RESUMEN
BACKGROUND: Survival data for recurrent pediatric atypical teratoid rhabdoid tumor (ATRT) and its association to molecular groups are extremely limited. METHODS: Single-institution retrospective study of 64 children less than 21 years old with recurrent or treatment-refractory (progressive disease [PD]) ATRT treated at St. Jude Hospital from January 2000 to December 2020. Demographic, clinicopathologic, treatment, molecular grouping (SHH, TYR, and MYC) and germline data were collected. Progression-free survival (PFS2: time from PD to subsequent first progression) and overall survival (OSpostPD: time from PD to death/last follow-up) were estimated by Kaplan-Meier analysis. RESULTS: Median age at and time from initial diagnosis to PD were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5-125.6 months), respectively. Only five of 64 children (7.8%) are alive at median follow-up of 10.9 (range: 4.2-18.1) years from PD. The 2/5-year PFS2 and OSpostPD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.3% (±3.5%), respectively. Children with TYR group (n = 10) had a better OSpostPD compared to those with MYC (n = 11) (2-year survival estimates: 60.0% ± 14.3% vs. 18.2% ± 9.5%; p = .019), or those with SHH (n = 21; 4.8% ± 3.3%; p = .014). In univariate analyses, OSpostPD was better with older age at diagnosis (p = .037), female gender (p = .008), and metastatic site of PD compared to local or combined sites of PD (p < .001). Two-year OSpostPD for patients receiving any salvage therapy (n = 39) post PD was 33.3% ± 7.3%. CONCLUSIONS: Children with recurrent/refractory ATRT have dismal outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of PD were associated with relatively longer survival in our study.
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Recurrencia Local de Neoplasia , Tumor Rabdoide , Teratoma , Humanos , Tumor Rabdoide/mortalidad , Tumor Rabdoide/terapia , Tumor Rabdoide/patología , Masculino , Femenino , Niño , Preescolar , Estudios Retrospectivos , Lactante , Adolescente , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/mortalidad , Teratoma/mortalidad , Teratoma/patología , Teratoma/terapia , Tasa de Supervivencia , Estudios de Seguimiento , Pronóstico , Recién Nacido , Biomarcadores de Tumor/genéticaRESUMEN
PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare malignancy of the central nervous system in young children with a dismal prognosis. Prognostic markers have been extensively investigated but have not been validated. The role of radiation therapy (RT) remains controversial. We evaluated the impact of RT as part of multimodality treatment by analyzing data of a European AT/RT cohort. METHODS AND MATERIALS: We retrospectively analyzed data of the European Registry for Rhabdoid Tumors and its precursors. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Potential impact of prognostic factors was analyzed using univariable and multivariable Cox regression analyses with RT as a time-dependent factor. RESULTS: Data of 186 children (118 male, 68 female) treated from 1990 to 2016 were evaluable. The median age at diagnosis was 1.57 years (range, 0.01-26.70 years); 47% (87/186) of the patients were under the age of 18 months. Sixty-nine percent (128/186) received RT (focal RT, n = 93; craniospinal treatment with local boost, n = 34; spinal irradiation, n = 1). The median follow-up duration of the entire cohort was 1.73 years (range, 0.06-20.11 years). The estimated PFS and OS rates were 48% (95% CI, 41%-55%) and 72% (95% CI, 65%-78%) at 1 year and 33% (95% CI, 26%-40%) and 49% (95% CI, 41%-56%) at 2 years, respectively. On multivariable analysis, RT was an independent significant prognostic factor for PFS (hazard ratio, 0.45; 95% CI, 0.27-0.75; P = .002) and OS (hazard ratio, 0.54; 95% CI, 0.32-0.93; P = .025). CONCLUSIONS: This analysis confirms the relevance of local therapies. RT was an independent prognostic factor for outcomes in children experiencing AT/RT. However, long-term sequelae have to be carefully evaluated and considered given the young age at time of RT.
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Supervivencia sin Progresión , Tumor Rabdoide , Teratoma , Humanos , Tumor Rabdoide/radioterapia , Tumor Rabdoide/mortalidad , Masculino , Femenino , Preescolar , Lactante , Teratoma/radioterapia , Teratoma/mortalidad , Estudios Retrospectivos , Niño , Adolescente , Europa (Continente) , Adulto Joven , Adulto , Recién Nacido , Pronóstico , Sistema de Registros , Modelos de Riesgos ProporcionalesRESUMEN
PURPOSE: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. MATERIALS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3-21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. CONCLUSIONS: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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Biomarcadores de Tumor , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/etiología , Teratoma/diagnóstico , Teratoma/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Metilación de ADN , Diagnóstico Diferencial , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Mutación de Línea Germinal , Humanos , Lactante , Masculino , Mutación , Pronóstico , Tumor Rabdoide/mortalidad , Tumor Rabdoide/terapia , Proteína SMARCB1/genética , Teratoma/mortalidad , Teratoma/terapia , Resultado del TratamientoRESUMEN
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/inmunología , Regulación Neoplásica de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario/inmunología , Neoplasias Renales/inmunología , Tumor Rabdoide/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/inmunología , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas de Punto de Control Inmunitario/genética , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/inmunología , Estudios Retrospectivos , Tumor Rabdoide/tratamiento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidad , Transducción de Señal , Análisis de Supervivencia , Transcripción Genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunología , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/inmunologíaRESUMEN
BACKGROUND: Malignant rhabdoid tumor of the kidney (RTK) is a rare and highly aggressive pediatric malignancy. Immune system dysfunction is significantly correlated with tumor initiation and progression. METHODS: We integrated and analyzed the expression profiles of immune-related genes (IRGs) in 65 RTK patients based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Prognostic related IRGs in RTK patients were analyzed using univariate and multivariate analysis, based on which a prognostic model with IRGs was constructed. Correlation analysis between the risk score of our model and tumor-infiltrating cell were also investigated. RESULTS: Twenty two IRGs were significantly associated with the clinical outcomes of RTK patients. Gene ontology (GO) analysis revealed that inflammatory pathways were most frequently implicated in RTK. A prognostic model was constructed using 7 IRGs (MMP9, SERPINA3, FAM19A5, CCR9, PLAUR, IL1R2, PRKCG), which were independent prognostic indices that could differentiate patients based on their survival outcomes. Furthermore, the risk scores from our prognostic model was positively associated with cancer-associated fibroblasts (CAFs). CONCLUSIONS: We screened seven IRGs of clinical significance to distinguish patients with different survival outcomes. This may enhance our understanding of the immune microenvironment of RTK, and could use to design individualized treatments for RTK patients. BACKGROUND: Malignant rhabdoid tumor of the kidney (RTK) is a rare and highly aggressive pediatric malignancy. Immune system dysfunction is significantly correlated with tumor initiation and progression. METHODS: We integrated and analyzed the expression profiles of immune-related genes (IRGs) in 65 RTK patients based on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Prognostic related IRGs in RTK patients were analyzed using univariate and multivariate analysis, based on which a prognostic model with IRGs was constructed. Correlation analysis between the risk score of our model and tumor-infiltrating cell were also investigated. RESULTS: Twenty two IRGs were significantly associated with the clinical outcomes of RTK patients. Gene ontology (GO) analysis revealed that inflammatory pathways were most frequently implicated in RTK. A prognostic model was constructed using 7 IRGs (MMP9, SERPINA3, FAM19A5, CCR9, PLAUR, IL1R2, PRKCG), which were independent prognostic indices that could differentiate patients based on their survival outcomes. Furthermore, the risk scores from our prognostic model was positively associated with cancer-associated fibroblasts (CAFs). CONCLUSIONS: We screened seven IRGs of clinical significance to distinguish patients with different survival outcomes. This may enhance our understanding of the immune microenvironment of RTK and could use to design individualized treatments for RTK patients.
Asunto(s)
Neoplasias Renales/genética , Tumor Rabdoide/genética , Estudios de Casos y Controles , Conjuntos de Datos como Asunto , Redes Reguladoras de Genes , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/inmunología , Neoplasias Renales/mortalidad , Linfocitos Infiltrantes de Tumor , Pronóstico , Modelos de Riesgos Proporcionales , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/inmunología , Tumor Rabdoide/mortalidad , Estados Unidos/epidemiologíaRESUMEN
Objective: Malignant rhabdoid tumor (MRT) is a rare but aggressive malignancy. It has been a long time since data on this tumor have been updated. Methods: We retrospectively reviewed patients from the SEER database who were pathologically diagnosed with MRT and analyzed incidence rates, clinical features and survival using Stata 12.0. Results: In total, 544 patients were included in the epidemiological analysis. There were two peak periods of MRT incidence: patients younger than 4 years and those older than 70 years. Further survival analysis showed that the survival of children (especially younger than 1 year) was markedly worse than that of adults (P<0.01), and different primary sites were associated with different age groups and survival outcomes. The central nervous system (CNS) was the most common primary site (50.00%), followed by the kidney (15.66%). Patients with MRTs that originated from the digestive system experienced worse survival outcomes than those with MRTs originating from other locations. Primary site surgery conferred survival benefits to patients with renal and digestive system MRTs (HR = 0.06, CI: 0.02-0.23, P<0.01; HR=0.10, CI: 0.02-0.48, P<0.01), whereas radiotherapy conferred benefits to patients with CNS, bone and soft tissue MRTs (HR=0.22, CI: 0.15-0.34, P<0.01; HR=0.44, CI: 0.21-0.90 P=0.03). Conclusions: Our results indicate that age and the primary site of MRT are critical clinical factors that affect patient survival and treatment choices. Primary site tumor resection should be considered for renal and digestive system MRTs, and systematic therapy, including surgery and radiotherapy, should be recommended for the treatment of CNS, bone and soft tissue MRTs.
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Neoplasias Óseas/mortalidad , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Digestivo/mortalidad , Neoplasias Renales/mortalidad , Tumor Rabdoide/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Neoplasias Óseas/terapia , Neoplasias del Sistema Nervioso Central/terapia , Quimioterapia Adyuvante/estadística & datos numéricos , Niño , Preescolar , Neoplasias del Sistema Digestivo/terapia , Femenino , Humanos , Incidencia , Lactante , Estimación de Kaplan-Meier , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Radioterapia Adyuvante/estadística & datos numéricos , Estudios Retrospectivos , Tumor Rabdoide/terapia , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Programa de VERF/estadística & datos numéricos , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years. MATERIALS AND METHODS: A search of medical records from seven centers was performed between January 2005 and December 2016. RESULTS: Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01). CONCLUSION: Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
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Neoplasias del Sistema Nervioso Central/diagnóstico , Tumor Rabdoide/diagnóstico , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/patología , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Supervivencia sin Progresión , Tumor Rabdoide/mortalidad , Tumor Rabdoide/patologíaRESUMEN
PURPOSE: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus, Delta-24-RGD, which selectively replicates in and kills tumor cells. EXPERIMENTAL DESIGN: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model, and immunocompetent humanized mouse models (hCD34+-NSG-SGM3). RESULTS: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8+ T-cell infiltration. CONCLUSIONS: Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
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Neoplasias del Sistema Nervioso Central/terapia , Tumores Neuroectodérmicos Primitivos/terapia , Oligopéptidos/genética , Viroterapia Oncolítica/métodos , Virus Oncolíticos/genética , Tumor Rabdoide/terapia , Teratoma/terapia , Animales , Apoptosis , Proliferación Celular , Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Inmunidad Celular , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Tumores Neuroectodérmicos Primitivos/inmunología , Tumores Neuroectodérmicos Primitivos/mortalidad , Tumores Neuroectodérmicos Primitivos/patología , Tumor Rabdoide/inmunología , Tumor Rabdoide/mortalidad , Tumor Rabdoide/patología , Teratoma/inmunología , Teratoma/mortalidad , Teratoma/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Atypical teratoid/rhabdoid tumor (AT/RT) represents a rare malignant embryonic tumor of infant and early childhood. Its prognosis remains dismal despite aggressive multimodal treatment. We report the case of a 24-year-old male who was diagnosed with left parietal AT/RT after total resection and who is still in good health and recurrence free 4 years after surgery and adjuvant chemotherapy and radiotherapy.
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Neoplasias Encefálicas/mortalidad , Tumor Rabdoide/mortalidad , Teratoma/mortalidad , Adulto , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Terapia Combinada , Humanos , Masculino , Pronóstico , Tumor Rabdoide/patología , Tumor Rabdoide/terapia , Tasa de Supervivencia , Teratoma/patología , Teratoma/terapia , Adulto JovenRESUMEN
BACKGROUND: Treatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose. RESULTS: In this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM. CONCLUSION: Daily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.
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Lesión Renal Aguda/prevención & control , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/terapia , Carboplatino/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Acondicionamiento Pretrasplante/efectos adversos , Lesión Renal Aguda/sangre , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Encefálicas/mortalidad , Carboplatino/administración & dosificación , Niño , Preescolar , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Meduloblastoma/mortalidad , Meduloblastoma/terapia , Estudios Retrospectivos , Tumor Rabdoide/mortalidad , Tumor Rabdoide/terapia , Teratoma/mortalidad , Teratoma/terapia , Tiotepa/administración & dosificación , Tiotepa/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/métodos , Resultado del TratamientoRESUMEN
Central nervous system (CNS) tumors are the most common solid tumor in pediatrics, accounting for approximately 25% of all childhood cancers, and the second most common pediatric malignancy after leukemia. CNS tumors can be associated with significant morbidity, even those classified as low grade. Mortality from CNS tumors is disproportionately high compared to other childhood malignancies, although surgery, radiation, and chemotherapy have improved outcomes in these patients over the last few decades. Current therapeutic strategies lead to a high risk of side effects, especially in young children. Pediatric brain tumor survivors have unique sequelae compared to age-matched patients who survived other malignancies. They are at greater risk of significant impairment in cognitive, neurological, endocrine, social, and emotional domains, depending on the location and type of the CNS tumor. Next-generation genomics have shed light on the broad molecular heterogeneity of pediatric brain tumors and have identified important genes and signaling pathways that serve to drive tumor proliferation. This insight has impacted the research field by providing potential therapeutic targets for these diseases. In this review, we highlight recent progress in understanding the molecular basis of common pediatric brain tumors, specifically low-grade glioma, high-grade glioma, ependymoma, embryonal tumors, and atypical teratoid/rhabdoid tumor (ATRT). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Cerebelosas/genética , Ependimoma/genética , Glioma/genética , Meduloblastoma/genética , Tumor Rabdoide/genética , Teratoma/genética , Edad de Inicio , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Cerebelosas/clasificación , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Ependimoma/clasificación , Ependimoma/mortalidad , Ependimoma/patología , Predisposición Genética a la Enfermedad , Glioma/clasificación , Glioma/mortalidad , Glioma/patología , Humanos , Meduloblastoma/clasificación , Meduloblastoma/mortalidad , Meduloblastoma/patología , Clasificación del Tumor , Fenotipo , Tumor Rabdoide/clasificación , Tumor Rabdoide/mortalidad , Tumor Rabdoide/patología , Teratoma/clasificación , Teratoma/mortalidad , Teratoma/patologíaRESUMEN
BACKGROUND: Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients. METHODS: We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital. RESULTS: Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P < 0.0001), IT (P = 0.01), and AuHCR (P < 0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P < 0.0001) were independently associated with reduced risk of death. CONCLUSIONS: Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/terapia , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Evaluación de Procesos y Resultados en Atención de Salud/estadística & datos numéricos , Radioterapia/estadística & datos numéricos , Tumor Rabdoide/terapia , Teratoma/terapia , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Preescolar , Terapia Combinada , Femenino , Humanos , Lactante , Masculino , Tumor Rabdoide/mortalidad , Tumor Rabdoide/secundario , Teratoma/mortalidad , Teratoma/secundarioRESUMEN
PURPOSE: Rhabdoid tumor of the kidney (RTK) is one of the most aggressive childhood renal tumors. Overall survival ranges from 22% to 47%. The indication for radiation therapy (RT) in usually very young patients is an ongoing discussion. Recent protocols recommend RT independent of local stage, the latter being a good discriminator in other childhood kidney tumors. In this study, we analyze the evidence for RT in regard to risk factors, including tumor stage. METHODS AND MATERIALS: This study analyzed 58 patients with RTK from Austria, Switzerland, and Germany treated in the framework of 4 consecutive, prospective renal/rhabdoid tumor studies from 1991 to 2014. All treatment protocols included multimodality treatment, including high-intensity chemotherapy, surgery, and RT. RESULTS: Local stage distribution was not applicable, I, II, and III in 1, 6, 11, and 40, respectively. Twenty-nine (50%) patients had stage IV disease at diagnosis. Thirty-seven patients (64%) achieved complete remission, and 49% (18/37) relapsed. Thirty-four patients (60%) patients had progressive disease and died, 17 had local disease, 10 had combined disease, and 7 had distant disease; 2 treatment-related deaths were reported (3%). Twenty-one patients received RT during first-line treatment, 18 of them to all involved sites. Eight of the 34 cases of progressive disease occurred in irradiated patients. The local failure rate of treated patients with local stage II or III disease was 29% (6/18) in patients irradiated to all sites compared with 68% (15/22) in nonirradiated patients. One of 6 stage I patients received RT, and 1 patient experienced distant relapse (2-year progression-free and overall survival both 83% ± 15%). Progression-free survival for local stage II and III disease treated with RT, adjusted for early relapse or treatment abandonment, was 67% ± 11%, compared with 15% ± 7% without RT (P < .0001). CONCLUSION: The 68% local failure rate in nonirradiated patients underlines the importance of local treatment. Our experience supports the use of RT for local control in higher stage disease. In contrast, no local relapse in 6 local stage I patients, including 5 nonirradiated patients, suggests omission of RT in this favorable subset of usually infant patients with RTK.
Asunto(s)
Neoplasias Renales/radioterapia , Tumor Rabdoide/radioterapia , Austria , Preescolar , Terapia Combinada/métodos , Alemania , Humanos , Lactante , Estimación de Kaplan-Meier , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Supervivencia sin Progresión , Dosificación Radioterapéutica , Inducción de Remisión , Tumor Rabdoide/mortalidad , Tumor Rabdoide/patología , Tumor Rabdoide/cirugía , Factores de Riesgo , Estadísticas no Paramétricas , SuizaRESUMEN
PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS: Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS: Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION: The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Radioterapia Conformacional/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidad , Proteína SMARCB1/genética , Teratoma/genética , Teratoma/mortalidad , Adulto JovenRESUMEN
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
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Neoplasias Encefálicas/genética , Mutación/genética , Glándula Pineal , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Proteína SMARCB1/genética , Adolescente , Adulto , Factores de Edad , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tumor Rabdoide/mortalidad , Tasa de Supervivencia , Adulto JovenRESUMEN
Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive malignant primitive neoplasms that commonly occur in children younger than 2 years of age. The prognosis is generally dismal with a median survival time of <1 year. The majority of AT/RT occur in the posterior fossa and less frequently the supratentorium. Primary pediatric spinal AT/RT are exceedingly rare and only 15 cases have been reported to date. Here we report a very unusual case of primary spinal AT/RT extensively involving the spinal cord from T11 down to the cauda equina. In this patient, the tumor was highly aggressive and resulted in extensive dissemination into the nerve roots and paraspinal soft tissue rapidly resulting in the patient's death 1 month after diagnosis. to the best of our knowledge, this degree of involvement of the spine by a primary AT/RT has not been described before.
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Cauda Equina/patología , Tumor Rabdoide/fisiopatología , Neoplasias de la Médula Espinal/fisiopatología , Teratoma/fisiopatología , Biopsia , Cauda Equina/diagnóstico por imagen , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Pronóstico , Tumor Rabdoide/diagnóstico por imagen , Tumor Rabdoide/mortalidad , Tumor Rabdoide/secundario , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/mortalidad , Neoplasias de la Médula Espinal/patología , Teratoma/diagnóstico por imagen , Teratoma/mortalidad , Teratoma/secundarioRESUMEN
No standard treatment protocol to guide the management of the primary central nervous system atypical teratoid rhabdoid tumors (ATRTs). To evaluate the efficacy of GTR (gross total resection), RT (radiotherapy), CCMT (conventional chemotherapy), or intensified chemotherapy (ICMT) and verify the optimal treatment strategy. A total of 501 cases (18 cases from our center and 483 cases from published literature) were eligible for analysis. Clinical characteristics were reviewed, and overall survival (OS) of each combined treatment modality was compared. These prior publication data were processed according to PRISMA guidelines. This study included 265 (52.9%) males and 216 (43.1%) females. The median age of the cohort was 2.2 years with 295 (58.9%) cases younger than 3 years. GTR was achieved in 217 (43.3%) patients. Initial adjuvant CCMT, CCMT plus intrathecal chemotherapy (ITCMT), CCMT plus high-dose chemotherapy (HDCMT), and CCMT plus ITCMT and HDCMT were administered in 228 (45.5%), 78 (15.6%), 55 (11.0%), and 24 (4.8%) patients, respectively. Radiotherapy (RT) was prescribed in 266 (53.1%) patients. Fewer patients younger than 3 years old received RT (21.9% vs 33.0%, p < 0.001, chi-square test). The OS of the entire cohort at 1, 3, and 5 years were 56.6, 35.9, and 30.8%, respectively. After adjusting for age and sex, GTR (HR 0.630; p < 0.001), RT (HR = 0.295; p < 0.001), CCMT (HR = 0.382; p < 0.001), and ICMT (HR = 0.209; p < 0.001) were independent prognostic factors. The 3-year OS of surgery alone, surgery plus CCMT, surgery plus RT, surgery plus ICMT, surgery plus CCMT and RT, and surgery plus ICMT and RT were 8.9, 13.4, 23.7, 37.4, 48.3, and 68.5%, respectively. When taking into consideration the extent of tumor resection (n = 462), GTR followed by RT, CCMT, intrathecal chemotherapy, and high-dose chemotherapy provided the best OS (5-year OS 88.2%). In younger children, adjuvant ICMT had a greater 3-year OS than adjuvant RT alone (34.0% vs 0%, p = .001). This study identified independent favorable predictors for OS of ATRTs and distinguished significantly different OS following various treatment modalities. If tolerable, intensive treatment with GTR followed by adjuvant RT and ICMT is recommended. Intensified CCMT could be an alternative to avoid radiological radiotoxicity for younger children CRD42018098841.
Asunto(s)
Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Tumor Rabdoide/mortalidad , Tumor Rabdoide/terapia , Teratoma/mortalidad , Teratoma/terapia , Adolescente , Adulto , Anciano , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Radiocirugia , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.
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Biomarcadores de Tumor/genética , Tumor Rabdoide/mortalidad , Neoplasias de la Médula Espinal/mortalidad , Teratoma/mortalidad , Niño , Preescolar , Terapia Combinada , ADN Helicasas/genética , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Proteínas Nucleares/genética , Pronóstico , Estudios Retrospectivos , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Tumor Rabdoide/terapia , Proteína SMARCB1/genética , Neoplasias de la Médula Espinal/genética , Neoplasias de la Médula Espinal/patología , Neoplasias de la Médula Espinal/terapia , Tasa de Supervivencia , Teratoma/genética , Teratoma/patología , Teratoma/terapia , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: SEER 18 Custom Data registries were queried for AT/RT (ICD-0-3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias. RESULTS: The majority of patients were <3 years old (75.8%). Patients <3 were more likely to be treated without RT as compared with older patients (62% vs 38%). Doubly robust MVA identified distant disease as a negative prognostic factor (HR 2.1, P = 0.003), whereas trimodality therapy was strongly protective (HR 0.39, P < 0.001). Infants (<1), toddlers (1-2), and older children (3+) all benefited from trimodality therapy, with largest benefit for infants (HR 0.34, P = 0.02) and toddlers (HR 0.31, P < 0.001). CONCLUSION: The current study provides further evidence that trimodality therapy improves clinical outcomes among patients with AT/RT. This finding was most pronounced for younger patients; therefore, further studies are needed to confirm this finding in this vulnerable population.
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Recurrencia Local de Neoplasia/mortalidad , Tumor Rabdoide/mortalidad , Teratoma/mortalidad , Adolescente , Niño , Preescolar , Estudios de Cohortes , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Michigan/epidemiología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/terapia , Vigilancia de la Población , Pronóstico , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/epidemiología , Tumor Rabdoide/terapia , Tasa de Supervivencia , Teratoma/diagnóstico , Teratoma/epidemiología , Teratoma/terapiaRESUMEN
BACKGROUND: We evaluated the factors influencing overall survival (OS) and event-free survival (EFS) in children with atypical teratoid/rhabdoid tumors (ATRTs). METHODS: We performed a retrospective study of children aged <16 years and tumor histological diagnosis of ATRT. Univariate and multivariate analyses were performed to determine the effect of individual and interdependent variables and survival. RESULTS: A total of 34 children had undergone surgery, with a male/female ratio of 1.8:1. On univariate analysis, the factors with statistically significant influence on OS and EFS were the extent of resection (P = 0.012 and P = 0.015, respectively), adjuvant therapy (P ≤ 0.001 and P = 0.001, respectively), and rhabdoid cell percentage (P = 0.004 and P = 0.005, respectively). On survival analysis, the median OS and EFS were better for those who had completed adjuvant therapy versus those who had not received adjuvant therapy (OS, 22.7 months vs. 3.5 months; EFS, 10.9 months vs. 3.5 months), those who had undergone gross total resection versus those who had undergone partial decompression (OS, 10.9 months vs. 2 months; EFS, 8.9 months vs. 2.5 months), and those with <50% rhabdoid cells in the biopsy specimen versus those with >50% rhabdoid cells (OS, 10.9 months vs. 3.7 months; EFS, 8.9 months vs. 3.5 months). On multivariate analysis, only the extent of resection and adjuvant therapy status had a significant influence on OS and EFS. CONCLUSION: Achieving gross total resection should be the aim of surgery, depending on the tumor location, and these children should undergo upfront adjuvant treatment.