Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ...ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.
The consistent focus of 'Advances in Neuroblastoma Research' congresses on the topic neuroblastoma sets it as a model for a circumscribed scientific community.
The contributions of authors, ...institutions and countries to congress abstracts and their collaborations were compared to the Hirsch index (h-index) calculated from the Web of Science publication output on the topic 'neuroblastoma'.
From 1975 to 2016, 18 congresses were held. 8459 authors affiliated to 553 institutions of 53 countries presented 3,993 abstracts. The number of coauthors increased over the years from 2 to 7. A considerable proportion of authors, institutions and countries presented only once (53.7%/25.7%/13.2%). Authors with a high number of abstracts and with a large local network were often among those with a higher publication rate and success (R2 = 0.508 for Pearson's correlation between weight and h-index, R2 = 0.474 for degree centrality, R2 = 0.364 for lobby-index). Closeness and betweenness centralities were less correlated (R2 = 0.127/R2 = 0.33, resp.). The institutions showed a similar impact of local interactions on publication success (degree centrality R2 = 0.417, weight R2 = 0.308), while countries demonstrated a higher correlation of betweenness centrality and h-Index (R2 = 0.704) emphasizing their brokerage role. Of 553 institutions, 520 collaborated within 13 communities and belonged to the large scientific network. 33 satellite institutions had no connections to the central network. They attended 1-4 congresses over a period of 1-16 years.
A large scientific network has been developed during the recent 42 years. Growth and interaction at congresses were correlated to publication success. Weight is suggested as a useful and simple estimate.
Although intensive multimodal treatment has improved the prognosis of patients with metastatic neuroblastoma, the impact of primary tumor resection on outcome is a matter of medical debate.
Patients ...from the German prospective clinical trial NB97 with stage 4 neuroblastoma and age 18 months or older at diagnosis were included. Operation notes and imaging reports were reviewed by two independent experienced physicians. Finally, the extent of tumor resections was correlated with local control rate and outcome.
A total of 278 patients were included in this study. Image-defined risk factors present at diagnosis were found to be predictive for the extent of tumor resection at first (P < .001) and best (P < .001) operation. No patient died from surgery. Before chemotherapy, complete resection, incomplete resection, and biopsy or no surgery were performed in 6.1%, 5.0%, and 88.5% of patients, respectively. The extent of first operation had no impact on event-free survival (EFS; P = .207), local progression-free survival (LPFS; P = .195), and overall survival (OS; P = .351). After induction chemotherapy, 54.7% of patients underwent complete resection of the primary tumor, 30.6% underwent incomplete resection, and 13.3% had only biopsy or no surgery of the primary tumor. The extent of best operation also had no impact on EFS (P = .877), LPFS (P = .299), and OS (P = .778). Moreover, multivariate analyses showed that surgery did not affect EFS, LPFS, and OS.
In intensively treated patients with stage 4 neuroblastoma age 18 months or older at diagnosis, surgery of the primary tumor site has no impact on local control rate and outcome.
Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an ...inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.
Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of ...patients.
Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010.
Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p < 0.001), less frequently with adrenal tumors (31 % vs. 43 %, p = 0.001) and positive mIBG-uptake (34 % vs. 90 %, p < 0.001), and had less often elevated urine catecholamine metabolites (homovanillic acid 39 % vs. 62 %, p < 0.001, vanillylmandelic acid 27 % vs. 64 %, p < 0.001). Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001). Complete tumor resection was achieved at diagnosis in 70 % of 162 GN and 67 % of 55 GNBI, and after 4 to 32 months of observation in 4 GN (2 %) and 5 GNBI (9 %). Eleven patients received chemotherapy without substantial effect. Fifty-five residual tumors (42 GN, 13 GNBI) are currently under observation (median: 44 months). Five patients (3 GN, 2 GNBI) showed local progression; all had tumor residuals > 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression.
GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment.
ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006).
Thromboembolism is a serious complication of induction therapy for childhood acute lymphoblastic leukemia. We prospectively compared the efficacy and safety of antithrombotic interventions in the ...consecutive leukemia trials ALL-BFM 2000 and AIEOP-BFM ALL 2009. Patients with newly diagnosed acute lymphoblastic leukemia (n=949, age 1 to 18 years) were randomized to receive low-dose unfractionated heparin, prophylactic low molecular weight heparin (enoxaparin) or activity-adapted antithrombin throughout induction therapy. The primary objective of the study was to determine whether enoxaparin or antithrombin reduces the incidence of thromboembolism as compared to unfractionated heparin. The principal safety outcome was hemorrhage; leukemia outcome was a secondary endpoint. Thromboembolism occurred in 42 patients (4.4%). Patients assigned to unfractionated heparin had a higher risk of thromboembolism (8.0%) compared with those randomized to enoxaparin (3.5%;
=0.011) or antithrombin (1.9%;
<0.001). The proportion of patients who refused antithrombotic treatment as allocated was 3% in the unfractionated heparin or antithrombin arms, and 33% in the enoxaparin arm. Major hemorrhage occurred in eight patients (no differences between the groups). The 5-year event-free survival was 80.9±2.2% among patients assigned to antithrombin compared to 85.9±2.0% in the unfractionated heparin group (
=0.06), and 86.2±2.0% in the enoxaparin group (
=0.10). In conclusion, prophylactic use of antithrombin or enoxaparin significantly reduced thromboembolism. Despite the considerable number of patients rejecting the assigned treatment with subcutaneous injections, the result remains unambiguous. Thromboprophylaxis - for the present time primarily with enoxaparin - can be recommended for children and adolescents with acute lymphoblastic leukemia during induction therapy. Whether and how antithrombin may affect leukemia outcome remains to be determined.
Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always ...cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.
Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.
Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.
These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
Survival after neuroblastoma relapse is poor. Understanding the relationship between clinical and biologic features and outcome after relapse may help in selection of optimal therapy. Our aim was to ...determine which factors were significantly predictive of postrelapse overall survival (OS) in patients with recurrent neuroblastoma--particularly whether time from diagnosis to first relapse (TTFR) was a significant predictor of OS.
Patients with first relapse/progression were identified in the International Neuroblastoma Risk Group (INRG) database. Time from study enrollment until first event and OS time starting from first event were calculated. Cox regression models were used to calculate the hazard ratio of increased death risk and perform survival tree regression. TTFR was tested in a multivariable Cox model with other factors.
In the INRG database (N = 8,800), 2,266 patients experienced first progression/relapse. Median time to relapse was 13.2 months (range, 1 day to 11.4 years). Five-year OS from time of first event was 20% (SE, ± 1%). TTFR was statistically significantly associated with OS time in a nonlinear relationship; patients with TTFR of 36 months or longer had the lowest risk of death, followed by patients who relapsed in the period of 0 to less than 6 months or 18 to 36 months. Patients who relapsed between 6 and 18 months after diagnosis had the highest risk of death. TTFR, age, International Neuroblastoma Staging System stage, and MYCN copy number status were independently predictive of postrelapse OS in multivariable analysis.
Age, stage, MYCN status, and TTFR are significant prognostic factors for postrelapse survival and may help in the design of clinical trials evaluating novel agents.
Although several studies have been conducted on the role of surgery in localized neuroblastoma, the impact of surgical timing and extent of primary tumor resection on outcome in high-risk patients ...remains controversial.
Patients from the German neuroblastoma trial NB97 with localized neuroblastoma INSS stage 1-3 age > 18 months were included for retrospective analysis. Imaging reports were reviewed by two independent physicians for Image Defined Risk Factors (IDRF). Operation notes and corresponding imaging reports were analyzed for surgical radicality. The extent of tumor resection was classified as complete resection (95-100%), gross total resection (90-95%), incomplete resection (50-90%), and biopsy (<50%) and correlated with local control rate and outcome. Patients were stratified according to the International Neuroblastoma Risk Group (INRG) staging system. Survival curves were estimated according to the method of Kaplan and Meier and compared by the log-rank test.
A total of 179 patients were included in this study. 77 patients underwent more than one primary tumor operation. After best surgery, 68.7% of patients achieved complete resection of the primary tumor, 16.8% gross total resection, 14.0% incomplete surgery, and 0.5% biopsy only. The cumulative complication rate was 20.3% and the surgery associated mortality rate was 1.1%. Image defined risk factors (IDRF) predicted the extent of resection. Patients with complete resection had a better local-progression-free survival (LPFS), event-free survival (EFS) and OS (overall survival) than the other groups. Subgroup analyses showed better EFS, LPFS and OS for patients with complete resection in INRG high-risk patients. Multivariable analyses revealed resection (complete vs. other), and MYCN (non-amplified vs. amplified) as independent prognostic factors for EFS, LPFS and OS.
In patients with localized neuroblastoma age 18 months or older, especially in INRG high-risk patients harboring MYCN amplification, extended surgery of the primary tumor site improved local control rate and survival with an acceptable risk of complications.
Radioiodinated metaiodobenzylguanidine ((123)I-mIBG) scintigraphy is an established imaging method in neuroblastoma. Semiquantitative scoring systems have been developed to assess the extent of ...disease and response to chemotherapy. We present the results of the comparison between the SIOPEN International Society of Pediatric Oncology Europe Neuroblastoma Group score and the modified Curie score.
We retrospectively analyzed 147 mIBG scans of 58 patients older than 1 year of age with stage 4 neuroblastoma from German Neuroblastoma Trial NB97 that were assessed according to the SIOPEN and the Curie scoring method. mIBG examinations were performed at diagnosis and after four and six cycles of chemotherapy.
Scoring results were highly correlated between both methods, and interobserver reliability was excellent. A Curie score ≤ 2 and a SIOPEN score ≤ 4 (best cutoff) at diagnosis were correlated to significantly better event-free and overall survival compared with higher scores. After four cycles of chemotherapy, overall survival was significantly better for mIBG-negative patients compared with those with any residual mIBG-positive metastases. After six cycles of chemotherapy, there was no difference in survival between mIBG-negative patients and patients with residual mIBG-positive metastases. Patients without mIBG-positive metastases after four and six cycles of chemotherapy had a better overall survival, but late clearance of mIBG-positive metastases did not improve outcome.
Higher mIBG scores at diagnosis and occurrence of any residual mIBG-positive metastases after four cycles of chemotherapy predicted unfavorable outcome for patients with stage 4 neuroblastoma. Later clearance of metastases did not improve prognosis. The Curie and the SIOPEN score were equally reliable and predictive.
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