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1.
Cancer ; 130(13): 2351-2360, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38400828

RESUMEN

BACKGROUND: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event-free survival and provide a rationale for risk stratification in future trials. METHODS: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005-000217-35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second-order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5-year event-free survival (EFS) probabilities. RESULTS: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%-73.1%) and 81.0% (95% confidence interval, 78.9%-82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5-year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively, and the corresponding 5-year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. CONCLUSIONS: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG.


Asunto(s)
Nomogramas , Rabdomiosarcoma , Humanos , Rabdomiosarcoma/mortalidad , Rabdomiosarcoma/patología , Rabdomiosarcoma/terapia , Masculino , Femenino , Preescolar , Niño , Pronóstico , Lactante , Medición de Riesgo , Adolescente , Europa (Continente)/epidemiología , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Proteínas de Fusión Oncogénica/genética
2.
Pediatr Surg Int ; 40(1): 171, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38958763

RESUMEN

PURPOSE: Split abdominal wall muscle flap (SAWMF) is a technique to repair large defects in congenital diaphragmatic hernia (CDH). A possible objection to this intervention could be any associated abdominal muscle weakness. Our aim is to analyze the evolution of this abdominal muscle wall weakness. METHODS: Retrospective review of CDH repair by SAWMF (internal oblique muscle and transverse) from 2004 to 2023 focusing on the evolution of muscle wall weakness. RESULTS: Eighteen neonates of 148 CDH patients (12,1%) were repaired using SAWMF. Mean gestational age and birth weight were 35.7 ± 3.5 weeks and 2587 ± 816 g. Mean lung-to-head ratio was 1.49 ± 0.28 and 78% liver-up. Seven patients (38%) were prenatally treated by tracheal occlusion. Ninety-four percent of the flaps were used for primary repair and one to repair a recurrence. One patient (5.6%) experienced recurrence. Abdominal muscle wall weakness was present in the form of a bulge. Resolution of weakness at 1, 2 and 3 years was 67%, 89% and 94%, respectively. No patient required treatment for weakness or died. CONCLUSIONS: Abdominal muscular weakness after a split abdominal wall muscle flap repair is not a limitation for its realization since it is asymptomatic and presents a prompt spontaneous resolution. LEVEL OF EVIDENCE: IV.


Asunto(s)
Músculos Abdominales , Pared Abdominal , Hernias Diafragmáticas Congénitas , Debilidad Muscular , Colgajos Quirúrgicos , Humanos , Hernias Diafragmáticas Congénitas/cirugía , Hernias Diafragmáticas Congénitas/complicaciones , Recién Nacido , Estudios Retrospectivos , Masculino , Femenino , Pared Abdominal/cirugía , Debilidad Muscular/etiología , Debilidad Muscular/cirugía , Músculos Abdominales/cirugía , Herniorrafia/métodos , Complicaciones Posoperatorias/cirugía , Resultado del Tratamiento
3.
Acta Obstet Gynecol Scand ; 102(7): 883-890, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37194337

RESUMEN

INTRODUCTION: The primary aim of the study was to identify risk factors associated with fetal or neonatal loss, neonatal morbidity, and the need for surgery in fetuses diagnosed with an abdominal cyst. The secondary aim was to compare the characteristics of the cyst according to trimester at diagnosis. MATERIAL AND METHODS: This was an observational retrospective study performed at Vall d'Hebron University Hospital. The study included pregnant women aged 18 years or older with diagnosis of a fetal abdominal cyst from 2008 to 2021. RESULTS: A total of 82 women with a median gestational age of 31+1 weeks (12+0-39+4) were included in the analysis. Seven (8.5%) cases were diagnosed in the first trimester, 28 (34.1%) in the second trimester, and 47 (57.3%) in the third trimester. Fetal or neonatal loss occurred in 10 (12.2%) cases; significant predictors were diagnosis in the first trimester (OR 36.67, 95% CI: 4.89-274.79), male gender (OR 4.75, 95% CI: 1.13-19.9), and associated abnormalities (OR 15.2, 95% CI: 2.92-79.19). A total of 10 of 75 (13.3%) neonates showed at least one neonatal complication, and the only predictor was occurrence of associated abnormalities (OR 7.36, 95% CI: 1.78-30.51). A total of 16 of 75 (21.3%) neonates required postnatal surgery, and the predictors were second-trimester diagnosis (OR 3.92, 95% CI: 1.23-12.51), associated abnormalities (OR 3.81, 95% CI: 1.15-12.64), and bowel location (OR 10.0, 95% CI: 1.48-67.55). CONCLUSIONS: Factors associated with adverse outcomes in fetuses diagnosed with abdominal cysts are first-trimester diagnosis and associated abnormalities. Cysts detected in the second trimester and those of intestinal origin are more likely to require surgery.


Asunto(s)
Quistes , Resultado del Embarazo , Recién Nacido , Embarazo , Humanos , Masculino , Femenino , Estudios Retrospectivos , Tercer Trimestre del Embarazo , Primer Trimestre del Embarazo , Quistes/diagnóstico , Quistes/epidemiología , Quistes/cirugía , Ultrasonografía Prenatal
4.
Cell Mol Life Sci ; 79(11): 546, 2022 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-36221013

RESUMEN

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.


Asunto(s)
Neuroblastoma , Rabdomiosarcoma , Proteínas ADAM/metabolismo , Humanos , Cadenas alfa de Integrinas , Integrinas , Metástasis de la Neoplasia , Neuroblastoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico
5.
Pediatr Blood Cancer ; 69(9): e29739, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35460336

RESUMEN

BACKGROUND/OBJECTIVES: Rhabdomyosarcoma of the perianal/perineal region (PRMS) is rare, with poor survival and limited understanding of the functional consequences of treatment. DESIGN/METHODS: International Society of Pediatric Oncology (SIOP) malignant mesenchymal tumor (MMT) 95, Italian RMS 96, and European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 studies were interrogated to identify factors that impact survival; in RMS 2005, functional outcomes were analyzed. RESULTS: Fifty patients (nonmetastatic) were identified, median age 6.4 years (range: 0.1-19.6): 29 male, 21 female. Tumors were >5 cm in 33 patients. Histopathological subtype was alveolar in 35. Lymph nodes were involved in 23 patients. In RMS 2005, 16/21 (76%) tested alveolar tumors had positive FOXO1 fusion status. Diagnostic biopsy was performed in 37. Primary resection (13) was complete (R0) in one. Delayed primary excision (16) was complete in three. Radiotherapy (RT) in 34/50 patients included external beam (28), brachytherapy (3), and both (3). Nodal RT was given in 16/23 N1 patients (70%). Median follow-up of alive patients (29) was 84.1 months (range: 3.6-221.1). Relapse or progression occurred in 24 patients (48%), 87% were fatal and most events (63%) were locoregional. Five-year event-free survival (EFS) was 47.8 (95% CI: 32.8-61.3), and 5-year overall survival (OS) was 52.6 (95% CI: 36.7-66.2), with age ≥10 years and tumor size >5 cm impacting 5-year EFS and OS (p < .05). Functional outcome data showed bowel, genito-urinary, and psychological issues; fecal incontinence in four of 21 survivors, and urinary symptoms in two of 21. CONCLUSIONS: About 60% of patients with nonmetastatic PRMS survive; older patients and those with large tumors have the worst outcomes. Biopsy should be the initial procedure, and definitive local therapy individualized. Quality-of-life and functional studies are needed to better understand the consequences of treatment.


Asunto(s)
Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Adulto Joven , Mesenquimoma , Recurrencia Local de Neoplasia/radioterapia , Rabdomiosarcoma/patología
6.
J Hepatol ; 73(2): 328-341, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32240714

RESUMEN

BACKGROUND & AIMS: Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS: We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS: These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY: Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.


Asunto(s)
Colina Quinasa , Hepatoblastoma , Neoplasias Hepáticas , beta Catenina/genética , Biomarcadores de Tumor/análisis , Proteínas de Unión al Calcio/genética , Colina Quinasa/antagonistas & inhibidores , Colina Quinasa/metabolismo , Metilación de ADN , Descubrimiento de Drogas/métodos , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Hepatoblastoma/mortalidad , Hepatoblastoma/patología , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactante , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de Neoplasias/genética , Pronóstico , Medición de Riesgo/métodos
7.
Sex Transm Infect ; 90(2): 119-24, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24412996

RESUMEN

OBJECTIVES: To quantify the extent to which guideline recommendations for routine testing for HIV are adhered to outside of genitourinary medicine (GUM), sexual health (SH) and antenatal clinics. METHODS: A systematic review of published data on testing levels following publication of 2008 guidelines was undertaken. Medline, Embase and conference abstracts were searched according to a predefined protocol. We included studies reporting the number of HIV tests administered in those eligible for guideline recommended testing. We excluded reports of testing in settings with established testing surveillance (GUM/SH and antenatal clinics). A random effects meta-analysis was carried out to summarise level of HIV testing across the studies identified. RESULTS: Thirty studies were identified, most of which were retrospective studies or audits of testing practice. Results were heterogeneous. The overall pooled estimate of HIV test coverage was 27.2% (95% CI 22.4% to 32%). Test coverage was marginally higher in patients tested in settings where routine testing is recommended (29.5%) than in those with clinical indicator diseases (22.4%). Provider test offer was found to be lower (40.4%) than patient acceptance of testing (71.5%). CONCLUSIONS: Adherence to 2008 national guidelines for HIV testing in the UK is poor outside of GUM/SH and antenatal clinics. Low levels of provider test offer appear to be a major contributor to this. Failure to adhere to testing guidelines is likely to be contributing to late diagnosis with implications for poorer clinical outcomes and continued onwards transmission of HIV. Improved surveillance of HIV testing outside of specialist settings may be useful in increasing adherence testing guidelines.


Asunto(s)
Adhesión a Directriz , Seropositividad para VIH/diagnóstico , VIH-1 , Tamizaje Masivo , Diagnóstico Tardío , Femenino , Humanos , Masculino , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos , Reino Unido/epidemiología
8.
Cancers (Basel) ; 15(3)2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36765685

RESUMEN

Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours-among them sarcomas-mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting.

9.
Eur J Pediatr Surg ; 2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37054980

RESUMEN

BACKGROUND: Thoracoscopic repair of esophageal atresia (EA) with tracheoesophageal fistula (TEF) is becoming an increasingly widespread technique; there is still controversy about its indication in certain patients. Our objective is to analyze if potential risk factors such as major congenital heart disease (CHD) or low birth weight (LBW) are a limitation to this approach. METHODS: Retrospective study (2017-2021) of patients with EA and distal TEF who underwent thoracoscopic repair were included. Patients with LBW less than 2,000 g or major CHD were compared with the rest. RESULTS: Twenty-five patients underwent thoracoscopic surgery. Nine patients (36%) had major CHD. Five of them (20%) were LBW less than 2,000 g, and only 8% (2/25) presented both risk factors. There were no differences in terms of operative time, conversion rate, tolerance evaluated with gasometric parameters (pO2, pCO2, pH) or complications (anastomotic leak and stricture, both early or during follow-up) in patients with major CHD and LBW (1,473 ± 319 vs. 2,664 ± 402 g). One conversion to thoracotomy was performed in a neonate weighing 1,050 g due to anesthetic intolerance. There was no recurrence of TEF. One patient died at the age of 9 months, due to major uncorrectable heart disease. CONCLUSION: Thoracoscopic repair of EA/TEF is feasible technique in patients with CHD or LBW, with similar results to other patients. The complexity of this technique warrants individualizing the indication in each case. LEVEL OF EVIDENCE: IV.

10.
J Matern Fetal Neonatal Med ; 35(25): 7011-7014, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34096446

RESUMEN

BACKGROUND: Anastomosis near the ileocecal valve (ICV) are controversial due to the increased pressure on the suture; in this situation, the valve could be removed at a first stage or at the moment of stoma closure. However, preservation of the ICV has proved important benefits in the long term. The aim of this study is to evaluate its feasibility in neonates with focal intestinal perforation (FIP). METHODS: Retrospective study (2010-2019) of neonates with FIP who underwent intestinal resection and primary anastomosis. Patients were divided into group A (anastomosis less than 5 cm from ICV) and group B (more than 5 cm). RESULTS: Forty patients were treated. Patients ostomized or with resection of ICV were excluded. Finally, 24 patients (birth weight 1043 ± 594 g (520-3000), age 8.8 ± 7.8 days (2-39)) were included for analysis. Patent ductus arteriosus was present in 75%. There were 6 patients in group A (25%) and 18 in group B (75%). Groups were comparable in terms of gestational age, birth weight, and age at the time of surgery (p > .05). There were no cases of dehiscence nor stenosis of the anastomosis. There were no differences in reoperation rate, infectious complications, time to enteral feeding, days of parenteral nutrition, hospital stay nor survival (p > .05). CONCLUSION: Ileo-ileal anastomosis closer to the ileocecal junction, in neonates with focal intestinal perforation, is an effective and safe option which also allows the preservation of the ICV avoiding the complications derived from its absence in a group of patients with high morbidity.


Asunto(s)
Válvula Ileocecal , Perforación Intestinal , Recién Nacido , Humanos , Perforación Intestinal/etiología , Perforación Intestinal/cirugía , Estudios Retrospectivos , Peso al Nacer , Válvula Ileocecal/cirugía , Anastomosis Quirúrgica/efectos adversos
11.
Cell Death Discov ; 8(1): 172, 2022 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-35393436

RESUMEN

Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse. We observed that the MEK1/2 inhibitor trametinib rapidly depleted the pro-apoptotic protein NOXA, thus increasing MCL-1 availability. Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.

12.
Eur J Cancer ; 175: 19-30, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36087394

RESUMEN

BACKGROUND: Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1-0.2/1,000,000 per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of the EXPeRT group aimed to fill. PATIENTS AND METHODS: We performed a retrospective case series of children (aged 0-18 years) with primary lung carcinoma, as collected through the EXPeRT databases between 2000 and 2021. We recorded relevant clinical characteristics including treatment and outcome. RESULTS: Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range: 0-17). Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 20), followed by adenocarcinoma (n = 12), squamous cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and small-cell lung cancer (n = 1). Patients with MEC presented rarely with lymph node metastases (2/20 cases). Overall, 19/20 patients achieved long-lasting remission by surgical resection only. Patients with other histologies often presented in advanced stages (14/18 TNM stage IV). With multimodal treatment, 3-year overall survival was 52% ± 13%. While all patients with squamous cell carcinoma died, the 12 patients with adenocarcinoma had a 3-year overall survival of 64% ± 15%. CONCLUSIONS: Primary lung carcinomas rarely occur in children. While the outcome of children with MEC is favourable with surgery alone, patients with other histotypes have a poor prognosis, despite aggressive treatment, highlighting the need to develop new strategies for these children, such as mutation-guided treatment.


Asunto(s)
Adenocarcinoma , Carcinoma Adenoescamoso , Carcinoma Mucoepidermoide , Carcinoma de Células Escamosas , Adenocarcinoma/patología , Adolescente , Carcinoma Mucoepidermoide/patología , Carcinoma de Células Escamosas/patología , Niño , Humanos , Pulmón/patología , Estudios Retrospectivos , Tasa de Supervivencia , Síndrome
13.
Lancet Child Adolesc Health ; 6(8): 545-554, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35690071

RESUMEN

BACKGROUND: Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. We aimed to compare the findings of adolescent and young adult patients with children enrolled in two prospective clinical protocols. METHODS: This retrospective observational analysis was based on data from the European paediatric Soft tissue sarcoma Study Group (EpSSG) rhabdomyosarcoma 2005 trial (phase 3 randomised trial for localised rhabdomyosarcoma, open from April, 2006, to December, 2016) and the EpSSG MTS 2008 protocol (prospective, observational, single-arm study for metastatic rhabdomyosarcoma, open from June, 2010, to December, 2016), which involved 108 centres from 14 different countries in total. For this analysis, patients were categorised according to their age into children (age 0-14 years) and adolescents and young adults (age 15-21 years). For the analysis of adherence to treatment and toxicity, only patients with high-risk localised rhabdomyosarcoma included in the randomised part of the rhabdomyosarcoma 2005 study were considered. The primary outcome of event-free survival (assessed in all participants) was defined as the time from diagnosis to the first event (eg, tumour progression, relapse) or to the latest follow-up. Secondary outcomes were overall survival, response to chemotherapy, and toxicity. FINDINGS: Our analysis included 1977 patients, 1720 children (median age 4·7 years; IQR 2·6-8·4) and 257 adolescents and young adults (16·6 years; 15·8-18·0). 1719 patients were from the EpSSG rhabdomyosarcoma 2005 study (1523 aged <15 years and 196 aged 15-21 years) and 258 patients were from the EPSSG MTS 2008 study (197 aged <15 years and 61 aged 15-21 years). Adolescent and young adult patients were more likely than were children to have metastatic tumours (61 [23·7%] of 257 vs 197 [11·5%] of 1720; p<0·0001), unfavourable histological subtypes (119 [46·3%] vs 451 [26·2%]; p<0·0001), tumours larger than 5 cm (177 [68·9%] vs 891 [51·8%]; p<0·0001), and regional lymph node involvement (109 [42·4%] vs 339 [19·7%]; p<0·0001). Adolescent and young adult patients had lower 5-year event-free survival (52·6% [95% CI 46·3-58·6] vs 67·8% [65·5-70·0]; p<0·0001) and lower 5-year overall survival (57·1% [50·4-63·1] vs 77·9% [75·8-79·8]; p<0·0001) than did children. The multivariable analysis confirmed the inferior prognosis of patients aged 15-21 years (hazard ratios 1·48 [95% CI 1·20-1·83; p=0·0002] for poorer event-free survival and 1·73 [1·37-2·19; p<0·0001] for poorer overall survival). Modifications of administered chemotherapy occurred in 13 (15·3%) of 85 adolescents and young adults, and in 161 (21·4%) of 754 children. Grade 3-4 haematological toxicity and infection were observed more frequently in children than in adolescent and young adult patients. INTERPRETATION: This study found better outcomes for adolescent and young adult patients than those reported in epidemiological studies (eg, the EUROCARE-5 study reported 5-year overall survival of 39·6% for patients aged 15-19 years in the 2000-07 study period), suggesting that adolescent and young adult patients, at least up to age 21 years, can be treated with intensive paediatric therapies with no major tolerability issues and should be included in paediatric rhabdomyosarcoma trials. However, the inferior outcomes in adolescent and young adult patients compared with those in children, despite receiving similar therapy, suggest that a tailored and intensive treatment strategy might be warranted for these patients. FUNDING: Fondazione Città della Speranza.


Asunto(s)
Rabdomiosarcoma , Sarcoma , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Estudios de Cohortes , Supervivencia sin Enfermedad , Humanos , Recurrencia Local de Neoplasia/patología , Estudios Observacionales como Asunto , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Rabdomiosarcoma/terapia , Adulto Joven
14.
Cancers (Basel) ; 13(19)2021 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-34638328

RESUMEN

Neuroblastoma is a pediatric tumor of the peripheral nervous system that accounts for up to ~15% of all cancer-related deaths in children. Recently, it has become evident that epigenetic deregulation is a relevant event in pediatric tumors such as high-risk neuroblastomas, and a determinant for processes, such as cell differentiation blockade and sustained proliferation, which promote tumor progression and resistance to current therapies. Thus, a better understanding of epigenetic factors implicated in the aggressive behavior of neuroblastoma cells is crucial for the development of better treatments. In this study, we characterized the role of ZRF1, an epigenetic activator recruited to genes involved in the maintenance of the identity of neural progenitors. We combined analysis of patient sample expression datasets with loss- and gain-of-function studies on neuroblastoma cell lines. Functional analyses revealed that ZRF1 is functionally dispensable for those cellular functions related to cell differentiation, proliferation, migration, and invasion, and does not affect the cellular response to chemotherapeutic agents. However, we found that high levels of ZRF1 mRNA expression are associated to shorter overall survival of neuroblastoma patients, even when those patients with the most common molecular alterations used as prognostic factors are removed from the analyses, thereby suggesting that ZRF1 expression could be used as an independent prognostic factor in neuroblastoma.

15.
J Laparoendosc Adv Surg Tech A ; 30(4): 458-463, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32013689

RESUMEN

Background: Laparoscopy is widely accepted for the surgical treatment of benign ovarian lesions in adult women, with results similar to an open approach when spillage is avoided by different means such as endobag retrieval. This approach is controversial in children. Materials and Methods: Retrospective study (2009-2018) of all pediatric ovarian tumors with histological confirmation treated in a tertiary center. Data regarding preoperative selection criteria, surgical technique, and follow-up were registered. Laparoscopy was used only in tumors without malignant features and whose size allowed retrieving them through a small incision without morcellating. Emphasis was set in ovarian sparing surgery (OSS), comparing the results of open (OP) and laparoscopic (LPC) approach. Results: During the study period, 48 suspicious lesions in 45 patients were operated. Thirty cases (32 tumors) showed benign features (10 cystadenomas, 14 mature teratomas, 6 nontumor lesions); treatment consisted in oophorectomy in 13 (OP 6, LPC 7) and OSS in 17 (OP 5, LPC 12). There was one conversion in the LPC group. Mean follow-up was 3.44 years (range 0.03-8.84), based on annual ultrasound (US) and tumor markers during at least 5 years, recommending a lifetime follow-up by a gynecologist. There was only one relapse in a laparoscopically enucleated cystadenoma, and 2 patients developed contralateral metacronous teratomas. No procedure-related complications happened. Conclusions: Our series, although small and with a limited follow-up, suggest that laparoscopy could be an option of treatment in a subset of highly selected patients, although laparotomy remains the gold standard approach if malignancy is suspected.


Asunto(s)
Laparoscopía , Tratamientos Conservadores del Órgano , Neoplasias Ováricas/cirugía , Ovariectomía , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Laparotomía , Registros Médicos , Neoplasias Ováricas/patología , Estudios Retrospectivos , Resultado del Tratamiento
16.
J Pediatr Surg ; 55(9): 1897-1902, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32067808

RESUMEN

OBJECTIVE: Distinguishing retrohepatic end-to-side portocaval shunts (ES-PCS) and side-to-side portocaval shunts (SS-PCS) can be difficult, but it is essential for determining the treatment strategy. Our experience with retrohepatic PCS is analyzed. METHODS: Since 2007, 9 children (5/9 ES-PCS and 4/9 SS-PCS) were surgically treated. Radiology studies included Doppler-ultrasound, CT/MRI and angiography/occlusion test (8/9). RESULTS: CT in 5/5 ES-PCS revealed the portal vein (PV) entering the left side of the vena cava with a uniform shape. 4/4 SS-PCS showed aneurysmal PV containing the origin of the main intrahepatic portal branches (IHPB) entering the cava anterior aspect or slightly to the right with a variable length (from long to short/wide). ES-PCS anatomy showed caudate lobe absence with the fistula entering the left cava aspect free of parenchyma, but anterior through the caudate lobe in SS-PCS. With the angiography/occlusion test, the IHPB was undeveloped in ES-PCS (portal pressure > 38 mmHg) and hypoplasic in SS-PCS (portal pressure < 25 mmHg). ES-PCS treatment included: 1/5 hepatectomy and 4/5 definitive banding (one by laparoscopy); while in SS-PCS: 1/4 liver transplantation, 2/4 1-step closure (one by laparoscopy), and 1/4 definitive banding. CONCLUSION: Fistula shape, cava relationship, IHPB and portal pressures differ between the two shunt types. A question arises regarding the need for secondary complete closure after banding. LEVEL OF EVIDENCE: Level IV.


Asunto(s)
Vena Porta , Malformaciones Vasculares , Vena Cava Inferior , Adolescente , Niño , Preescolar , Femenino , Fístula/diagnóstico por imagen , Fístula/cirugía , Humanos , Masculino , Vena Porta/anomalías , Vena Porta/diagnóstico por imagen , Vena Porta/cirugía , Estudios Retrospectivos , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/cirugía , Vena Cava Inferior/anomalías , Vena Cava Inferior/diagnóstico por imagen , Vena Cava Inferior/cirugía
17.
Cell Death Dis ; 11(8): 634, 2020 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-32801295

RESUMEN

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers impairs the development of new therapies. Here, we utilize dynamic BH3 profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We employ this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse. Indeed, we found that BH3 mimetics that selectively target anti-apoptotic BCL-xL and MCL-1, synergistically enhance the effect of clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft model and observed a reduction in tumor growth with a tendency to stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. We identified the molecular mechanism by which RMS cells acquire resistance to vincristine: an enhanced binding of BID and BAK to MCL-1 after drug exposure, which is suppressed by subsequently adding S63845. Our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for combining BH3 mimetics with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency, and decrease undesired secondary effects.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas/farmacología , Rabdomiosarcoma/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Biomarcadores Farmacológicos/análisis , Biomarcadores Farmacológicos/sangre , Línea Celular Tumoral , Doxorrubicina/farmacología , Humanos , Masculino , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/efectos de los fármacos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirimidinas/farmacología , Tiofenos/farmacología , Vincristina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína bcl-X/efectos de los fármacos , Proteína bcl-X/metabolismo
18.
AIDS ; 34(14): 2115-2123, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-32796213

RESUMEN

OBJECTIVES: This study estimates the costs of community-based HIV testing services (HTS) in Lesotho and assesses the potential efficiency gains achieved by adding HIV self-testing (HIVST) and then self-testing booths. DESIGN: Micro-costing analysis using longitudinal data from a real-world intervention. METHODS: We collected data prospectively on provider's costs and programmatic outcomes over three time periods of approximately 8 months each, between May 2017 and April 2019. The scope of services was extended during each period as follows: HTS only, HTS and HIVST, HTS and HIVST with individual HIVST booths wherein clients were encouraged to self-test on-site followed by on-site confirmative testing for those with reactive self-test. For each implementation period, we estimated the full financial and economic implementation costs, the incremental costs of adding HIVST onto conventional HTS and the cost per HIV positive case identified. RESULTS: Costs per HIV-positive case identified increased between period 1 (US$956) and period 2 (US$1249) then dropped in period 3 (US$813). Full versus incremental cost analyses resulted in large differences in the magnitude of costs, attributable to methods rather than resource use: for example, in period 3, the average full and incremental cost estimates for HTS were US$34.3 and US$23.5 per person tested, and for HIVST were US$37.7 and US$14.0 per kit provided, respectively. CONCLUSION: In Lesotho, adding HIVST to community-based HTS improves its overall affordability for HIV-positive case finding. The reporting of both full and incremental cost estimates increase transparency for use in priority setting, budgeting and financial planning for scale-up.


Asunto(s)
Servicios de Salud Comunitaria/organización & administración , Infecciones por VIH/diagnóstico , Prueba de VIH/economía , Autoevaluación , Investigación Participativa Basada en la Comunidad , Costos y Análisis de Costo , Infecciones por VIH/prevención & control , Prueba de VIH/métodos , Humanos , Lesotho , Tamizaje Masivo
19.
J Laparoendosc Adv Surg Tech A ; 19 Suppl 1: S95-101, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19281423

RESUMEN

BACKGROUND: Delayed presentation of a congenital diaphragmatic hernia (CDH) is not usual. Primary laparoscopic repair is becoming the standard in many centers. Different approaches and techniques have been proposed. There is not enough evidence in the literature to recommend one technique over another. PATIENTS AND METHODS: In this paper, we report one case of Morgagni hernia (MH) and one case of Bochdalek hernia (BH), 2 and 6 years old, respectively, operated on in our hospital. In the first case, the diaphragmatic defect was directly sutured with extracorporeal interrupted nonabsorbable sutures, passed through the abdominal wall with a Reverdin needle. In the second one, intracorporeal nonabsorbable stitches were placed. A search of the literature was made using PubMed and the following words: congenital diaphragmatic hernia, laparoscopy or thoracoscopy, and children. The neonatal Bochdalek hernias were discarded. Data about surgical approach, suturing technique, management of the hernia sac, complications, and recurrence were summarized for both pathologies. RESULTS: Both patients were discharged 48 hours after surgery. There were no complications. No recurrence was evident after 6 months. Eleven articles on the treatment of MHs were found, with a total of 30 patients. For BHs, 10 articles met the inclusion criteria, with a total of 54 patients. In both groups, all the papers were case reports or retrospective reviews of case series. The MH is best approached through laparoscopy, and the BH can be treated through thoracoscopy or laparoscopy. Most researchers prefer direct suture with nonabsorbable material. Both complication and recurrence rates are very low. CONCLUSIONS: The endoscopic approach of late-presenting Morgagni and Bochdalek CDH is a safe technique. It offers all the advantages of minimally invasive surgery (MIS), and laparoscopy also permits the diagnosis and treatment of other associated conditions. There are a short number of cases reported and no prospective study comparing open with the MIS approach for the treatment of diaphragmatic malformations.


Asunto(s)
Hernia Diafragmática/cirugía , Hernias Diafragmáticas Congénitas , Laparoscopía , Niño , Preescolar , Humanos , Masculino
20.
J Laparoendosc Adv Surg Tech A ; 19(2): 229-36, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19260783

RESUMEN

BACKGROUND: Prenatal ultrasound study allows the detection of fetal malformations. Intrauterine interventions are now contemplated to correct, or interfere with, the natural history of these anomalies. Minimally invasive techniques, such as the so-called "Fetendo" (fetal endoscopy), are now therapeutic possibilities. METHODS: From 2002 to 2007, 205 fetoscopies were performed in our hospital's fetal surgery program. Fetoscopic interventions were carried out under epidural anesthesia, accessing the uterine cavity with a fetoscope containing a 1.2-mm telescope. Following ultrasound-guided needle puncture of the amniotic cavity, the fetoscope was inserted through a 3-mm sheath by the Seldinger technique. Visibility was maintained with an amnioinfusion system. This procedure offers access to the placental surface, umbilical cord, and fetus. RESULTS: Fetoscopy was used to perform laser coagulation of communicant placental vessels in 148 biamniotic monochorionic gestations with twin-to-twin transfusion syndrome (TTTS) and to occlude the umbilical cord in 32 cases of discordant monochorionic twins with a severe or lethal anomaly in one of the fetuses, and 5 cases of reversed arterial perfusion (TRAP) sequence. In addition, fetoscopy was performed in 18 cases to treat severe congenital diaphragmatic hernia by tracheal occlusion with an endotracheal balloon. Finally, in 2 cases, fetoscopic release of amniotic bands was performed to rescue extremities and the umbilical cord. The most common complications (10%) were preterm rupture of membranes, which resulted in preterm delivery. Other indications for fetoscopy, which we are currently using in experimental animal models, include low urinary tract obstruction, sacrococcygeal teratoma, and repair of myelomeningocele defects. CONCLUSIONS: Fetoscopy can lower the incidence of preterm labor that occurs in response to the aggression of open surgery. At present, fetoscopy is effective for treating several fetal anomalies. Preterm rupture of membranes remains the weak link of fetoscopy. Refinement of the technique and technologic advances will help this problem and allow the use of fetoscopy for other pathologies in the future.


Asunto(s)
Anomalías Congénitas/cirugía , Transfusión Feto-Fetal/cirugía , Fetoscopía/métodos , Femenino , Humanos , Embarazo , Resultado del Embarazo , Resultado del Tratamiento
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