131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients

Incomplete response to therapy may compromise the outcome of children with advanced neuroblastoma. In an attempt to improve tumour response we incorporated 131I-metaiodobenzylguanidine (131I-MIBG) in the treatment regimens of selected stage 3 and stage 4 patients. Between 1986 and 1997, 43 neuroblastoma patients older than 1 year at diagnosis, 13 with stage 3 (group A) and 30 with stage 4 disease (group B) who had completed the first-line protocol without achieving complete response entered in this study. 131I-MIBG dose/course ranged from 2.5 to 5.5 Gbq (median, 3.7). The number of courses ranged from 1 to 5 (median 3) depending on the tumour response and toxicity. The most common acute side-effect was thrombocytopenia. Later side-effects included severe interstitial pneumonia in one patient, acute myeloid leukaemia in two, reduced thyroid reserve in 21. Complete response was documented in one stage 4 patient, partial response in 12 (two stage 3, 10 stage 4), mixed or no response in 25 (ten stage 3, 15 stage 4) and disease progression in five (one stage 3, four stage 4) Twenty-four patients (12/13 stage 3, 12/30 stage 4) are alive at 22–153 months (median, 59) from diagnosis. 131I-MIBG therapy may increase the cure rate of stage 3 and improve the response of stage 4 neuroblastoma patients with residual disease after first-line therapy. A larger number of patients should be treated to confirm these results but logistic problems hamper prospective and coordinated studies. Long-term toxicity can be severe. © 1999 Cancer Research Campaig

Exosomal microRNAs from Longitudinal Liquid Biopsies for the Prediction of Response to Induction Chemotherapy in High-Risk Neuroblastoma Patients: A Proof of Concept SIOPEN Study

Despite intensive treatment, 50% of children with high-risk neuroblastoma (HR-NB) succumb to their disease. Progression through current trials evaluating the efficacy of new treatments for children with HR disease usually depends on an inadequate response to induction chemotherapy, assessed using imaging modalities. In this study, we sought to identify circulating biomarkers that might be detected in a simple blood sample to predict patient response to induction chemotherapy. Since exosomes released by tumor cells can drive tumor growth and chemoresistance, we tested the hypothesis that exosomal microRNA (exo-miRNAs) in blood might predict response to induction chemotherapy. The exo-miRNAs expression profile in plasma samples collected from children treated in HR-NBL-1/SIOPEN before and after induction chemotherapy was compared to identify a three exo-miRs signature that could discriminate between poor and good responders. Exo-miRNAs expression also provided a chemoresistance index predicting the good or poor prognosis of HR-NB patients

Repeated Radionuclide therapy in metastatic paraganglioma leading to the highest reported cumulative activity of 131I-MIBG

131I-MIBG therapy for neuroendocrine tumours may be dose limited. The common range of applied cumulative activities is 10-40 GBq. We report the uneventful cumulative administration of 111 GBq (= 3 Ci) 131I-MIBG in a patient with metastatic paraganglioma. Ten courses of 131I-MIBG therapy were given within six years, accomplishing symptomatic, hormonal and tumour responses with no serious adverse effects. Chemotherapy with cisplatin/vinblastine/dacarbazine was the final treatment modality with temporary control of disease, but eventually the patient died of progression. The observed cumulative activity of 131I-MIBG represents the highest value reported to our knowledge, and even though 12.6 GBq of 90Y-DOTATOC were added intermediately, no associated relevant bone marrow, hepatic or other toxicity were observed. In an individual attempt to palliate metastatic disease high cumulative activity alone should not preclude the patient from repeat treatment

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS

Transcribed-ultra conserved region expression is associated with outcome in high-risk neuroblastoma

<p>Abstract</p> <p>Background</p> <p>Neuroblastoma is the most common, pediatric, extra-cranial, malignant solid tumor. Despite multimodal therapeutic protocols, outcome for children with a high-risk clinical phenotype remains poor, with long-term survival still less than 40%. Hereby, we evaluated the potential of non-coding RNA expression to predict outcome in high-risk, stage 4 neuroblastoma.</p> <p>Methods</p> <p>We analyzed expression of 481 Ultra Conserved Regions (UCRs) by reverse transcription-quantitative real-time PCR and of 723 microRNAs by microarrays in 34 high-risk, stage 4 neuroblastoma patients.</p> <p>Results</p> <p>First, the comparison of 8 short- versus 12 long-term survivors showed that 54 UCRs were significantly (<it>P </it>< 0.0491) over-expressed in the former group. For 48 Ultra Conserved Region (UCRs) the expression levels above the cut-off values defined by ROC curves were strongly associated with good-outcome (OS: 0.0001 <<it>P </it>< 0.0185, EFS: 0.0001 <<it>P </it>< 0.0491). Then we tested the Transcribed-UCR (T-UCR) threshold risk-prediction model on an independent cohort of 14 patients. The expression profile of 28 T-UCRs was significantly associated to prognosis and at least 15 up-regulated T-UCRs are needed to discriminate (<it>P </it>< 0.0001) short- from long-survivors at the highest sensitivity and specificity (94.12%). We also identified a signature of 13 microRNAs differently expressed between long- and short-surviving patients. The comparative analysis of the two classes of non-coding RNAs disclosed that 9 T-UCRs display their expression level that are inversely correlated with expression of 5 complementary microRNAs of the signature, indicating a negative regulation of T-UCRs by direct interaction with microRNAs. Moreover, 4 microRNAs down-regulated in tumors of long-survivors target 3 genes implicated in neuronal differentiation, that are known to be over-expressed in low-risk tumors.</p> <p>Conclusions</p> <p>Our pilot study suggests that a deregulation of the microRNA/T-UCR network may play an important role in the pathogenesis of neuroblastoma. After further validation on a larger independent set of samples, such findings may be applied as the first T-UCR prognostic signature for high-risk neuroblastoma patients.</p

Criteria for evaluation of disease extent by 123I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force

BackgroundNeuroblastoma is an embryonic tumour of the sympathetic nervous system, metastatic in half of the patients at diagnosis, with a high preponderance of osteomedullary disease, making accurate evaluation of metastatic sites and response to therapy challenging. Metaiodobenzylguanidine (mIBG), taken into cells via the norepinephrine transporter, provides a sensitive and specific method of assessing tumour in both soft tissue and bone sites. The goal of this report was to develop consensus guidelines for the use of mIBG scans in staging, response assessment and surveillance in neuroblastoma.MethodsThe International Neuroblastoma Risk Group (INRG) Task Force, including a multidisciplinary group in paediatric oncology of North and South America, Europe, Oceania and Asia, formed a subcommittee on metastatic disease evaluation, including expert nuclear medicine physicians and oncologists, who developed these guidelines based on their experience and the medical literature, with approval by the larger INRG Task Force.ResultsGuidelines for patient preparation, radiotracer administration, techniques of scanning including timing, energy, specific views, and use of single photon emission computed tomography are included. Optimal timing of scans in relation to therapy and for surveillance is reviewed. Validated semi-quantitative scoring methods in current use are reviewed, with recommendations for use in prognosis and response evaluation.ConclusionsMetaiodobenzylguanidine scans are the most sensitive and specific method of staging and response evaluation in neuroblastoma, particularly when used with a semi-quantitative scoring method. Use of the optimal techniques for mIBG in staging and response, including a semi-quantitative score, is essential for evaluation of the efficacy of new therapy

Factors associated with recurrence and survival length following relapse in patients with neuroblastoma

Background: Despite therapeutic advances, survival following relapse for neuroblastoma patients remains poor. We investigated clinical and biological factors associated with length of progression-free and overall survival following relapse in UK neuroblastoma patients. Methods: All cases of relapsed neuroblastoma, diagnosed during 1990-2010, were identified from four Paediatric Oncology principal treatment centres. Kaplan-Meier and Cox regression analyses were used to calculate post-relapse overall survival (PROS), post-relapse progression-free survival (PRPFS) between relapse and further progression, and to investigate influencing factors. Results: One hundred eighty-nine cases were identified from case notes, 159 (84.0%) high risk and 17 (9.0%), unresectable, MYCN non-amplified (non-MNA) intermediate risk (IR). For high-risk patients diagnosed >2000, median PROS was 8.4 months (interquartile range (IQR)=3.0-17.4) and median PRPFS was 4.7 months (IQR=2.1-7.1). For IR, unresectable non-MNA patients, median PROS was 11.8 months (IQR 9.0-51.6) and 5-year PROS was 24% (95% CI 7-45%). MYCN amplified (MNA) disease and bone marrow metastases at diagnosis were independently associated with worse PROS for high-risk cases. Eighty percent of high-risk relapses occurred within 2 years of diagnosis compared with 50% of unresectable non-MNA IR disease. Conclusions: Patients with relapsed HR neuroblastomas should be treatment stratified according to MYCN status and PRPFS should be the primary endpoint in early phase clinical trials. The failure to salvage the majority of IR neuroblastoma is concerning, supporting investigation of intensification of upfront treatment regimens in this group to determine whether their use would diminish likelihood of relapse

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988–June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994–1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted