RESUMEN
Inflammatory myofibroblastic tumor (IMT) is a genetically heterogenous tumor of the viscera and soft tissues, with multiple molecular features having been demonstrated in this tumor type. About 50% of cases harbor an anaplastic lymphoma kinase (ALK) gene rearrangement, and recent studies have described novel fusions involving the ROS1 and PDGFRß genes in a subset of ALK-negative cases. However, the molecular features of the remaining subset of cases are not yet defined. We report a case of a large, highly aggressive IMT of the lung in a 17-year-old girl. This case was molecularly characterized through whole-genome and transcriptome sequencing. Subsequently, we investigated a cohort of 15 ALK-negative IMTs of various anatomic sites. All cases were screened using fluorescence in situ hybridization (FISH) for rearrangement of the ETV6 locus and with reverse transcription polymerase chain reaction (RT-PCR) for the ETV6-NTRK3 fusion transcript. Whole-genome and transcriptome sequencing revealed an ETV6-NTRK3 fusion transcript in our index case. This was confirmed by FISH studies for ETV6 gene rearrangement, as well as by RT-PCR. In addition, 2 additional cases in our cohort demonstrated ETV6 rearrangement by FISH. The presence of ETV6-NTRK3 fusion transcript was demonstrated by RT-PCR in one of these additional cases. In summary, we demonstrate the expression of the ETV6-NTRK3 fusion oncogene in a small subset of IMTs, lending further support to the role of oncogenic tyrosine kinases in the pathophysiology of this tumor type. Our data also further expand the growing spectrum of tumor types expressing the ETV6-NTRK3 fusion.
Asunto(s)
Neoplasias Pulmonares/genética , Miofibroma/genética , Proteínas de Fusión Oncogénica/genética , Adolescente , Adulto , Anciano , Quinasa de Linfoma Anaplásico , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas Receptoras , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
PURPOSE: To report the final analysis of survival outcomes for children with newly diagnosed high-grade glioma (HGG) treated on the "Head Start" (HS) II and III protocols with chemotherapy and intent to avoid irradiation in children <6 years old. PATIENTS AND METHODS: Between 1997 and 2009, 32 eligible children were enrolled in HS II and III with anaplastic astrocytoma (AA, n = 19), glioblastoma multiforme (GBM, n = 11), or other HGG (n = 2). Central pathology review was completed on 78% of patients. Patients with predominantly brainstem tumors were excluded. Patients were to be treated with single induction chemotherapy regimen C, comprising four cycles of vincristine, carboplatin, and temozolomide. Following induction, patients underwent marrow-ablative chemotherapy and autologous hematopoietic cell rescue. Irradiation was used for patients with residual tumor after consolidation or >6 years old or at the time of tumor progression. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) for all HGG patients were 25 ± 8% and 36 ± 9%, respectively. The EFS at 5 years for patients with AA and GBM were 24 ± 11% and 30 ± 16%, respectively (P = 0.65). The OS at 5 years for patients with AA and GBM was 34 ± 12% and 35 ± 16%, respectively (P = 0.83). Children <36 months old experienced improved 5-year EFS and OS of 44 ± 17% and 63 ± 17%, compared with children 36-71 months old (31 ± 13% and 38 ± 14%) and children >72 months old (0% and 13 ± 12%). CONCLUSIONS: Irradiation-avoiding treatment strategies should be evaluated further in young children with HGG given similar survival rates to older children receiving standard irradiation-containing therapies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/radioterapia , Niño , Preescolar , Ensayos Clínicos como Asunto , Femenino , Glioma/mortalidad , Glioma/radioterapia , Humanos , Quimioterapia de Inducción , Lactante , Recién Nacido , Masculino , Recurrencia Local de Neoplasia , Pronóstico , Tasa de SupervivenciaRESUMEN
Cisplatin, a major antineoplastic drug used in the treatment of solid tumors, is a known nephrotoxin. This retrospective cohort study evaluated the prevalence and severity of cisplatin nephrotoxicity in 54 children and its impact on height and weight.We recorded the weight, height, serum creatinine, and electrolytes in each cisplatin cycle and after 12 months of treatment. Nephrotoxicity was graded as follows: normal renal function (Grade 0); asymptomatic electrolyte disorders, including an increase in serum creatinine, up to 1.5 times baseline value (Grade 1); need for electrolyte supplementation <3 months and/or increase in serum creatinine 1.5 to 1.9 times from baseline (Grade 2); increase in serum creatinine 2 to 2.9 times from baseline or need for electrolyte supplementation for more than 3 months after treatment completion (Grade 3); and increase in serum creatinine ≥3 times from baseline or renal replacement therapy (Grade 4).Nephrotoxicity was observed in 41 subjects (75.9%). Grade 1 nephrotoxicity was observed in 18 patients (33.3%), Grade 2 in 5 patients (9.2%), and Grade 3 in 18 patients (33.3%). None had Grade 4 nephrotoxicity. Nephrotoxicity patients were younger and received higher cisplatin dose, they also had impairment in longitudinal growth manifested as statistically significant worsening on the height Z Score at 12 months after treatment. We used a multiple logistic regression model using the delta of height Z Score (baseline-12 months) as dependent variable in order to adjust for the main confounder variables such as: germ cell tumor, cisplatin total dose, serum magnesium levels at 12 months, gender, and nephrotoxicity grade. Patients with nephrotoxicity Grade 1 where at higher risk of not growing (OR 5.1, 95% CI 1.07-24.3, P=0.04). The cisplatin total dose had a significant negative relationship with magnesium levels at 12 months (Spearman r=-0.527, P=<0.001).
Asunto(s)
Antineoplásicos/efectos adversos , Estatura/efectos de los fármacos , Cisplatino/efectos adversos , Crecimiento/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Neoplasias/tratamiento farmacológico , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Enfermedades Renales/epidemiología , Masculino , Prevalencia , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Extraordinary advancements in sequencing technology have made what was once a decade-long multi-institutional endeavor into a methodology with the potential for practical use in a clinical setting. We therefore set out to examine the clinical value of next-generation sequencing by enrolling patients with incurable or ambiguous tumors into the Personalized OncoGenomics initiative at the British Columbia Cancer Agency whereby whole genome and transcriptome analyses of tumor/normal tissue pairs are completed with the ultimate goal of directing therapeutics. First, we established that the sequencing, analysis, and communication with oncologists could be completed in less than 5 weeks. Second, we found that cancer diagnostics is an area that can greatly benefit from the comprehensiveness of a whole genome analysis. Here, we present a scenario in which a metastasized sphenoid mass, which was initially thought of as an undifferentiated squamous cell carcinoma, was rediagnosed as an SMARCB1-negative rhabdoid tumor based on the newly acquired finding of homozygous SMARCB1 deletion. The new diagnosis led to a change in chemotherapy and a complete nodal response in the patient. This study also provides additional insight into the mutational landscape of an adult SMARCB1-negative tumor that has not been explored at a whole genome and transcriptome level.
Asunto(s)
Carcinoma de Células Escamosas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Tumor Rabdoide/genética , Factores de Transcripción/genética , Adulto , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Análisis Mutacional de ADN , Perfilación de la Expresión Génica , Genoma Humano , Humanos , Masculino , Tumor Rabdoide/tratamiento farmacológico , Tumor Rabdoide/patología , Proteína SMARCB1RESUMEN
Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition.
Asunto(s)
Neoplasias Encefálicas/tratamiento farmacológico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Meduloblastoma/tratamiento farmacológico , Terapia Molecular Dirigida , Medicina de Precisión/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/uso terapéutico , Adolescente , Animales , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteínas de Ciclo Celular/genética , Niño , Preescolar , Estudios de Cohortes , Humanos , Lactante , Meduloblastoma/genética , Meduloblastoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Factores de Riesgo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa Tipo Polo 1RESUMEN
As "atypical teratoid rhabdoid tumors" (ATRTs) may mimic "small round blue cell tumors" (SRBCT), we reexamined our ATRT experience focusing upon INI-1 immunohistochemistry (IHC). All high-grade pediatric brain tumors occurring from 1986-2006 at our institution underwent INI-1 IHC. Clinicopathologic data from each INI-1 immunonegative case were reviewed. Additional genetic, epigenetic and IHC analyses (including interrogation of INI-1 and CLDN6) were performed on a subset of the INI-1 immunonegative cases. Twelve INI-1 IHC negative tumors were identified retrospectively, of which only two previously carried the diagnosis of ATRT. Overall, the clinicopathologic and genetic data supported the assertion that all 12 cases represented ATRT. Unexpectedly, three long-term survivors (4.2, 7.0 and 8.5 years) were identified. As hypothesized, "teratoid" and "rhabdoid" histologic features were relatively infrequent despite gross total resections in some cases. Methylation specific polymer chain reaction (PCR) (MSP) revealed a uniform methylation pattern across all cases and gene promoters tested (ie, MGMT, HIC1, MLH3 and RASSF1); notably, all cases demonstrated unmethylated MGMT promoters. Our data demonstate that a primitive non-rhabdoid histophenotype is common among ATRTs and highlights the diagnostic importance of INI-1 IHC. Epigenetically, the MGMT promoter is usually unmethylated in ATRT, suggesting that potential temozolomide-based chemotherapy may be of limited efficacy.