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1.
Int J Mol Sci ; 24(4)2023 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-36835213

RESUMEN

Novel anti-EGFR therapies target resistance to standard-of-care anti-EGFR in patients with metastatic lung cancer. We describe tumors at progression versus at the initiation of novel anti-EGFR agents in patients with metastatic lung adenocarcinoma harboring EGFR mutation. This clinical case series reports the histological and genomic features and their evolution following disease progression under amivantamab or patritumab-deruxtecan in clinical trials. All patients had a biopsy at disease progression. Four patients harboring EGFR gene mutations were included. Three of them received anterior anti-EGFR treatment. Median delay to disease progression was 15 months (range: 4-24). At progression, all tumors presented a mutation in the TP53 signaling pathway associated with a loss of heterozygosis (LOH) of the allele in 75% (n = 3), and two tumors (50%) presented an RB1 mutation associated with LOH. Ki67 expression increased above 50% (range 50-90%) in all samples compared to baseline (range 10-30%), and one tumor expressed a positive neuroendocrine marker at progression. Our work reports the potential molecular mechanisms of resistance under novel anti-EGFR in patients with metastatic EGFR-mutated lung adenocarcinoma, with the transformation to a more aggressive histology with acquired TP53 mutation and/or the increase in Ki67 expression. These characteristics are usually found in aggressive Small Cell Lung Cancer.


Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Antígeno Ki-67/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología
2.
J Pathol ; 255(1): 1-15, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33999421

RESUMEN

Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
ADN Helicasas/deficiencia , Proteínas Nucleares/deficiencia , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Factores de Transcripción/deficiencia , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Preescolar , ADN Helicasas/genética , Femenino , Humanos , Lactante , Masculino , Proteínas Nucleares/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína SMARCB1/deficiencia , Proteína SMARCB1/genética , Factores de Transcripción/genética
3.
Pediatr Blood Cancer ; 68(3): e28819, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33245195

RESUMEN

BACKGROUND: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far. METHODS: Investigators of seven European countries representing national reference or large oncological centers convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings. RESULTS: From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/[restricted]/no) and the presence of tumor cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good, and on the percentage of tumor cells slight to moderate. Though the value of cytology is unquestioned to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed. CONCLUSION: For any work with bone marrow aspirates, the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore, its use as response criterion should be reconsidered.


Asunto(s)
Examen de la Médula Ósea/métodos , Neoplasias de la Médula Ósea/secundario , Citodiagnóstico/métodos , Neuroblastoma/patología , Estudios de Seguimiento , Humanos , Pronóstico , Reproducibilidad de los Resultados
4.
Pediatr Blood Cancer ; 67(4): e28154, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31930719

RESUMEN

BACKGROUND: Esthesioneuroblastoma (ENB) is a rare neuroectodermal tumor that seldom occurs during childhood. Multimodal treatments are currently proposed, but the place of each therapy is still in debate. Our objective is to describe clinical evolution, especially the pattern of relapses and determine contributors to tumor progression. PROCEDURE: Medical charts of all children (≤18 years) affected by ENB treated in France from January 1990 to December 2015 were retrospectively analyzed. RESULTS: Eighteen patients were selected (10 males). Median age at diagnosis was 12.2 years (0.9-18). Tumor extension was Kadish stage A (n = 1), B (n = 3), C (n = 10), and D (n = 4). Hyams histological grades were I (n = 1), II (n = 3), III (n = 6), and IV (n = 6) (in two cases not defined). Initial cervical nodal spread was assessed by magnetic resonance imaging (n = 15), computed tomography scan (n = 16), fluorodeoxyglucose-positron emission tomography-computed tomography (n = 7), and cytological/histological analysis (n = 2). N1 stage was confirmed by imaging in two of 18 cases and one of two cases had cervical node dissection with neck irradiation (58 Gy). After a median follow-up of survivors of 7.6 years (3.8-17.9), 10 patients developed neuromeningeal progression, whereas no cervical nodal relapse occurred and only eight survived. Both 5-year overall and event-free survival rates were 44.4% (±11.7%). CONCLUSIONS: The poor prognosis is mainly related to neuromeningeal dissemination that should be considered during treatment strategy. However, cervical lymph node relapse is rare.


Asunto(s)
Estesioneuroblastoma Olfatorio/patología , Cavidad Nasal/patología , Recurrencia Local de Neoplasia/patología , Neoplasias Nasales/patología , Enfermedades Raras/patología , Adolescente , Niño , Preescolar , Terapia Combinada , Estesioneuroblastoma Olfatorio/terapia , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Recurrencia Local de Neoplasia/terapia , Neoplasias Nasales/terapia , Pronóstico , Enfermedades Raras/terapia , Estudios Retrospectivos , Tasa de Supervivencia
5.
Pediatr Blood Cancer ; 67(1): e27998, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31571399

RESUMEN

BACKGROUND: Retinoblastoma with macroscopic optic nerve (ON) invasion depicted by imaging at diagnosis remains a major problem and carries a poor prognosis. We sought to describe the treatment and outcome of these high-risk patients. METHODS: Retrospective mono-institutional clinical, radiological, and histological review of patients with uni- or bilateral retinoblastoma with obvious ON invasion, defined by radiological optic nerve enlargement (RONE) depicted by computed tomography scan or magnetic resonance imaging (MRI), was performed. RESULTS: Between 1997 and 2014, among the 936 patients with retinoblastoma treated at Institut Curie, 11 had detectable RONE. Retinoblastoma was unilateral in 10 and bilateral in one. Median age at diagnosis was 28 months (range, 11-96). ON enlargement extended to the orbital portion in three patients, to the optic canal in five, to the prechiasmatic portion in two, and to the optic chiasm in one. Nine patients received neoadjuvant chemotherapy and partial response was obtained in all. Enucleation was performed in 10/11 patients-by an anterior approach in three and by anterior and subfrontal approaches in seven. Three patients had a positive ON resection margin (2/3 after primary enucleation). All enucleated patients received adjuvant treatment (conventional chemotherapy: 10, high-dose chemotherapy: seven, radiotherapy: five). Leptomeningeal progression occurred in four patients. Seven are in first complete remission (median follow up: 8 years [3.5-19.4]). CONCLUSION: Neoadjuvant chemotherapy and microscopic complete resection have a pivotal role in the management of retinoblastoma with RONE. MRI is recommended for initial and pre-operative accurate staging. Surgery should be performed by neurosurgeons in case of posterior nerve invasion. Radiotherapy is required in case of incomplete resection.


Asunto(s)
Neoplasias del Nervio Óptico/patología , Nervio Óptico/patología , Neoplasias de la Retina/patología , Retinoblastoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Terapia Combinada , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Invasividad Neoplásica , Neoplasias del Nervio Óptico/diagnóstico por imagen , Neoplasias del Nervio Óptico/terapia , Pronóstico , Neoplasias de la Retina/diagnóstico por imagen , Neoplasias de la Retina/terapia , Retinoblastoma/diagnóstico por imagen , Retinoblastoma/terapia , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos
6.
Clin Exp Ophthalmol ; 48(4): 500-511, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31872542

RESUMEN

BACKGROUND: Retinoblastoma is a rare intraocular malignancy in children. Current treatments have many adverse effects. New therapeutic approaches like intravitreal injections of chemotherapies are currently being developed but their toxicities need to be evaluated on animal models. This study compares the efficacy and toxicity of intravitreal melphalan, topotecan and carboplatin, alone or in combination (sequential administration), in the LHBetaTag retinoblastoma mice. METHODS: Mice were divided into nine groups: control, carboplatin 1.5 and 4 µg, melphalan 0.1 and 1 µg, topotecan 0.1 and 1 µg, carboplatin 4 µg/topotecan 0.1 µg and melphalan 1 µg/topotecan 0.1 µg. The follow-up was performed using fundus imaging and optical coherence tomography combined with histopathological analysis. Absence of tumour and presence of calcified tumours were the criteria for therapeutic response assessment. Ocular complications were assessed after four weekly injections. Retinal toxicity was defined by the decrease of retinal thickness and of the number of retinal layers. RESULTS: Topotecan was inactive on retinal tumours. Melphalan (1 µg) led to a complete tumour control in 91.7% of eyes. Carboplatin strongly decreased the tumour burden (85.7-93.8% of eyes without retinal tumour). The intravitreal injection itself led to ocular complications (25% of media opacities and 45.7% of retinal detachment). Only melphalan at 1 µg showed a strong retinal toxicity. The two combinations showed a good efficacy in reducing the number of eyes with retinal tumours with a reduced retinal toxicity. CONCLUSIONS: This preclinical study suggests that intravitreal injection of carboplatin has a low toxicity and could be evaluated in clinical practice to treat patients suffering from retinoblastoma.


Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Animales , Carboplatino/uso terapéutico , Humanos , Inyecciones Intravítreas , Melfalán/uso terapéutico , Melfalán/toxicidad , Ratones , Retina , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Estudios Retrospectivos
7.
Int J Cancer ; 144(1): 68-79, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29923174

RESUMEN

Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms' tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations-CNAs, SNVs or both-in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.


Asunto(s)
Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Neoplasias Renales/genética , Tumor de Wilms/genética , Biomarcadores de Tumor/sangre , Niño , Preescolar , ADN Tumoral Circulante/sangre , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Lactante , Neoplasias Renales/diagnóstico , Neoplasias Renales/terapia , Masculino , Terapia Neoadyuvante , Nefrectomía , Estudios Retrospectivos , Sensibilidad y Especificidad , Secuenciación Completa del Genoma/métodos , Tumor de Wilms/diagnóstico , Tumor de Wilms/terapia
8.
J Pathol ; 245(1): 29-40, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29431183

RESUMEN

Sarcoma represents a highly heterogeneous group of tumours. We report here the first unbiased and systematic search for gene fusions combined with unsupervised expression analysis of a series of 184 small round cell sarcomas. Fusion genes were detected in 59% of samples, with half of them being observed recurrently. We identified biologically homogeneous groups of tumours such as the CIC-fused (to DUX4, FOXO4 or NUTM1) and BCOR-rearranged (BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR, and BCOR internal duplication) tumour groups. VGLL2-fused tumours represented a more biologically and pathologically heterogeneous group. This study also refined the characteristics of some entities such as EWSR1-PATZ1 spindle cell sarcoma or FUS-NFATC2 bone tumours that are different from EWSR1-NFATC2 tumours and transcriptionally resemble CIC-fused tumour entities. We also describe a completely novel group of epithelioid and spindle-cell rhabdomyosarcomas characterized by EWSR1- or FUS-TFCP2 fusions. Finally, expression data identified some potentially new therapeutic targets or pathways. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Neoplasias Óseas/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma de Células Pequeñas/genética , Transcriptoma/genética , Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Fusión Génica/genética , Humanos , Proteínas Musculares/genética , Proteínas Represoras/genética , Factores de Transcripción/genética
9.
Pediatr Blood Cancer ; 64(12)2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28643357

RESUMEN

BACKGROUND: Nuclear protein of the testis (NUT) carcinoma (formerly NUT midline carcinoma) is an aggressive tumor defined by the presence of NUT rearrangement with a poor prognosis. This rare cancer is underdiagnosed and poorly treated. OBJECTIVE: The primary objective of this study was to describe the clinical, radiologic, and biological features of NUT carcinoma. The secondary objective was to describe the various treatments and assess their efficacy. METHODS: This retrospective multicenter study was based on review of the medical records of children and adults with NUT carcinoma with specific rearrangement or positive anti-NUT nuclear staining (>50%). RESULTS: This series of 12 patients had a median age of 18.1 years (ranges: 12.3-49.7 years). The primary tumor was located in the chest in eight patients, the head and neck in three patients, and one patient had a multifocal tumor. Nine patients presented regional lymph node involvement and eight distant metastases. One-half of patients were initially misdiagnosed. Specific NUT antibody was positive in all cases tested. A transient response to chemotherapy was observed in four of 11 patients. Only two patients were treated by surgery and five received radiotherapy with curative intent. At the end of follow-up, only one patient was still in remission more than 12 years after the diagnosis. Median overall survival was 4.7 months (95% confidence interval [CI]: 2.1-17.7). CONCLUSION: NUT carcinoma is an aggressive disease refractory to conventional therapy. Early diagnosis by NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma to identify the specific rearrangement of NUT gene is useful to propose the optimal therapeutic strategy.


Asunto(s)
Carcinoma/terapia , Proteínas Nucleares/análisis , Proteínas Oncogénicas/análisis , Adolescente , Adulto , Carcinoma/química , Carcinoma/mortalidad , Niño , Femenino , Reordenamiento Génico , Neoplasias de Cabeza y Cuello/química , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Estudios Retrospectivos , Neoplasias Torácicas/química , Neoplasias Torácicas/mortalidad , Neoplasias Torácicas/terapia , Adulto Joven
10.
Pediatr Blood Cancer ; 64(6)2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27896933

RESUMEN

BACKGROUND: The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. PROCEDURE: We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. RESULTS: Mean age was 12 ± 5.7 years (range 0.1-21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). CONCLUSIONS: Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors.


Asunto(s)
Glioma/genética , Glioma/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Adolescente , Adulto , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Glioma/terapia , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Neuroblastoma/terapia , Sarcoma/terapia
11.
J Pediatr Hematol Oncol ; 39(5): e279-e284, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28338568

RESUMEN

Antiangiogenic drugs are currently standard of care in adults with renal cell carcinoma (RCC), including translocation RCC. Although antitumor activity and toxicity profile are well known in adults, few data have been reported in children. Here we present the case of a patient diagnosed at 2 years old with a metastatic translocation RCC, consecutively treated with 5 tyrosine kinase inhibitors during 6 years. The antitumor activity and toxic effects are described, and a brief review of the literature is presented.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Carcinoma de Células Renales/patología , Preescolar , Femenino , Humanos , Metástasis de la Neoplasia , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores
12.
Clin Exp Ophthalmol ; 43(1): 12-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-24923774

RESUMEN

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) is associated with an excellent survival rate greater than 85%, and is considered to be a favourable site for this tumour. Treatment is based on combination chemotherapy together with best local therapy, sometimes surgery but more often radiation therapy. Local therapy is associated with frequent and potentially severe late sequelae. DESIGN: Retrospective hospital single-centre analysis. PARTICIPANTS: Eighty-two patients treated in Institut Curie, Paris. METHODS: To define long-term status of survivors after localized ORMS, patients treated between 1975 and 2010 were analysed. MAIN OUTCOME MEASURES: Clinical structural and functional orbital, and general sequelae. RESULTS: Median age at diagnosis was 6 years (range: 8 months-19 years), and median follow up was 8.5 years (range: 7 months-24 years). The 5-year globe conservation rate was 90.4%. Ophthalmic dysfunction was present in 79% of patients. Impaired visual acuity (VA), was present in 62% of patients; 38% of them had severe visual disability with VA < 6/60. Late effects on orbitofacial structure were present in 39.8% of patients. Ocular or palpebral sequelae were present in 79% of survivors, mainly cataract (42%), ocular surface lesions such as keratoconjunctivitis (40%) and eyelid abnormalities (29%). General late effects were rare. CONCLUSIONS: These data suggest that ocular and orbital late effects are frequent after treatment of ORMS, indicating the need for systematic long-term ophthalmologic follow up of these patients. Radiation therapy is an important part of the total burden of therapy.


Asunto(s)
Neoplasias Orbitales/patología , Rabdomiosarcoma/patología , Adolescente , Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Neoplasias Orbitales/mortalidad , Neoplasias Orbitales/terapia , Complicaciones Posoperatorias , Radioterapia , Estudios Retrospectivos , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/terapia , Tasa de Supervivencia , Adulto Joven
13.
Pediatr Surg Int ; 31(4): 375-9, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25652760

RESUMEN

Congenital/infantile fibrosarcoma (IFS) is a relatively rare form of fibrosarcoma diagnosed at birth or during early years of life and that differs from its adult counterpart because of a more favorable behavior. IFS is also known as cellular congenital mesoblastic nephroma, when it affects the kidney and is often but not always characterized by the ETV6-NTRK3 fusion transcript. We report herein the first series of an exceptional tumor of the small intestine occurring in newborns. The four patients shared a stereotyped clinico-pathological presentation with early and acute onset, intestinal perforation, and an infiltration by a highly cellular spindle cell tumor within the dilated intestinal wall exhibiting pathologic features typical of IFS. Molecular studies for the ETV6-NTRK3 translocation were negative in the three cases tested. Patients were treated by surgical wide resection alone and are alive and well (follow-up: 36 months-25 years). Thus, this new clinico-pathological entity, even with lack of documented evidence of the ETV6-NTRK3 translocation, should be included in the differential diagnosis of congenital bowel perforation or obstruction and may represent an intestinal counterpart of IFS.


Asunto(s)
Fibrosarcoma/congénito , Neoplasias Intestinales/congénito , Intestino Delgado/patología , Diagnóstico Diferencial , Femenino , Fibrosarcoma/patología , Humanos , Lactante , Recién Nacido , Neoplasias Intestinales/patología , Masculino
14.
Breast Cancer Res ; 16(3): R46, 2014 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-24887297

RESUMEN

INTRODUCTION: Pure invasive micropapillary carcinoma (IMPC) is a special type of breast carcinoma characterised by clusters of cells presenting polarity abnormalities. The biological alterations underlying this pattern remain unknown. METHODS: Pangenomic analysis (n=39), TP53 (n=43) and PIK3CA (n=41) sequencing in a series of IMPCs were performed. A subset of cases was also analysed with whole-exome sequencing (n=4) and RNA sequencing (n=6). Copy number variation profiles were compared with those of oestrogen receptors and grade-matched invasive ductal carcinomas (IDCs) of no special type. RESULTS: Unsupervised analysis of genomic data distinguished two IMPC subsets: one (Sawtooth/8/16) exhibited a significant increase in 16p gains (71%), and the other (Firestorm/Amplifier) was characterised by a high frequency of 8q (35%), 17q (20% to 46%) and 20q (23% to 30%) amplifications and 17p loss (74%). TP53 mutations (10%) were more frequently identified in the amplifier subset, and PIK3CA mutations (4%) were detected in both subsets. Compared to IDC, IMPC exhibited specific loss of the 6q16-q22 region (45%), which is associated with downregulation of FOXO3 and SEC63 gene expression. SEC63 and FOXO3 missense mutations were identified in one case each (2%). Whole-exome sequencing combined with RNA sequencing of IMPC allowed us to identify somatic mutations in genes involved in polarity, DNAH9 and FMN2 (8% and 2%, respectively) or ciliogenesis, BBS12 and BBS9 (2% each) or genes coding for endoplasmic reticulum protein, HSP90B1 and SPTLC3 (2% each) and cytoskeleton, UBR4 and PTPN21 (2% each), regardless of the genomic subset. The intracellular biological function of the mutated genes identified by gene ontology analysis suggests a driving role in the clinicopathological characteristics of IMPC. CONCLUSION: In our comprehensive molecular analysis of IMPC, we identified numerous genomic alterations without any recurrent fusion genes. Recurrent somatic mutations of genes participating in cellular polarity and shape suggest that they, together with other biological alterations (such as epigenetic modifications and stromal alterations), could contribute to the morphological pattern of IMPC. Though none of the individual abnormalities demonstrated specificity for IMPC, whether their combination in IMPC may have a cumulative effect that drives the abnormal polarity of IMPC needs to be examined further with in vitro experiments.


Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Polaridad Celular/genética , Invasividad Neoplásica/genética , Dineínas Axonemales/genética , Secuencia de Bases , Mama/patología , Neoplasias de la Mama/patología , Proteínas de Unión a Calmodulina/genética , Carcinoma Ductal de Mama/patología , Chaperoninas , Fosfatidilinositol 3-Quinasa Clase I , Proteínas del Citoesqueleto/genética , Variaciones en el Número de Copia de ADN , Exoma/genética , Femenino , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Forminas , Amplificación de Genes/genética , Chaperoninas del Grupo II/genética , Humanos , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas de Microfilamentos/biosíntesis , Chaperonas Moleculares , Mutación Missense , Proteínas de Neoplasias/genética , Proteínas Nucleares/biosíntesis , Fosfatidilinositol 3-Quinasas/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas de Unión al ARN , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/biosíntesis , Estudios Retrospectivos , Análisis de Secuencia de ADN , Análisis de Secuencia de ARN , Eliminación de Secuencia/genética , Serina C-Palmitoiltransferasa/genética , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas
16.
J Pediatr Hematol Oncol ; 36(8): 605-12, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25171453

RESUMEN

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) treatment is based on combination chemotherapy associated with best local therapy, sometimes surgery but more often radiation therapy. A retrospective single-center analysis was conducted to more clearly define the long-term outcome of patients with ORMS, to identify patients in whom aggressive first-line local therapy can be avoided. POPULATION: A total of 95 patients with localized parameningeal (PM) or nonparameningeal (NPM) ORMS, treated at the Institut Curie between 1975 and 2010, were analyzed. RESULTS: Median age at diagnosis was 6 years (range, 8 mo to 19.5 y), and median follow-up was 8.5 years (range, 7 mo to 24 y). A total of 25 patients presented PM extension. Radiation therapy was part of primary therapy for 78 patients. Five-year event-free survival and overall survival rates were 65.4%±5.2% and 85.6%±3.9%, respectively. On multivariate analysis, initial tumor size was identified as a significant prognostic factor. Event-free survival was similar for PM and NPM tumors (60.3%±10.4% vs. 62.7%±5.9%, P=0.57), whereas there was a trend for overall survival to be better for NPM tumors (90%±3.9% vs. 72.7%±9.6%, P=0.07). CONCLUSIONS: Localized ORMS has a favorable outcome despite the current trend toward less aggressive and more limited indications of local therapy. Patients with a favorable pattern of strictly ORMS can be treated without first-line radiation therapy.


Asunto(s)
Quimioradioterapia/métodos , Neoplasias Orbitales/terapia , Rabdomiosarcoma/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Ciclofosfamida/uso terapéutico , Dactinomicina/uso terapéutico , Supervivencia sin Enfermedad , Epirrubicina/uso terapéutico , Estudios de Seguimiento , Humanos , Ifosfamida/uso terapéutico , Lactante , Estadificación de Neoplasias , Neoplasias Orbitales/diagnóstico por imagen , Neoplasias Orbitales/patología , Pronóstico , Cintigrafía , Estudios Retrospectivos , Rabdomiosarcoma/diagnóstico por imagen , Rabdomiosarcoma/patología , Resultado del Tratamiento , Vincristina/uso terapéutico , Adulto Joven
17.
J Pediatr Hematol Oncol ; 36(4): 257-62, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24633301

RESUMEN

Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient's age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the "rhabdomyosarcoma philosophy." In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults.


Asunto(s)
Sarcoma Sinovial/patología , Sarcoma Sinovial/terapia , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Invasividad Neoplásica , Sarcoma Sinovial/epidemiología , Factores de Tiempo
18.
Br J Radiol ; 97(1156): 734-743, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38327010

RESUMEN

OBJECTIVES: The neurotrophic tyrosine receptor kinase (NTRK) fusion transcript (FT) is a major genetic landmark of infantile fibrosarcoma (IFS) and cellular congenital mesoblastic nephroma (cCMN) but is also described in other tumours. The recent availability of NTRK-targeted drugs enhances the need for better identification. We aimed to describe the anatomic locations and imaging features of tumours with NTRK-FT in children. CASE SERIES: Imaging characteristics of NTRK-FT tumours of 41 children (median age: 4 months; 63% <1 year old; range: 0-188) managed between 2001 and 2019 were retrospectively analysed. The tumours were located in the soft tissues (n = 24, including 19 IFS), kidneys (n = 9, including 8 cCMN), central nervous system (CNS) (n = 5), lung (n = 2), and bone (n = 1). The tumours were frequently deep-located (93%) and heterogeneous (71%) with necrotic (53%) or haemorrhagic components (29%). Although inconstant, enlarged intratumoural vessels were a recurrent finding (70%) with an irregular distribution (63%) in the most frequent anatomical locations. CONCLUSION: Paediatric NTRK-FT tumours mainly occur in infants with very variable histotypes and locations. Rich and irregular intra-tumoural vascularization are recurrent findings. ADVANCES IN KNOWLEDGE: Apart from IFS of soft tissues and cCMN of the kidneys, others NTRK-FT tumours locations have to be known, as CNS tumours. Better knowledge of the imaging characteristics may help guide the pathological and biological identification.


Asunto(s)
Fibrosarcoma , Neoplasias Renales , Nefroma Mesoblástico , Receptores de Aminoácidos , Lactante , Niño , Humanos , Estudios Retrospectivos , Nefroma Mesoblástico/congénito , Nefroma Mesoblástico/genética , Nefroma Mesoblástico/patología , Fibrosarcoma/genética , Fibrosarcoma/patología , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/genética
19.
Pediatr Radiol ; 43(9): 1174-81, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23681452

RESUMEN

BACKGROUND: Alveolar soft part sarcoma is a rare but highly malignant tumour and little is known about its radiologic pattern in children. OBJECTIVE: To describe the radiologic features of alveolar soft part sarcoma in children and adolescents. MATERIALS AND METHODS: We retrospectively analysed the clinical and imaging data of six children age 7-17 years at diagnosis, with histologically or genetically proven alveolar soft part sarcoma. RESULTS: The tumours were located deep within muscles of the limbs (n = 4), in chest wall muscle (n = 1) and in the orbit (n = 1). High-flow feeding arteries, large drainage veins and intense enhancement were consistent findings by all imaging modalities. At MRI, all tumours demonstrated high signal intensity on T2-weighted images and high or iso-intense signal on T1-W imaging compared to muscle. In tumours larger than 70 mm in one dimension (n = 3/6), large vessels converging toward the tumour centre led to a highly vascularised central stellar area pattern. Five children demonstrated synchronous (n = 4/5) and metachronous (n = 1/5) lung metastases. CONCLUSION: Alveolar soft part sarcoma should be suggested when a highly vascularised, intramuscular mass demonstrating large feeding and drainage vessels converging toward a central stellar area is seen in children, especially if synchronous lung metastases are present.


Asunto(s)
Diagnóstico por Imagen/métodos , Neoplasias de los Músculos/diagnóstico , Sarcoma de Parte Blanda Alveolar/diagnóstico , Adolescente , Niño , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
20.
Ocul Oncol Pathol ; 9(3-4): 96-100, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37900191

RESUMEN

Introduction: The aim of the study was to describe the successful conservative management of diffuse infiltrating retinoblastoma (DIR). Identification of RB1 pathogenic variant was done after cell-free DNA (cfDNA) analysis in aqueous humor. Case presentation: Herein, we report 2 patients with unilateral, non-familial DIR with anterior and posterior involvement. Both patients underwent liquid biopsy for tumor cfDNA analysis in aqueous humor. Treatment consisted of a combination of systemic and intra-arterial chemotherapy, with consecutive intracameral and intravitreal injections of melphalan. One patient also required iodine-125 brachytherapy. In both cases, tumor cfDNA analysis revealed biallelic somatic alterations of the RB1 gene. These alterations were not found in germline DNA. Both patients retained their eyes and had a useful vision after a follow-up of 2 years. Conclusion: In selected cases, conservative management of DIR is safe and effective. Tumor cfDNA analysis in aqueous humor is an effective technique to disclose RB1 somatic alterations that guide the germline molecular explorations and improve genetic counseling after conservative treatment.

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