenance of genome integrity by affecting genes, which produces mitotic defects and polyploidy. Finally, this case is the first to support the theory that loss of INI1 could induce the chromosomal instability that might be responsible for the genesis of this tumor.