Incidence of subclinical and overt hypothyroidism in children treated with [131I]mIBG: a systematic review and meta-analysis.

INTRODUCTION: Treatment with [131I]mIBG is commonly used in pediatric metastatic neuroblastoma (NB); however, unbound [131I]I might be taken up by the thyroid, causing hypothyroidism. To prevent this occurrence, thyroid blockade with iodine salts is commonly used; despite this precaution, thyroid dysfunction still occurs. This review and meta-analysis aim to clarify the mean frequency of hypothyroidism in children with NB treated with [131I]mIBG and to investigate the possible causes. EVIDENCE ACQUISITION: The literature was searched for English-language scientific manuscripts describing the incidence of TSH elevation and overt hypothyroidism in children with NB treated with [131I]mIBG. Preclinical studies, small-case series, and reviews were excluded. A proportion meta-analysis was conducted to test the influence of potentially relevant factors (type and duration of thyroid blockade, year of the study, sample size) on the incidence of TSH elevation/overt hypothyroidism. EVIDENCE SYNTHESIS: Eleven studies were included. The pooled percentage of TSH elevation was 0.41 (95% CI: 0.27-0.55); the duration of the thyroid blockade (P=0.004) was inversely correlated with the incidence of TSH elevation. Moreover, a TSH increase was more common in patients treated with potassium iodide (KI) alone than in those managed with a multi-drug thyroid blockade (P<0.001). The pooled percentage of children requiring hormone replacement therapy was 0.33 (95% CI: 0.16-0.49). As in the case of TSH elevation, a longer duration of the thyroid blockade (P=0.006) and a multi-pronged approach (P<0.001) were associated with a lower incidence of overt hypothyroidism. CONCLUSIONS: Hypothyroidism appears to occur frequently in children treated with [131I]mIBG, which should be monitored closely after the radionuclide treatment to start hormone replacement therapy as soon as needed. The duration, as well as the type of thyroid blockade, seem to influence the incidence of hypothyroidism; however, more data from prospective evaluations are needed.

Reaching the target dose with one single 131 I-mIBG administration in high-risk neuroblastoma: The determinant impact of the primary tumour.

BACKGROUND: 131 I-metaiodobenzylguanidine (131 I-mIBG) effectiveness in children with metastasised neuroblastoma (NB) is linked to the effective dose absorbed by the target; a target of 4 Gy whole-body dose threshold has been proposed. Achieving this dose often requires administering 131 I-mIBG twice back-to-back, which may cause haematological toxicity. In this study, we tried identifying the factors predicting the achievement of 4 Gy whole-body dose with a single radiopharmaceutical administration. MATERIALS AND METHODS: Children affected by metastatic NB and treated with a high 131 I-mIBG activity (>450 MBq (megabecquerel)/kg) were evaluated retrospectively. Kinetics measurements were carried out at multiple time points to estimate the whole-body dose, which was compared with clinical and activity-related parameters. RESULTS: Seventeen children (12 females, median age 3 years, age range: 1.5-6.9 years) were included. Eleven of them still bore the primary tumour. The median whole-body dose was 2.88 Gy (range: 1.63-4.22 Gy). Children with a 'bulky' primary (>30 mL) received a higher whole-body dose than those with smaller or surgically removed primaries (3.42 ± 0.74 vs. 2.48 ± 0.65 Gy, respectively, p = .016). Conversely, the correlation between activity/kg and the whole-body dose was moderate (R: 0.42, p = .093). In the multivariate analysis, the volume of the primary tumour was the most relevant predictor of the whole-body dose (p = .002). CONCLUSIONS: These data suggest that the presence of a bulky primary tumour can significantly prolong the 131 I-mIBG biological half-life, effectively increasing the absorbed whole-body dose. This information could be used to model the administered activity, allowing to attain the target dose without needing a two-step radiopharmaceutical administration.

A Simple, Test-Based Method to Control the Overestimation Bias in the Analysis of Potential Prognostic Tumour Markers.

The early evaluation of prognostic tumour markers is commonly performed by comparing the survival of two groups of patients identified on the basis of a cut-off value. The corresponding hazard ratio (HR) is usually estimated, representing a measure of the relative risk between patients with marker values above and below the cut-off. A posteriori methods identifying an optimal cut-off are appropriate when the functional form of the relation between the marker distribution and patient survival is unknown, but they are prone to an overestimation bias. In the presence of a small sample size, which is typical of rare diseases, the external validation sets are hardly available and internal cross-validation could be unfeasible. We describe a new method to obtain an unbiased estimate of the HR at an optimal cut-off, exploiting the simple relation between the HR and the associated p-value estimated by a random permutation analysis. We validate the method on both simulated data and set of gene expression profiles from two large, publicly available data sets. Furthermore, a reanalysis of a previously published study, which included 134 Stage 4S neuroblastoma patients, allowed for the identification of E2F1 as a new gene with potential oncogenic activity. This finding was confirmed by an immunofluorescence analysis on an independent cohort.

Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). STUDY DESIGN: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The ß coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). RESULTS: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. CONCLUSIONS: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

Abdominal rhabdoid tumor presenting with symptomatic spinal epidural compression in a newborn. A case report.

The occurrence of an abdominal tumor invading the spinal canal and causing symptoms of epidural compression is rare in an infant, and exceptional at birth. Peripheral neuroblastic tumors are by far the most common cause. Emergency chemotherapy is commonly curative, though permanent sequelae are possible. Although other malignancies may be involved, no case of rhabdoid tumors at birth has been reported. We describe the case of a neonate who presented symptoms of spinal epidural compression at birth secondary to a rhabdoid tumor. As expected with this highly malignant tumor, the patient experienced a rapidly progressive clinical course and died within three months of diagnosis.

Neuroblastic tumors and neurofibromatosis type 1: A retrospective multicenter study in Italy and systematic review of the literature.

Background: Neuroblastic tumors (NBTs) are the most common extra-cranial solid tumors of childhood. Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disorder with a predisposition to tumors. The co-occurrence of NBTs in the setting of NF1 has been occasionally reported, suggesting a non-casual association and likely configuring a spectrum of neural crest-derived disorders. Aim of the study: To explore the occurrence of NBTs within NF1 and to report on its natural history, therapeutic strategies, and outcomes in an Italian cohort of children with NF1 and in the literature. Subjects and Methods: Study (a): a retrospective analysis of questionnaire-based data [years 1979-2017] derived from the databases of the Italian Registry for Neuroblastoma (RINB) of the Italian Society of Pediatric Onco-Haematology (AIEOP); and Study (b): a systematic review search on NF1/NB co-occurrence. Results: Study (a) identified eight children with NBTs, 0.2% of patients registered in the RINB, fulfilling the diagnostic criteria for NF1. The primary site of NBTs was abdominal in six patients. The NBTs were neuroblastoma (NB) in five patients, ganglioneuroblastoma (GNB) in one, patient, and ganglioneuroma (GN) in two. Metastatic diffusion occurred in three out of eight children. MYCN gene testing, performed in the tumors of five patients, resulted not-amplified. The major features of NF1 included the following: NF1 family history in four patients, café-au-lait spots in all, freckling in six, Lisch nodules in three, and neurofibromas in three. With regard to the outcome, four children survived three of these for the progression of NB and one for a second tumor. Study (b) identified 12 patients with NF1/NB from the years 1966-2017, and the median age at diagnosis was 27 months (range = 0-168 months). The primary site of NB was thoracic. The prevalent histotype was NB in nine patients, GNB in two, and GN in one. Eight/nine NBs were metastatic. The MYCN gene was amplified in the only studied case. The NF1 features included NF1 family history in seven patients; the major NF1 features were café-au-lait spots in nine patients, freckling in one, Lisch nodules in none, and neurofibromas in six. The outcome was good for only two children, while eight children died of neuroblastoma, at a median age of 49.5 months (range = 2.4-174 months), with a median survival time of 21.75 months after diagnosis. Conclusions: To our knowledge, this represents the first systematic study on the occurrence of NBTs in NF1. This confirms that NBs are rare per se in the setting of NF1 (0.2% of all NBs) and even if compared to the overall frequency of malignancies in NF1 (i.e., 14.7%). The male:female ratio in study (a) (0.6) was different from what was recorded in study (b) (1.5) and in line with the overall increased frequency of malignancies in females with NF1. The median ages at diagnosis of NB in either study (a) or (b) were concordant with what occurred in the NB population. In study (a) versus study (b), the frequency of metastatic diffusion was lower, likely indicating less awareness on work-ups for malignancies in old NF1 series in the literature. The outcome was much better in study (a) than in study (b), indicating that multidisciplinary treatment for NB is highly recommended.

Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants.

High-risk neuroblastomas (HR-NB) still have an unacceptable 5-year overall survival despite the aggressive therapy. This includes standardized immunotherapy combining autologous hemopoietic stem cell transplantation (HSCT) and the anti-GD2 mAb. The treatment did not significantly change for more than one decade, apart from the abandonment of IL-2, which demonstrated unacceptable toxicity. Of note, immunotherapy is a promising therapeutic option in cancer and could be optimized by several strategies. These include the HLA-haploidentical αßT/B-depleted HSCT, and the antibody targeting of novel NB-associated antigens such as B7-H3, and PD1. Other approaches could limit the immunoregulatory role of tumor-derived exosomes and potentiate the low antibody-dependent cell cytotoxicity of CD16 dim/neg NK cells, abundant in the early phase post-transplant. The latter effect could be obtained using multi-specific tools engaging activating NK receptors and tumor antigens, and possibly holding immunostimulatory cytokines in their construct. Finally, treatments also consider the infusion of novel engineered cytokines with scarce side effects, and cell effectors engineered with chimeric antigen receptors (CARs). Our review aims to discuss several promising strategies that could be successfully exploited to potentiate the NK-mediated surveillance of neuroblastoma, particularly in the HSCT setting. Many of these approaches are safe, feasible, and effective at pre-clinical and clinical levels.

Presenting features of neuroblastoma with spinal canal invasion. A prospective study of the International Society of Pediatric Oncology Europe - Neuroblastoma (SIOPEN).

Introduction: Between 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features. Materials and methods: This SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021. Results: Of the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant). Conclusion: This prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.

Prognostic value of texture analysis of the primary tumour in high-risk neuroblastoma: An 18 F-DOPA PET study.

PURPOSE: To evaluate the prognostic value of texture analysis of the primary tumour with 18 fluorine-dihydroxyphenylalanine positron emission tomography/X-ray computed tomography (18 F-DOPA PET/CT) in patients affected by high-risk neuroblastoma (HR-NBL). METHODS: We retrospectively analysed 18 patients with HR-NBL, which had been prospectively enrolled in the course of a previous trial investigating the diagnostic role of 18 F-DOPA PET/CT at the time of the first onset. Texture analysis of the primary tumour was carried out on the PET images using LifeX. Conventional indices, histogram parameters, grey level co-occurrence (GLCM), run-length (GLRLM), neighbouring difference (NGLDM) and zone-length (GLZLM) matrices parameter were extracted; their values were compared with the overall metastatic load, expressed by means of whole-body metabolic burden (WBMB) score and the progression-free/overall survival (PFS and OS). RESULTS: There was a direct correlation between WBMB and radiomics parameter describing uptake intensity (SUVmean : p = .004) and voxel heterogeneity (entropy: p = .026; GLCM_Contrast: p = .001). Conversely, texture indices of homogeneity showed an inverse correlation with WBMB (energy: p = .026; GLCM_Homogeneity: p = .006). On the multivariate model, WBMB (p < .01) and the first standardised uptake value (SUV) quartile (p < .001) predicted PFS; OS was predicted by WBMB and the N-myc proto-oncogene protein (MYCN) amplification (p < .05) for both. CONCLUSIONS: Textural parameters describing heterogeneity and metabolic intensity of the primary HR-NBL are closely associated with its overall metastatic burden. In turn, the whole-body tumour load appears to be one of the most relevant predictors of progression-free and overall survival.

E2F3 gene expression is a potential negative prognostic marker for localised and MYCN not-amplified neuroblastoma: Results of in silico analysis of 786 samples.

BACKGROUND: Neuroblastoma (NB) is an enigmatic childhood malignancy characterised by a wide range of clinical behaviour. Many potential oncogenes for NB have recently been identified. Among them, E2 transcription factor 3 (E2F3) expression was associated with a poor survival in 134 stage 4S patients, but evidence for other stage groups remains poorly investigated. METHODS: We have analysed the expression of E2F3 gene from a database of 786 NB samples. Overall and event-free survivals (EFS) were assessed by the Kaplan-Meier method, splitting the data on the median and tertile expression values. The Cox model was applied to control for the confounding by stage, age and MYCN amplification. Validation was performed by an in silico analysis of an independent cohort of 283 NB patients. Furthermore, an immunofluorescence analysis on 48 formalin-fixed, paraffin-embedded NB specimens was also performed. RESULTS: E2F3 overexpression was associated with a poor survival (EFS = 84%, 95% CI: 79%-95%, for low expression levels; EFS = 62%, 95% CI: 56%-68% for middle levels; EFS = 30%, 95% CI: 24%-36%, for high levels, p < .001). This association was confirmed in multivariable analysis and was more evident in patients with MYCN not-amplified and localised stages. Immunofluorescence results and the validation on an independent cohort of NB primary samples confirmed these findings. CONCLUSIONS: E2F3 is a new potential prognostic marker in NB with favourable characteristics at diagnosis. Further studies are needed to elucidate the potential role of E2F3 in NB oncogenesis and progression, in order to identify new targets for therapeutic interventions.

Bilateral adrenal primary tumor in Stage 4S neuroblastoma: The Italian experience and review of the literature.

Bilateral adrenal neuroblastoma (NB) is rare and is mainly stage 4S. Its incidence, presenting features, management, and outcome have not been fully defined yet. We searched the Italian NB Registry (RINB) for stage 4S NB infants with bilateral adrenal primary tumor to compare them with stage 4S NB with unilateral tumor. Between 1979 and 2016, the RINB enrolled 3731 NB patients aged 0-18 years including 317 infants (8.5%) diagnosed with stage 4S NB. Eleven/317 (3.5%) had a bilateral adrenal primary tumor (Group 1) and 190/317 (59.9%) had a unilateral tumor (Group 2). Group 1 infants were significantly younger (51 vs. 89 days) but were comparable with Group 2 for any other presenting features. In the absence of specific protocols, upfront treatment was based on symptoms, size of adrenal tumors, and biology, and consisted of observation in 5 cases, radiotherapy in one, chemotherapy in 2, and surgery in 3. Five/11 developed progression and 2 of them, both with MYCN amplification, died. The 5-year EFS rates of Group 1 and 2 were 54.5% vs. 73.3% (P=.14) and 5-year OSs were 81.8% and 89.4%, respectively (P=.44). Our data support the hypothesis that 4S NB infants with bilateral adrenal tumors can have favorable outcome with personalized therapeutic approach. The three patients with MYCN amplified tumor benefited from upfront aggressive chemotherapy, in accordance with current protocols. Because of the rarity of this intriguing form of neuroblastoma, collaborative prospective studies are warranted, especially in view of gaining a better insight on its biological and genetic features.

Clinical impact of primary tumour 123ImIBG response to induction chemotherapy in children with high-risk neuroblastoma.

BACKGROUND: More than 50% children with high-risk neuroblastoma (HR-NBL) experience disease progression, which we hypothesise is due to non-response of primary tumour to treatment. Current imaging techniques are unable to characterise response in primary tumour (necrotic versus viable tissue) at diagnosis or follow-up. OBJECTIVES: Compare clinico-histological characteristics between primary 123ImIBG-avid tumours that became entirely 123ImIBG-non-avid (responders) after induction chemotherapy (IC) versus primary 123ImIBG-avid tumour that remained 123ImIBG-avid (non-responders). METHODS: Retrospective review of clinico-radiological data of children diagnosed with 123ImIBG-avid HR-NBL at our centre (2005-2016). Patients received Rapid COJEC IC and two additional courses of TVD if metastatic response was inadequate. Primary tumour 123ImIBG response was assessed qualitatively as positive, negative or intermediate at diagnosis and after IC. Post-surgical histopathology slices were marked considering percentage of viable tissue. RESULTS: Sixteen of 61 patients showed complete primary tumour 123ImIBG response, 20 partial response, while 25 no response. There was no statistically significant difference between clinical demographics of complete responders and group of non- or partial responders. Mean percentage of viable tumour cells was higher in non-responders than in complete responders (44.6% vs 20.6%; p = 0.05). Five-year EFS was significantly higher in complete responders than non-responders (43 ± 15% vs 7 ± 6%; p < 0.005). CONCLUSIONS: 123ImIBG response in primary HR-NBL correlates with amount of necrotic tissue, skeletal metastatic 123ImIBG response and outcome. An entirely 123ImIBG non-avid tumour can still harbour viable tumour cells. Therefore, our findings do not support utility of primary tumour 123ImIBG response in decision making regarding residual tumour surgery. Combining both, primary and metastatic 123ImIBG response will improve interpretability of clinical trial results.

A rare case of adrenal ganglioneuroblastoma-intermixed in an adult and a review of literature.

Peripheral neuroblastic tumors are extremely rare in the adult with less just over 20 cases involving adrenal gland described in the literature. We reported herewith the case of a 22-year-old young male who presented with epigastric pain and diarrhea. Imaging studies documented a 3.5cm x 3cm x 4cm solid well-circumscribed right adrenal mass, of heterogeneous structure and with fine calcifications. The lesion turned negative at MIBG scintigraphy. A right robotic-assisted adrenalectomy was performed leading to complete excision of the lesion without complications. Histology was consistent with intermixed stroma-rich ganglioneuroblastoma. A wait-and-see strategy was considered adequate. Two years after diagnosis patient is alive disease-free. Although the definitive diagnosis of a peripheral neuroblastic tumor is obtained after histopathological analysis, CT, and MRI are helpful to further characterize masses and useful in pretreatment risk stratification. Clinicians should be aware of the possibility of GNB development in adult population and its malignant potential.

Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study.

PURPOSE: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS: Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS: A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 (P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 (P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 (P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) (P < .001); infection 35% versus 25% (P = .011); stomatitis 25% versus 3% (P < .001); nausea and vomiting 17% versus 7% (P < .001); and diarrhea 7% versus 3% (P = .011). CONCLUSION: No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

Metastatic progression in infants diagnosed with stage 4S neuroblastoma. A study of the Italian Neuroblastoma Registry.

PURPOSE: Stage 4S neuroblastoma, a tumor affecting infants, is characterized by the capacity to regress spontaneously and high cure rate. About a third of these infants undergo tumor progression requiring antitumor treatment and 10-15% eventually die. In case of metastatic progression, it may occur either at 4S sites (mainly liver) or sites characterizing stage 4 (mainly bone). Aim of this study was to estimate incidence, presenting features and outcome of infants who progressed to stage 4S or stage 4 sites. PATIENTS: Of 280 Italian infants diagnosed with stage 4S neuroblastoma between 1979 and 2013 and registered in the Italian Neuroblastoma Registry, 268 were evaluable for this study, of whom 57 developed metastatic progression. RESULTS: Progression to stage 4S sites occurred in 29/268 infants (10.8%) (Group A) and to stage 4 in 28/268 (10.4%) (Group B). No significant difference was observed between the two groups at the time of diagnosis. At the time of progression, Group A infants were younger (7.3 vs 14.4 months, P = .001) and had a shorter interval from diagnosis to progression (3.8 vs 9.6 months, P = .001). Survival after progression was worse for Group B infants (45% vs 69%, P = .058) and was associated with age at diagnosis lower than 2 months (P = .005) and adrenal primary tumor site (P = .008). Survival rates increased for both groups along the study period. CONCLUSIONS: Infants who progressed to stage 4 did worse, possibly in relation to older age at progression and longer interval between diagnosis and progression. Large prospective studies of these patients may lead to more effective treatments.

131 I-Meta-iodobenzylguanidine followed by busulfan and melphalan and autologous stem cell rescue in high-risk neuroblastoma.

INTRODUCTION: Despite the progress in current treatments, the event-free survival of high-risk neuroblastoma (HR-NB) patients does not exceed 40%-50%, and the prognosis of refractory or relapsed patients is poor, still representing a challenge for pediatric oncologist. Therapeutic Iodine-131 meta-iodobenzylguanidine (Th-131 I-MIBG) is a recognized safe and potentially effective treatment for NB. MATERIALS: This retrospective study reports the outcomes of 28 MIBG-avid NB patients with advanced disease either refractory or relapsed, which was undertaken from 1996 to 2014. Th-131 I-MIBG was administered shortly before (median: 17 days) high-dose chemotherapy with busulfan and melphalan (HD-BuMel) and autologous stem cell rescue (ASCR) at the Gaslini Institute in Genoa, with the aim of analyzing the feasibility, safety, and efficacy of this approach. RESULTS: Engraftment occurred in all patients after a median of 14 (11-29) and 30 days (13-80) from ASCR for neutrophils and platelets, respectively. No treatment-related deaths were observed. The main high-grade (3-4) toxicity observed was oral and gastrointestinal mucositis in 78.6% and 7.1% of patients, respectively, whereas high-grade hepatic toxicity was observed in 10.7%. Two patients developed veno-occlusive-disease (7.1%), completely responsive to defibrotide. Hypothyroidism was the main late complication that occurred in nine patients (31.1%). After Th-131 MIBG and HD-BuMel, 19 patients (67.8%) showed an improvement in disease status. Over a median follow-up of 15.9 years, the three-year and five-year overall survival (OS) probabilities were 53% (CI 0.33-0.69) and 41% (CI 0.22-0.59), and the three-year and five-year rates of cumulative risk of progression/relapse were 64% (CI 0.47-0.81) and 73% (CI 0.55-0.88), respectively. MYCN amplification emerged as the only risk factor significantly associated with OS (HR, 3.58;P = 0.041). CONCLUSION: Th-131 I-MIBG administered shortly before HD-BuMel is a safe and effective regimen for patients with advanced MIBG-avid NB. These patients should be managed in centers with proven expertise.

Diagnosis, Treatment Response, and Prognosis: The Role of 18F-DOPA PET/CT in Children Affected by Neuroblastoma in Comparison with 123I-mIBG Scan: The First Prospective Study.

Our purpose was to evaluate the diagnostic role of 18F-3,4-dihydroxyphenylalanine (DOPA) PET/CT at the time of staging in children with neuroblastoma and to investigate its ability to assess treatment response. We also investigated the prognostic value of 18F-DOPA PET/CT at the same time points. Methods: We enrolled children with neuroblastoma at onset. Before and after induction chemotherapy, all patients underwent 18F-DOPA PET/CT and 123I-metaiodobenzylguanidine (MIBG) scanning plus SPECT/CT. 18F-DOPA PET/CT results were compared with those of 123I-MIBG whole-body scanning (WBS). For each modality, patient-based analysis and lesion-based analysis were performed and sensitivity was calculated. We applied scoring systems to 123I-MIBG scanning and 18F-DOPA PET/CT (i.e.,123I-MIBG WBS score and whole-body metabolic burden [WBMB], respectively) and evaluated the association between these parameters, the principal neuroblastoma risk factors, and outcome. Results: We enrolled 16 high-risk and 2 intermediate-risk neuroblastoma patients. On patient-based analysis, sensitivity in detecting primary tumors, soft-tissue metastases, and bone or bone-marrow metastases was 83%, 50%, and 92%, respectively, for 123I-MIBG WBS versus 94%, 92%, and 100%, respectively, for 18F-DOPA PET/CT. On lesion-based analysis, the sensitivity of 18F-DOPA PET/CT in detecting soft-tissue and bone or bone-marrow metastases was 86% and 99%, respectively-significantly higher than that of 123I-MIBG WBS, at 41% and 93%, respectively. After therapy, on patient-based analysis, the sensitivity in detecting primary tumors, soft-tissue metastases, and bone or bone-marrow metastases was 72%, 33%, and 38%, respectively, for 123I-MIBG WBS versus 83%, 75% and 54%, respectively, for 18F-DOPA PET/CT. On lesion-based analysis, the sensitivity of 18F-DOPA PET/CT in detecting soft-tissue and bone or bone-marrow metastases was 77% and 86%, respectively-significantly higher than that of 123I-MIBG WBS, at 28% and 69%, respectively. During follow-up, 8 cases of disease progression and 5 deaths occurred. On multivariate analysis, only posttherapeutic 18F-DOPA WBMB (>7.5) was associated with progression-free survival. Conclusion:18F-DOPA PET/CT is more sensitive than 123I-MIBG WBS in staging neuroblastoma patients and evaluating disease persistence after chemotherapy. In a time-to-event analysis, posttherapeutic 18F-DOPA WBMB remained the only risk factor associated with disease progression.

A Review of Infants With Localized Neuroblastoma That Evolve to Stage 4s Disease.

The authors describe a newborn diagnosed with localized neuroblastoma that evolved to stage 4s at the age of 5 months. Peculiar features of the case included a bilateral adrenal primary, the skin as the only metastatic site, and the development of a muscular lesion late in the clinical course. The patient underwent left adrenalectomy and all other lesions regressed without further therapy. The case prompted a search for similar cases both in the Italian Neuroblastoma Registry and in the literature. All patients identified, although variously treated, survived with the exception of the 2 with MYCN gene amplification. We conclude that infants with neuroblastoma who undergo a transition from a localized to stage 4s disease could be less rare than expected. In the absence of unfavorable biology, a wait-and-see policy with strict follow-up could be adopted for these patients, avoiding potentially damaging systemic therapy.

Plasma free metanephrines for diagnosis of neuroblastoma patients.

INTRODUCTION: A substantial number of patients with neuroblastoma (NB) have increased excretion of catecholamines and metanephrines. Here, we have investigated the diagnostic role of plasma free metanephrines (PFM), metanephrine (MN), normetanephrine (NMN) and 3-methoxytyramine (3MT) for NB, the most common extra-cranial solid tumour in children. METHODS: PFM were quantified by using a commercial IVD-CE LC-MS/MS method on a TSQ Quantiva coupled to an Ultimate 3000. The method was further validated on 103 samples from pediatric subjects (54 patients with histologically confirmed NB and 49 age and sex matched controls). Correlations between PFM concentrations with clinical factors were tested. We directly compared MN, NMN, and 3MT concentrations in matched plasma and urine samples of NB patients (n = 29). RESULTS: 3MT and NMN showed an excellent diagnostic performance with very high specificity (100% and 95.8%, respectively) and sensitivity (88.2% and 80.4%). ROC curves were obtained (AUC of 0.93 and 0.91 for 3MT and NMN, respectively) and optimal cut-offs that could discriminate between controls and NB patients were defined. A positive correlation between NMN levels in urine and plasma (p = .0017) was found. DISCUSSION: The determination of plasma 3MT and NMN should be taken in consideration as a new diagnostic tool for NB. Validation in prospective clinical studies in comparison to urinary catecholamines and metanephrines is warranted.

Congenital Myoepithelial Carcinoma of Soft Tissue Associated With Cystic Myoepithelioma.

Myoepithelial neoplasms of soft tissue represent a heterogeneous group of lesions, encompassing both benign entities as myoepithelioma (ME) and highly aggressive tumors as myoepithelial carcinoma (MEC). We describe a case of pediatric soft tissue MEC with peculiar features that may lead to misdiagnosis: congenital onset and presence of a benign component with predominant cystic structure. Few cases of congenital MEC have been reported, but the coexistence of MEC with ME is even more rare, accounting for less than 1% of myoepithelial tumors. Moreover, an extensive cystic appearance had never been described in either ME or MEC of soft tissue. Despite several predictors of poor prognosis, the patient has been showing a favorable clinical course since the administration of ICpE (ifosfamide, cisplatin, and etoposide) chemotherapy. This report provides valuable information in the differential diagnosis of cystic congenital tumors and supports a possible efficacy of adjuvant combined treatment for patients with localized disease after surgery.