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.

Late Relapse in Genetically Determined Infantile Myofibromatosis. A Case Report and Brief Focus on Recurrences.

BACKGROUND: Infantile myofibromatosis (IM) is a rare disorder characterized by benign tumors in the skin, subcutaneous tissue, muscle, and occasionally viscera. IM can be hereditary due to PDGFRB or NOTCH3 variants. Treatment is mainly conservative or surgical. Combination regimens have been used in case of disseminated disease. OBSERVATION: We present relapsed disease of IM 11 years after diagnosis in a 2-year-old child initially treated by microscopically complete resection. A new heterozygous c.1687G>A (p.Glu563Lys) mutation in the PDGFRB gene was identified (considered likely pathogenic). CONCLUSIONS: In association with initial treatment, genetic testing is crucial for tailored clinical practice and follow-up in patients diagnosed with IM.

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.

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.

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.

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.

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.

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.

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.

Listeria Meningitis in an Immunocompetent Child.

Listeria monocytogenes is a facultative anerobic, gram-positive bacillus that is isolated from the soil, vegetables, and wild or domestic animals. Listeria infection is usually found in the older adults, immunocompromised patients, pregnant women, and newborns, whereas it is rare in healthy infants and children. Listeria monocytogenes may cause meningitis, meningoencephalitis, brain abscess, pyogenic arthritis, osteomyelitis, and liver abscess in children. The course of meningoencephalitis by Listeria is often severe and even fatal. Complications such as acute hydrocephalus, brain abscess, and spine abscess can develop, and the mortality associated with listeriosis is significantly high. We present a case of a previously healthy 7-year-old boy who developed Listeria monocytogenes meningitis.

Prognostic value of ¹8F-DOPA PET/CT at the time of recurrence in patients affected by neuroblastoma.

PURPOSE: The aim of this study was to investigate the relationship between (123)I-metaiodobenzylguanidine (MIBG) scan semi-quantification and a new (18)F-DOPA positron emission tomography (PET)/CT score in patients with suspected or documented neuroblastoma (NB) relapse and to assess the association between these two parameters and progression-free survival (PFS)/overall survival (OS). METHODS: We analysed 24 NB patients who had undergone (123)I-MIBG and (18)F-DOPA PET/CT scans at the time of suspected relapse, after applying a proper scoring system for each scan. In time-to-event analyses, the score distributions were regarded as continuous and were categorized in tertiles and medians. We used Kaplan-Meier curves and Cox proportional hazard models for PFS and OS in order to estimate the independent prognostic impact of (123)I-MIBG and (18)F-DOPA PET/CT scans. RESULTS: The (123)I-MIBG and (18)F-DOPA scores were highly and positively correlated (Spearman's rho = 0.8, p < 0.001). Over a median follow-up of 14 months (range 6-82), 12 cases of disease progression and 6 deaths occurred. Multivariate Cox models showed a higher risk of disease progression [hazard ratio (HR) 17.0, 95% confidence interval (CI) 2.7-109] in NB patients with (123)I-MIBG score > 3 (3rd tertile) and an even higher risk (HR:37.2, 95% CI 2.4-574) in those with (18)F-DOPA whole-body metabolic burden (WBMB) >7.5 (median), after adjustment for all main clinical/pathological factors considered. Kaplan-Meier analyses showed a significant association with OS (log-rank p = 0.01 and p = 0.03 for (123)I-MIBG and (18)F-DOPA WBMB, respectively). CONCLUSION: Our results confirm the good agreement between (18)F-DOPA PET/CT and (123)I-MIBG scan in patients affected by NB relapse. In time-to-event analyses, (123)I-MIBG scan and (18)F-DOPA PET/CT scores were independently and significantly associated with disease progression.

Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience.

BACKGROUND: Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. PATIENTS AND METHODS: Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. RESULTS: Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). CONCLUSIONS: Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted.

Neuroblastoma in the adult: the Italian experience with 21 patients.

BACKGROUND: Neuroblastoma in the adult is rare. No established therapeutic guidelines exist for these patients and the literature on this issue is scant and contradictory. MATERIALS AND METHODS: Between 1986 and 2011, 21 adults (18 to 38 y; median, 23) diagnosed with neuroblastoma were referred to our hospital. Three of the 21 were classified as neuroblastoma, not otherwise specified, 13 as neuroblastoma, schwannian stroma-poor, and 5 as ganglioneuroblastoma, nodular. Nine patients had a resectable (stage 1/2) and 6 an unresectable primary tumor (stage 3); 6 had disseminated disease (stage 4). RESULTS: Of 9 stage 1/2 patients, 6 underwent surgery alone (2 survive, 4 died), 2 received adjuvant chemotherapy (both survive), and 1 received radiation therapy (alive). Four of the 6 stage 3 patients received chemotherapy and died, 1 underwent partial tumor resection only and died, and 1 received radiation therapy after partial tumor resection and is alive. The 6 stage 4 patients received chemotherapy with/without radiotherapy, and all died. Event-free survival at 10 years was 33.3% for stage 1/2, 16.7% for stage 3, and 0% for stage 4 patients. The 10-year overall and event-free survival rates were 39.8% and 19.1%, respectively. CONCLUSIONS: The outcome of neuroblastoma in adults is poorer than in younger patients at all stages. The clinical course seems modestly influenced by therapy.

Widening the spectrum of players affected by genetic changes in Wilms tumor relapse.

Few studies investigated the genetics of relapsed Wilms tumor (WT), suggesting the SIX1 gene, the microRNA processing genes, and the MYCN network as possibly involved in a relevant percentage of relapses. We investigated 28 relapsing WT patients (10 new cases and 18 cases in which the involvement of SIX and miRNAPG had been excluded) with a panel of ∼5000 genes. We identified variants affecting genes involved in DNA damage prevention and repair in 12/28 relapsing patients (42.9%), and affecting genes involved in chromatin modification and regulation in 6/28 relapsing patients (21.4%), widening the spectrum of anomalies detected in relapsed tumors. The disclosure of molecular pathways possibly underlying tumor progression might allow to use molecularly targeted therapies at relapse. Surprisingly, germline anomalies, mostly affecting DNA damage prevention and repair genes, were identified in 13/28 patients (46.4%), raising the issue of performing a genetic testing to all children presenting with a WT.

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.

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.

Comparison of 18F-dopa PET/CT and 123I-MIBG scintigraphy in stage 3 and 4 neuroblastoma: a pilot study.

PURPOSE: (18)F-Dopa positron emission tomography (PET)/CT has proved a valuable tool for the assessment of neuroendocrine tumours. So far no data are available on (18)F-dopa utilization in neuroblastoma (NB). Our aim was to evaluate the role of (18)F-dopa PET/CT in NB and compare its diagnostic value with that of (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in patients affected by stage 3-4 NB. METHODS: We prospectively evaluated 28 paired (123)I-MIBG and (18)F-dopa PET/CT scans in 19 patients: 4 at the time of the NB diagnosis and 15 when NB relapse was suspected. For both imaging modalities we performed a scan-based and a lesion-based analysis and calculated sensitivity, specificity and accuracy. The standard of reference was based on clinical, imaging and histological data. RESULTS: NB localizations were confirmed in 17 of 19 patients. (18)F-Dopa PET/CT and (123)I-MIBG scintigraphy properly detected disease in 16 (94%) and 11 (65%), respectively. On scan-based analysis, (18)F-dopa PET/CT showed a sensitivity and accuracy of 95 and 96%, respectively, while (123)I-MIBG scanning showed a sensitivity and accuracy of 68 and 64%, respectively (p < 0.05). No significant difference in terms of specificity was found. In 9 of 28 paired scans (32%) PET/CT results influenced the patient management. We identified 156 NB localizations, 141 of which were correctly detected by (18)F-dopa PET/CT and 88 by MIBG. On lesion-based analysis, (18)F-dopa PET/CT showed a sensitivity and accuracy of 90% whereas (123)I-MIBG scintigraphy showed a sensitivity and accuracy of 56 and 57%, respectively (p < 0.001). No significant difference in terms of specificity was found. CONCLUSION: In our NB population (18)F-dopa PET/CT displayed higher overall accuracy than (123)I-MIBG scintigraphy. Consequently, we suggest (18)F-dopa PET/CT as a new opportunity for NB assessment.