Evaluación de una puntuación semicuantitativa de MIBG como factor pronóstico en neuroblastoma metastásico y correlación con otros factores pronósticos conocidos

SEMIQUANTITATIVE 123I-METAIODOBENZYLGUANIDINE SCORE AS A PROGNOSIS MARKER IN HIGH RISK NEUROBLASTOMA: CORRELATION WITH OTHER PROGNOSTIC MARKERS AND MINIMAL RESIDUAL DISEASE IN BONE MARROW. Purpose: Metaiodobenzylguanidine (MIBG), specifically taken up in cells of sympathetic origin, provides a highly sensitive and specific marker for the detection of metastases in neuroblastoma. Our aim has been to investigate whether response to induction therapy, evaluated by 123I-MIBG correlates with overall survival (OS) and other prognostic factors in children with metastatic neuroblastoma. Patients and Methods: Medical records and imaging studies from 28 patients with stage 4 neuroblastoma have been retrospectively reviewed. Treatment consisted of intensive chemotherapy, delayed surgery, megatherapy and local irradiation. The scintigraphic response was evaluated by 123I-MIBG scans, using a semi-quantitative scoring system for grading positivity (see ref). It was applied as a pilot retrospective study trying to determine the feasibility of this procedure in our setting, in order to be prospectively implemented in the next international cooperative study. Results: Patients whose score at diagnosis was ≤ 14 had better life-expectancy (>90 months) than those with score >14 at diagnosis (p value 0,052). Only 25% of patients with N-Myc amplified neuroblastoma survived more than 20 months compared to 89% of the non-amplified neuroblastoma patients (p value 0,03). A trend correlating abnormal MIBG after induction therapy and worse outcome was observed (survival was 0% if score >0 vs. 35% in the cases with score 0; p value 0.07). Patients with abnormal MIBG after induction were older than those with complete MIBG response (median age at diagnosis: 4.5 vs. 2.8 years respectively; p value 0.14). There were no statistical differences between N-Myc amplification and persistent MIBG uptake after induction (28% vs. 33%; p value 0.79), but there was correlation with time of survival between cases with MIBG after induction >0 and =0 (18.43 vs. 33.45 months respectively; p value 0.059) and Overall Survival between cases with MIBG after induction >0 and =0 (0% vs. 33%; p value 0.063). Conclusions: Semiquantitative 123I-MIBG score post induction therapy can be utilized to identify a subset of ultra-high-risk patients, with worse prognosis, and faster relapses. More studies are needed to obtain a cut point. Nonetheless, alternative therapeutic strategies should be considered for these patients with poor response

Retinoblastoma and mosaic 13q deletion: a case report

Patients with 13q-syndrome are at risk of retinoblastoma when the RB1 gene, located in the chromosomal band 13q14.2, is deleted. This syndrome is frequently associated with congenital malformations and developmental delay, although these signs could be mild. Mosaic 13q-deletion patients have been previously reported in the literature; their phenotype is variable, and they may not be recognized. CASE PRESENTATION: Retinoblastoma diagnosed in a child with 13q-mosaicism confirmed in blood, oral mucosa, healthy retina and retinoblastoma. A second RB1 hit is present exclusively in the retinoblastoma sample (RB1 c.958C>T p.Arg320Ter). Other detected molecular events in retinoblastoma are 6p12.3pter gain and 6q25.3qter loss. Clinical examination is unremarkable except for clinodactyly of the right fifth finger. DISCUSSION AND CONCLUSIONS: We describe a case of mosaic 13q deletion syndrome affected by retinoblastoma. Molecular data obtained from the tumor analysis are similar to previous data available about this malignancy. High clinical suspicion is essential for an adequate diagnosis of mosaic cases

Quantitative approach to assist neuroblastoma assessment by measuring I-123 mIBG uptake in scintigraphic images

Whole-body 123I-Metaiodobenzylguanidine (mIBG) scintigraphy is used as the primary image modality in neuroblastoma detection. It is the most sensitive and specific method for staging and response evaluation. Validated semi-quantitative scoring methods with low interobserver variability and high reproducibility have shown to be indispensable for the evaluation of response to therapy. However, low resolution, noise and acquisition difficulties, specially in children, make low definition scans. These facts increase observer dependent interpretations that limit assessment and complicate to put a scoring method succesfully into practice. It is essential to have an objective and reliable measure of response to test the activity of therapies. In this paper we propose the use of a quantitative observer-independent measurement of the strength of uptake to be used as an additional tool for assisting the International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOPEN) semi-quantitative scoring method. This is the scoring method recommended by the SIOPEN Nuclear Medicine and Physics Committee, in collaborative work with the Children’s Oncology Group, as the standard one for acquiring and reporting diagnostic paediatric mIBG scans across Europe. Our proposed method is based on the ratio between the amount of specific uptake at tumours and the amount of non-specific uptake at SIOPEN anatomical sectors which has shown to be constant in all the scans of the patients.This work has been supported by "Ayudas para Actividades Preparatorias de Proyectos Coordinados entre Investigadores de la Universitat Politecnica de Valencia e Investigadores del Hospital Universitario y Politecnico La Fe", II Call, 2013, AUTOSCOREMIBG project. The authors are very grateful to the referees for their useful comments.Martínez Díaz, R.; Balaguer Guill, J.; Sánchez Ruiz, LM.; Bello Arques, P.; Castel, V.; Rivas Sanchez, A.; Cañete Nieto, A.... (2015). Quantitative approach to assist neuroblastoma assessment by measuring I-123 mIBG uptake in scintigraphic images. Image Analysis and Stereology. 34(2):135-144. doi:10.5566/ias.1219S13514434

Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care

Knowledge about genetic predisposition to pediatric cancer is constantly expanding. The categorization and clinical management of the best-known syndromes has been refined over the years. Meanwhile, new genes for pediatric cancer susceptibility are discovered every year. Our current work shares the results of genetically studying the germline of 170 pediatric patients diagnosed with cancer. Patients were prospectively recruited and studied using a custom panel, OncoNano V2. The well-categorized predisposing syndromes incidence was 9.4%. Likely pathogenic variants for predisposition to the patient's tumor were identified in an additional 5.9% of cases. Additionally, a high number of pathogenic variants associated with recessive diseases was detected, which required family genetic counseling as well. The clinical utility of the Jongmans MC tool was evaluated, showing a high sensitivity for detecting the best-known predisposing syndromes. Our study confirms that the Jongmans MC tool is appropriate for a rapid assessment of patients; however, the updated version of Ripperger T criteria would be more accurate. Meaningfully, based on our findings, up to 9.4% of patients would present genetic alterations predisposing to cancer. Notably, up to 20% of all patients carry germline pathogenic or likely pathogenic variants in genes related to cancer and, thereby, they also require expert genetic counseling. The most important consideration is that the detection rate of genetic causality outside Jongmans MC et al. criteria was very low

Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors.Patients and methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries.Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy (P \u3c .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively (P = .02).Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas