Publications by authors named "Frank Berthold"

155 Publications

Hypercalcemia is a frequent side effect of 13-cis-retinoic acid treatment in patients with high-risk neuroblastoma.

Pediatr Blood Cancer 2021 Sep 26:e29374. Epub 2021 Sep 26.

Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany.

Purpose: 13-cis-Retinoic acid (13-cisRA) is used as a postconsolidation treatment in patients with high-risk neuroblastoma. Hypercalcemia is a known side effect of retinoids. Frequency, symptoms, treatment, and risk factors for hypercalcemia were analyzed.

Patients: Data were retrospectively analyzed for 350 patients registered in the German Neuroblastoma trials NB97 and NB04 who were treated with high-risk protocols-including myeloablative chemotherapy with autologous stem cell transplantation (SCT) or maintenance therapy-and had received 13-cisRA between January 1, 2000 and December 31, 2010.

Results: Hypercalcemia was reported in 78 patients (22.3%), and 37 patients (10.6%) developed Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 hypercalcemia. The calcium levels were 2.5-4.6 mmol/L (median 3.1 mmol/L). Patients with a single kidney were at a higher risk of developing hypercalcemia (p = .001). Regarding postinduction treatment, 69 of 280 patients with SCT (24.6%) and nine of 70 patients without SCT (12.9%) developed hypercalcemia during 13-cisRA treatment (p = .037). Most patients developed hypercalcemia in the first cycle of 13-cisRA, and only in a single cycle. Hypercalcemia symptoms were frequent but moderate. In most patients, treatment with 13-cisRA was continued without dose reduction in subsequent cycles.

Conclusion: In this cohort, grades 3 and 4 hypercalcemia were observed more often than previously reported. A single kidney and pretreatment with myeloablative chemotherapy with stem cell transplantation were identified as potential risk factors for the development of hypercalcemia.
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http://dx.doi.org/10.1002/pbc.29374DOI Listing
September 2021

Genetic Alterations and Resectability Predict Outcome in Patients with Neuroblastoma Assigned to High-Risk Solely by Amplification.

Cancers (Basel) 2021 Aug 28;13(17). Epub 2021 Aug 28.

Center for Molecular Medicine Cologne (CMMC) and Department of Experimental Pediatric Oncology, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.

Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of oncogene amplification (MNA).

Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group).

Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39-54%) and 56% (95%-CI 49-63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18-31%, < 0.001; OS 32% 95%-CI 25-39%, < 0.001). The presence of /p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS ( < 0.001 and = 0.011, respectively).

Conclusions: Neuroblastoma patients attributed to high risk solely by amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.
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http://dx.doi.org/10.3390/cancers13174360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430929PMC
August 2021

Neuroblastoma Screening at 1 Year of Age: The Final Results of a Controlled Trial.

JNCI Cancer Spectr 2021 Jul 5;5(4):pkab041. Epub 2021 May 5.

Department of Pediatric Oncology Hematology Children's Hospital, Cantonal Hospital, Luzern, Switzerland.

Background: Neuroblastoma screening aims to reduce neuroblastoma-related mortality. A controlled trial showed no reduction in stage 4 disease incidence and preliminary mortality data. This article presents epidemiologic and clinical data 20 years after cessation of the screening program.

Methods: The patients with detected disease in the screening area were compared with the clinically diagnosed patients in the control area and in the prestudy and poststudy cohorts. All statistical tests were 2-sided.

Results: The cumulative incidence for children aged 1 to 6 years in the birth study cohorts (1994-1999) in the screening arm was 13.4 cases per 100 000 births (95% confidence interval [CI] = 12.2 to 14.6) based on 61.2% of screening participants and 38.8% of nonparticipants. Screening participants had a cumulative incidence of 15.7 (95% CI = 14.0 to 17.4) per 100 000 births. The cumulative incidence in the contemporary control cohort was 9.3 (95% CI = 8.2 to 10.3) per 100 000 births, 7.6 (95% CI = 6.8 to 8.4) in the prestudy cohort, and 8.1 (95% CI = 7.4 to 8.9) in the poststudy cohort from 2000 to 2004 (<.001 each). The increased incidence in the screening cohort was restricted to stages 1 through 3, while stage 4 incidence was not reduced. The cumulative mortality for deaths within 10 years from diagnosis and per 100 000 births remained unchanged. Patients with stage 4 disease detected by screening had better biological characteristics and an improved outcome compared with those stage 4 cases not detected by screening.

Conclusions: Neuroblastoma screening at 1 year of age reduced neither stage 4 incidence nor neuroblastoma mortality and was affected by overdiagnosis, leading to unnecessary treatment. A few screening-detected stage 4 cases represent a biologically interesting subgroup but do not change the recommendation to close the "catecholamine-based neuroblastoma screening book."
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http://dx.doi.org/10.1093/jncics/pkab041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259619PMC
July 2021

Clinical and molecular characterization of patients with stage 4(M) neuroblastoma aged less than 18 months without MYCN amplification.

Pediatr Blood Cancer 2021 Aug 7;68(8):e29038. Epub 2021 Apr 7.

Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany.

Introduction: The survival of children with stage 4(M) neuroblastoma without MYCN amplification and below the age of 18 months is considered better than the still dismal outcome of older high-risk neuroblastoma patients. This study analyzes the impact of clinical and molecular characteristics on the long-term outcome.

Patients And Methods: Clinical presentation, survival, and recurrence patterns of patients enrolled onto trials NB90, NB97, and NB2004 were retrospectively analyzed. Gene expression signatures based on RNA microarrays (TH10) were investigated if tumor material was available.

Results: Between 1990 and 2015, 177 patients with stage 4(M) MYCN nonamplified neuroblastoma aged less than 18 months at diagnosis were eligible. After a median follow-up of 9.7 years (IQR 5.0, 13.4), the proportions of 10-year event-free survival (EFS) and overall survival (OS) were 73% (95% confidence interval [CI] 67-79%) and 86% (95% CI 80-92%), respectively. Of the 27 neuroblastoma recurrences, 44% occurred in more than one site. Four additional patients presented histologically mature ganglioneuroma at recurrence. Six patients developed a secondary malignancy. The secondary 5-year EFS and OS of the 27 patients with neuroblastoma recurrence were 44% and 59%, respectively. TH10 gene expression signature was not prognostically predictive in the investigated subcohort.

Conclusion: The outcome of patients with stage 4(M) neuroblastoma aged less than 18 months is favorable when treated with high-risk or otherwise intensive therapy. The development of secondary malignancies and the potential of maturation to ganglioneuroma call for a controlled stepwise reduction of treatment intensity.
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http://dx.doi.org/10.1002/pbc.29038DOI Listing
August 2021

The reliability of bone marrow cytology as response criterion in metastatic neuroblastoma.

Pediatr Blood Cancer 2021 03 27;68(3):e28819. Epub 2020 Nov 27.

Department of Pediatric Oncology and Hematology, National Neuroblastoma Reference Cytology Lab, University of Cologne, Cologne, Germany.

Background: The quantitative assessment of neuroblastoma cell content in bone marrow aspirates for response evaluation has been introduced recently. Data on the concordance of interobserver reports are lacking so far.

Methods: Investigators of seven European countries representing national reference or large oncological centers convened in 2016. They agreed to quantitatively assess routine bone marrow smears of the participating institutions and to discuss the discrepant results in joint meetings.

Results: From 2017 through 2019, three cytology rounds with 24, 28, and 28 bone marrow samples were run evaluating the representativity of the smears (yes/[restricted]/no) and the presence of tumor cells (yes/no and %). The comparison of the reports using κ (Fleiss) and α (Krippendorff) statistics demonstrated no robust reliabilities. The agreement on the representativity was moderate to poor, on the presence of tumor cells moderate to good, and on the percentage of tumor cells slight to moderate. Though the value of cytology is unquestioned to detect even tiny metastatic cells in bone marrow, the investigators unanimously agreed that a reliable quantification of the tumor cell content in bone marrow smears is unrealistic. For the key issue of representativity, a new practical definition was developed.

Conclusion: For any work with bone marrow aspirates, the representativity of the material is of paramount importance. A practical definition is proposed. A reliable quantitative cytological assessment of tumor cell content in bone marrow aspirates is not feasible in metastatic neuroblastoma. Therefore, its use as response criterion should be reconsidered.
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http://dx.doi.org/10.1002/pbc.28819DOI Listing
March 2021

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.

Pediatr Blood Cancer 2021 03 18;68(3):e28794. Epub 2020 Nov 18.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Background: Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort.

Methods: A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves.

Results: The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1).

Conclusions: In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.
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http://dx.doi.org/10.1002/pbc.28794DOI Listing
March 2021

[Quadruple negative SARS-CoV-2-PCR: still COVID-19 pneumonia!]

Dtsch Med Wochenschr 2020 Oct 31;145(20):1498-1502. Epub 2020 Aug 31.

Klinik für Innere Medizin, Krankenhaus Märkisch-Oderland, Strausberg.

Medical History And Clinical Findings:  A 78-year-old man fell ill with weakness, coughing and fever 19 days after a cruise in early April 2020 and was admitted 4 days later with increasing shortness of breath.

Examination And Diagnosis:  On admission, the patient had subfebrile temperatures, exercise dyspnea, and right-basal rales. CRP was moderately elevated and oxygen saturation was slightly reduced. Thoracic CT showed bilateral ground-glass infiltrates. Immediately after the cruise a nasopharyngeal swab was negative for SARS-CoV-2.

Therapy And Course:  Due to the fact that the patient's asymptomatic wife had been tested positive for SARS-CoV-2 immediately after returning from the cruise, we suspected COVID-19 disease and admitted the patient to our isolation ward. Two nasopharyngeal swabs and bronchial lavage yielded negative results for SARS-CoV-2. Finally, suspected COVID-19 diagnosis was verified serologically.

Conclusion:  In case of a high degree of clinical suspicion in combination with typical findings of thoracic imaging, the suspected diagnosis COVID-19 disease should be maintained even in case of multiple negative SARS-CoV-2-PCR. Seroconversion occurs a few days to 2 weeks after the onset of symptoms and can be used to confirm the diagnosis.
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http://dx.doi.org/10.1055/a-1202-3936DOI Listing
October 2020

The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

Pediatr Blood Cancer 2020 08 30;67(8):e28359. Epub 2020 May 30.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Purpose: Age, MYCN status, stage, and histology have been used as neuroblastoma (NB) risk factors for decades. Serum lactate dehydrogenase (LDH) and serum ferritin are reproducible, easily obtained, and prognostic, though never used in risk stratification, except one German trial. We analyzed the prognostic strength of LDH and ferritin, overall, within high-risk NB, and by era, using the International Neuroblastoma Risk Group Data Commons.

Patients And Methods: Children with NB (1990-2016) were categorized into LDH (n = 8867) and ferritin (n = 8575) risk groups using EFS. Cox models compared the prognostic strength of LDH and ferritin to age, MYCN status, and INSS stage.

Results: Higher LDH conferred worse EFS, overall (5-year EFS) (100-899 IU/L: 76 ± 0.6%; 0-99 or 900-1399 IU/L: 60 ± 1.2%; ≥1400 IU/L: 36 ± 1.2%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (117-381 IU/L: 67 ± 8.9%; 382-1334 IU/L: 58 ± 4.4%; 0-116 or ≥1335 IU/L: 46 ± 3.9%; P = .003). Higher ferritin conferred worse EFS, overall (5-year EFS) (1-29 ng/mL: 87 ± 0.9%; 0 or 30-89 ng/mL: 74 ± 0.8%; ≥90 ng/mL: 48 ± 0.9%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (1-53 ng/mL: 71 ± 9.3%; 0 or 54-354 ng/mL: 55 ± 4.7%; ≥355 ng/mL: 34 ± 6.1%; P = .0008). In multivariable analyses adjusting for age, MYCN, and stage, LDH and ferritin maintained independent prognostic ability (P < .0001; adjusted HRs (95% CI): 1.7 (1.5-1.9), 2.3 (2.0-2.7), respectively).

Conclusions: LDH and ferritin are strongly prognostic in NB, overall and within high-risk NB patients treated post-2009 with modern therapy. LDH and ferritin show promise for (a) identifying ultra-high-risk; (b) refining risk stratification; and (c) clinical utility in low-/middle-income countries. Routine collection of LDH and ferritin should be reinitiated for evolving NB risk stratification.
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http://dx.doi.org/10.1002/pbc.28359DOI Listing
August 2020

Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure.

BMC Pharmacol Toxicol 2020 05 28;21(1):37. Epub 2020 May 28.

Department of Paediatric Haematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Campus 1, A1, 48149, Muenster, Germany.

Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects.

Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process.

Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended.

Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
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http://dx.doi.org/10.1186/s40360-020-00417-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254632PMC
May 2020

Biochemical testing for neuroblastoma using plasma free 3-O-methyldopa, 3-methoxytyramine, and normetanephrine.

Pediatr Blood Cancer 2020 02 14;67(2):e28081. Epub 2019 Nov 14.

Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Background: Neuroblastoma, the most common extracranial solid tumor of childhood, produces catecholamines that are metabolized within tumor cells. Homovanillic acid (HVA) and vanillylmandelic acid (VMA), the end products of catecholamine metabolism, have limited accuracy for testing of the tumors. This study assessed whether metabolites produced in earlier steps of catecholamine metabolism might offer improved diagnostic accuracy over urinary HVA and VMA.

Procedure: Plasma concentrations of 3-methoxytyramine, normetanephrine, and metanephrine were measured in two pediatric cohorts: (i) 96 children with confirmed neuroblastoma and (ii) 41 children with signs and symptoms of a catecholamine-producing tumor or other neoplasms and in whom neuroblastoma was excluded. Additional measurements of plasma 3-O-methyldopa and relationships of metabolites to MYCN amplification were examined in patient subgroups.

Results: Overall, 94 of the 96 patients with neuroblastoma had concentrations of 3-methoxytyramine or normetanephrine above age-specific upper limits of reference intervals, providing a diagnostic sensitivity of 97.9% that was higher (P < 0.0001) than that of 82.2% for HVA and VMA. One of the two patients with normal plasma results showed an elevation of plasma 3-O-methyldopa. Diagnostic specificities were, respectively, 95.1% and 84.8%. Areas under receiver-operating characteristic curves confirmed the superior diagnostic power of the plasma than the urinary test (0.994 vs 0.945; P = 0.0095). Ratios of plasma 3-methoxytyramine to normetanephrine were 7.2-fold higher (P < 0.0001) for patients who had neuroblastomas with MYCN amplification than without MYCN amplification.

Conclusions: Measurements of plasma 3-methoxytyramine and normetanephrine provide a highly accurate diagnostic test for neuroblastoma and also offer potential for prognostic risk stratification.
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http://dx.doi.org/10.1002/pbc.28081DOI Listing
February 2020

A new risk score for patients after first recurrence of stage 4 neuroblastoma aged ≥18 months at first diagnosis.

Cancer Med 2019 12 20;8(17):7236-7243. Epub 2019 Oct 20.

Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.

Background: The prognosis of patients with recurrences from stage 4 neuroblastoma is not uniformly dismal. The evaluation of new therapies therefore needs to consider the individual risks of the treated patients. This study aims to define clinically useful risk criteria.

Patients And Methods: Inclusion criteria were: first recurrence of neuroblastoma stage 4 aged ≥18 months and enrollment in first line trials between 1997 and 2016. Patients were randomized into a training set (N = 310) and an independent validation set (N = 159). The primary endpoint was secondary event-free survival. The individual treatment elements the patients received during initial and recurrent disease were analyzed as binary and time-dependent variables. A five-step multiple time-dependent Cox regression analysis was performed on the training set to identify prognostic variables adjusted for the individual frontline treatment. The selected variables resulted in a prognostic index (PI) and were used to build a risk score system. The score was validated with the validation set.

Results: Of the 469 patients, 372 were treated with curative intent and 97 with palliative intent. The PI included the variables number of recurrence organs (hazard ratio [HR] = 2.27), time to recurrence (HR = 2.03), liver metastasis at diagnosis (HR = 1.77), first recurrence at site of the primary tumor (HR = 1.55), and age (HR = 1.29). Three risk groups were built and confirmed in the validation set. The scoring system was likewise useful for the curatively or palliatively treated subgroups.

Conclusion: A new risk score system for patients with first recurrence of stage 4 neuroblastoma aged ≥18 months at diagnosis is proposed.
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http://dx.doi.org/10.1002/cam4.2562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885891PMC
December 2019

From a single meeting to a scientific community: Quantification of the "Advances in Neuroblastoma Research Association" network.

Authors:
Frank Berthold

Pediatr Blood Cancer 2019 06 8;66(6):e27696. Epub 2019 Mar 8.

Department of Pediatric Oncology and Hematology, University of Cologne, D 50924, Cologne, Germany.

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http://dx.doi.org/10.1002/pbc.27696DOI Listing
June 2019

Are network growth and the contributions to congresses associated with publication success? A pediatric oncology model.

PLoS One 2019 25;14(1):e0210994. Epub 2019 Jan 25.

Max Planck Institute for the Study of Societies, Koeln, Germany.

Background: The consistent focus of 'Advances in Neuroblastoma Research' congresses on the topic neuroblastoma sets it as a model for a circumscribed scientific community.

Methods: 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'.

Results: 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.

Conclusion: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210994PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347190PMC
November 2019

A mechanistic classification of clinical phenotypes in neuroblastoma.

Science 2018 12;362(6419):1165-1170

Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.

Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance-negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients.
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http://dx.doi.org/10.1126/science.aat6768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875194PMC
December 2018

Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Center for Medical Genetics, Department of Biomolecular Medicine, and.

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of noninvasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in 2 independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis, and overall survival revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential abundance analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume. These findings were validated in longitudinal serum samples from metastatic neuroblastoma patients, where the 9 miRNAs were associated with disease burden and treatment response.
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http://dx.doi.org/10.1172/jci.insight.97021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328024PMC
December 2018

THROMBOTECT - a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents.

Haematologica 2019 04 27;104(4):756-765. Epub 2018 Sep 27.

Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.

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.
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http://dx.doi.org/10.3324/haematol.2018.194175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442986PMC
April 2019

Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation.

Br J Cancer 2018 08 11;119(3):282-290. Epub 2018 Jul 11.

Children's Hospital, University of Cologne, Cologne, Germany.

Background: This study was done to investigate the long-term event free and overall survival of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), compared to maintenance chemotherapy (MT). Patterns of recurrences and late sequelae of both arms were analysed.

Methods: A randomised open label trial was conducted nationwide during 1997-2004 in Germany and Switzerland. 295 patients with high-risk neuroblastoma were randomly assigned to high-dose chemotherapy with autologous stem cell transplantation (ASCT) or maintenance chemotherapy (MT) for consolidation. Analyses were done by intention-to-treat (ITT: ASCT/MT N = 149/146), as treated (AT: N = 110/102), and treated as randomised (TAR: N = 75/70).

Results: The event free survival was superior for the patients receiving ASCT compared to patients treated with MT in all three cohorts (hazard ratio [HR] for ITT 1.39, 95% confidence interval (CI) 1.05-1.85, P = 0.022, HR for AT 1.75, CI 1.24-2.47, P = 0.001; HR for TAR 2.07, CI 1.36-3.16, P = 0.001). Overall survival was also in favour of the ASCT groups (ITT: P = 0.075; AT: P = 0.017; TAR: P = 0.005). The frequencies of late sequelae were not different except for focal nodular hyperplasia of the liver observed more frequently in the ASCT arm.

Conclusions: High-dose chemotherapy with autologous stem cell transplantation had a better long-term outcome compared to maintenance chemotherapy.
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http://dx.doi.org/10.1038/s41416-018-0169-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068129PMC
August 2018

Front-line imatinib treatment in children and adolescents with chronic myeloid leukemia: results from a phase III trial.

Leukemia 2018 07 20;32(7):1657-1669. Epub 2018 Jun 20.

Institute of Pathology, Hannover Medical School, Hannover, Germany.

A total of 156 patients (age range 1.3-18.0 years, median 13.2 years; 91 (58.3%) male) with newly diagnosed CML (N = 146 chronic phase (CML-CP), N = 3 accelerated phase (CML-AP), N = 7 blastic phase (CML-BP)) received imatinib up-front (300, 400, 500 mg/m, respectively) within a prospective phase III trial. Therapy response, progression-free survival, causes of treatment failure, and side effects were analyzed in 148 children and adolescents with complete data. Event-free survival rate by 18 months for patients in CML-CP (median follow-up time 25 months, range: 1-120) was 97% (95% CI, 94.2-99.9%). According to the 2006 ELN-criteria complete hematologic response by month 3, complete cytogenetic response (CCyR) by month 12, and major molecular response (MMR) by month 18 were achieved in 98, 63, and 59% of the patients, respectively. By month 36, 86% of the patients achieved CCyR and 74% achieved MMR. Thirty-eight patients (27%) experienced imatinib failure because of unsatisfactory response or intolerance (N = 9). In all, 28/148 patients (19%) underwent stem cell transplantation (SCT). In the SCT sub-cohort 2/23 patients diagnosed in CML-CP, 0/1 in CML-AP, and 2/4 in CML-BP, respectively, died of relapse (N = 3) or SCT-related complications (N = 2). This large pediatric trial extends and confirms data from smaller series that first-line imatinib in children is highly effective.
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http://dx.doi.org/10.1038/s41375-018-0179-9DOI Listing
July 2018

Computer-Based Exercise Program: Effects of a 12-Week Intervention on Mood and Fatigue in Pediatric Patients With Cancer
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Clin J Oncol Nurs 2017 Dec;21(6):E280-E286

German Sport University.

Background: Increasing rates of survival present a new set of physical and psychological challenges for children dealing with side effects during cancer treatment. Physical activity has been shown to be an effective strategy to reduce several side effects.
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Objectives: The purpose of this pilot study was to determine the benefits of a 12-week computer-based exercise intervention on perceived physical, motivational, and fatigue syndrome and psychological state.
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Methods: Nine inpatient and outpatient pediatric patients with cancer participated in a 12-week intervention consisting of supervised computer-based exercise sessions. Participants completed measures assessing mood and fatigue pre- and postintervention.
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Findings: The intervention was feasible and provided preliminary evidence for the benefits on mood and fatigue in pediatric patients with cancer. The results promote the effectiveness of physical activity in pediatric oncology and call for continuing research in pediatric patients with cancer where sedentary behavior and the associated side effects are a growing concern.
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http://dx.doi.org/10.1188/17.CJON.E280-E286DOI Listing
December 2017

Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma.

Pediatr Hematol Oncol 2017 Aug 17;34(5):308-319. Epub 2017 Nov 17.

c Department of Pediatric Oncology and Hematology , University of Brno , Czech Republic.

The metronomic therapy concept uses low doses of continuously applied chemotherapeutic, anti-angiogenetic, and immunomodulating drugs. Twenty patients with recurrent and 3 with refractory high-risk neuroblastoma were treated by the metronomic concept using celecoxib, cyclophosphamide, vinblastine, and etoposide for up to 24 months. The outcome was compared to 274 matched patients with a first recurrence from stage 4 neuroblastoma using the variables time from diagnosis to first recurrence, number of organs involved, and MYCN amplification. All were treated with dose-intensive conventional chemotherapy. The study patients experienced 1-3 recurrences and had 1-3 sites involved (osteomedullary, primary tumor, central nervous system, lymph nodes, liver, lungs) before the metronomic therapy started. Two patients in complete remission and three with active refractory disease following recurrence treatment were excluded from the outcome analysis. The curves for secondary event-free and overall survival demonstrated no significant differences. The toxicity was minimal except for ≥3 grade thrombocytopenia and leukopenia (all heavily pretreated). The treatment was realized in an outpatient setting. The metronomic approach is similarly effective as standard treatment in recurrent high-risk neuroblastoma, has low toxicity, and is applicable in an outpatient setting. A prospective study including propranolol as a fifth drug is underway.
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http://dx.doi.org/10.1080/08880018.2017.1373314DOI Listing
August 2017

Molecular Classification Substitutes for the Prognostic Variables Stage, Age, and MYCN Status in Neuroblastoma Risk Assessment.

Neoplasia 2017 Dec 5;19(12):982-990. Epub 2017 Nov 5.

Department of Experimental Pediatric Oncology, Children's Hospital, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany. Electronic address:

Background: Current risk stratification systems for neuroblastoma patients consider clinical, histopathological, and genetic variables, and additional prognostic markers have been proposed in recent years. We here sought to select highly informative covariates in a multistep strategy based on consecutive Cox regression models, resulting in a risk score that integrates hazard ratios of prognostic variables.

Methods: A cohort of 695 neuroblastoma patients was divided into a discovery set (n=75) for multigene predictor generation, a training set (n=411) for risk score development, and a validation set (n=209). Relevant prognostic variables were identified by stepwise multivariable L1-penalized least absolute shrinkage and selection operator (LASSO) Cox regression, followed by backward selection in multivariable Cox regression, and then integrated into a novel risk score.

Results: The variables stage, age, MYCN status, and two multigene predictors, NB-th24 and NB-th44, were selected as independent prognostic markers by LASSO Cox regression analysis. Following backward selection, only the multigene predictors were retained in the final model. Integration of these classifiers in a risk scoring system distinguished three patient subgroups that differed substantially in their outcome. The scoring system discriminated patients with diverging outcome in the validation cohort (5-year event-free survival, 84.9±3.4 vs 63.6±14.5 vs 31.0±5.4; P<.001), and its prognostic value was validated by multivariable analysis.

Conclusion: We here propose a translational strategy for developing risk assessment systems based on hazard ratios of relevant prognostic variables. Our final neuroblastoma risk score comprised two multigene predictors only, supporting the notion that molecular properties of the tumor cells strongly impact clinical courses of neuroblastoma patients.
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http://dx.doi.org/10.1016/j.neo.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678736PMC
December 2017

Retrospective analysis of relapsed abdominal high-risk neuroblastoma.

J Pediatr Surg 2018 Mar 11;53(3):558-566. Epub 2017 Sep 11.

Division of Pediatric Surgery, University Hospital Cologne, Kerpenerstr. 62, 50937, Köln, Germany. Electronic address:

Background/purpose: The impact of abdominal topography and surgical technique on resectability and local relapse pattern of relapsed abdominal high-risk neuroblastoma (R-HR-NB) is not clearly defined.

Methods: A sample of thirty-nine patients with R-HR-NB enrolled in the German neuroblastoma trials between 2001 and 2010 was analyzed retrospectively using surgical and imaging reports. We evaluated resectability and local relapse pattern within 6 standardized abdominal regions, impact of extent of the first resective surgery on overall survival (OS), and of number of operations and a higher cumulative surgical assessment score (C-SAS) on OS after the first event.

Results: In the left upper abdomen, rates for tumor persistence and relapse were 45.9% and 13.5% and in the left lower abdomen 27.7% and 8.3%, respectively. OS in months did not differ between complete and incomplete first resections (median (interquartile range): 35 (45.6) vs. 40 (65.4), P=.649). Better OS after the first event was associated with repeated as compared to single surgery (47.7 (64.7) vs. 4.3 (12.5), P=.000), and with higher as compared to lower C-SAS (47.7 (64.3) vs. 7.6 (14.7), P=.002).

Conclusions: OS after relapse/progression was not dependent on the extent of first resection. The number of operations was associated with better outcome after event.

Type Of Study: Treatment study.

Level Of Evidence: LEVEL III Retrospective comparative study.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.09.002DOI Listing
March 2018

Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

Cochrane Database Syst Rev 2017 08 25;8:CD010685. Epub 2017 Aug 25.

Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Kerpener Str. 62, Cologne, Germany, 50937.

Background: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review.

Objectives: To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system).

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages.

Selection Criteria: Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life.

Data Collection And Analysis: We used standard methodological procedures expected by Cochrane.

Main Results: The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow-up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision.

Authors' Conclusions: We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion.
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http://dx.doi.org/10.1002/14651858.CD010685.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483698PMC
August 2017

Incidence, Survival, and Treatment of Localized and Metastatic Neuroblastoma in Germany 1979-2015.

Paediatr Drugs 2017 Dec;19(6):577-593

Department of Pediatric Oncology and Hematology, Children's Hospital, University of Giessen, Giessen, Germany.

Background: A comprehensive clinical long-term survey over the complete spectrum of neuroblatoma disease is lacking in the literature.

Objective: Our objective was to describe the incidence, risk profiles, therapies, and outcomes for the total cohort of German patients with neuroblastoma including all clinical stages and risk groups.

Methods: Epidemiological, clinical, and outcome data of neuroblastoma patients who participated in one of the six consecutive national trials between 1979 and 2015 were analyzed retrospectively.

Results: Of all German neuroblastoma patients known to the national childhood cancer registry, ninety seven percent enrolled in one of the trials. The absolute neuroblastoma rate has increased slightly, whereas the median age at diagnosis has decreased. Except for the screening period (1995-2000), the risk factors lactate dehydrogenase (LDH), ferritin, chromosome 1p, and the MYCN oncogene have remained largely constant, with the exception of an increase in MYCN amplification at stage 4 for those aged ≥18 months between trials NB97 (27%) and NB2004 (35%). The 10-year overall survival increased in patients with stage 1-3 neuroblastoma from 83 to 91%, for stage 4S from 80 to 85%, and for stage 4 aged ≥18 months from 2 to 38%. The fraction of patients in stages 1-3 who never received chemotherapy (neither for frontline nor at recurrence) increased from 35 to 60%. The proportion of macroscopically complete surgical resections of the primary tumor decreased for the total population as well as for patients with stage 4 aged ≥18 months. The impact of chemotherapy response on the outcome was trial dependent. The overall proportion of toxic death during the time of the protocol therapy was 6% for stage 4 patients aged ≥18 months and 2% for low-/intermediate-risk patients. The most frequently reported late sequelae in stage 4 patients aged ≥18 months were renal dysfunctions, hypothyroidism, major hearing impairment, and second malignancies.

Conclusion: The body of data for incidences, risk profiles, and survival rates from this survey of more than 37 years provides a useful perspective for future studies on neuroblastoma sub-cohorts.
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http://dx.doi.org/10.1007/s40272-017-0251-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680382PMC
December 2017

Complete surgical resection improves outcome in INRG high-risk patients with localized neuroblastoma older than 18 months.

BMC Cancer 2017 Aug 4;17(1):520. Epub 2017 Aug 4.

Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Str. 62, 50924, Cologne, Germany.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1186/s12885-017-3493-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543757PMC
August 2017

Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

Expert Opin Drug Discov 2017 08 26;12(8):801-811. Epub 2017 Jun 26.

c Paediatric Drug Development, Children and Young People's Unit , Royal Marsden Hospital , London , UK.

Introduction: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.
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http://dx.doi.org/10.1080/17460441.2017.1340269DOI Listing
August 2017

2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors.

Klin Padiatr 2017 May 30;229(3):147-167. Epub 2017 May 30.

Department of Pediatric Oncology and Hematology, Charité University Hospital Berlin.

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Most low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise patient characterization at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.
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http://dx.doi.org/10.1055/s-0043-103086DOI Listing
May 2017

Feasibility, Risk Profile and Diagnostic Yield of Stereotactic Biopsy in Children and Young Adults with Brain Lesions.

Klin Padiatr 2017 May 30;229(3):133-141. Epub 2017 May 30.

Department of Stereotaxy and Functional Neurosurgery, University of Cologne, Cologne, Germany.

To evaluate the feasibility, safety, and diagnostic yield of stereotactic biopsy (SB) in children and adolescents with cerebral lesions. We performed a systematic review of the literature and a retrospective analysis of all pediatric and adolescent patients who underwent SB for unclear brain lesions at our center. We collected patient and lesion-associated parameters, analysed the rate of procedural complications and diagnostic yield. Our institutional series consisted of 285 SBs in 269 children and young adults between 1989 and 2016 (median age, 9 (range 1-18) years). There was no procedure-related mortality. Permanent and transient morbidity was 0.7% and 5.8%, respectively. Lesions were located in brain lobes (26.3%) and in midline structures (73.7%). The diagnostic yield was 97.5% and histology consisted low-grade gliomas (44.2%), high-grade gliomas (15.1%), non-glial tumors (22.8%), and non-neoplastic disease (15.4%). Morbidity was not associated with tumor location, age, histology or intraoperative position of the patient. In order to compare our findings with previous reports, we reviewed 25 studies with 1 109 children and young adults which had underwent SB. The diagnostic yield ranged between 83% and 100%. The reported morbidity and mortality rates range from 0-27% and 0-3.3%, respectively. SB in this particular patient population is a safe and a high-yield diagnostic procedure and indicates therefore its importance in the light of personalized medicine with the development of individual molecular treatment strategies.
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http://dx.doi.org/10.1055/s-0043-101908DOI Listing
May 2017

Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting.

J Clin Oncol 2017 Aug 4;35(22):2580-2587. Epub 2017 May 4.

Julie R. Park, Seattle Children's Hospital and University of Washington School of Medicine, Seattle, WA; Rochelle Bagatell and John M. Maris, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA; Susan L. Cohn, University of Chicago, Chicago, IL; Andrew D. Pearson, Institute of Cancer Research and Royal Marsden National Health Service (NHS) Foundation Trust, Sutton, Surrey; Susan Burchill, Leeds Institute of Cancer and Pathology, St James University Hospital, Leeds; Kieran McHugh and Penelope Brock, Great Ormond Street Hospital for Children, NHS Trust, London, United Kingdom; Judith G. Villablanca, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles; Katherine K. Matthay, University of California San Francisco School of Medicine, San Francisco, CA; Frank Berthold, Children's Hospital and University of Cologne, Köln, Germany; Ariane Boubaker, Institute of Radiology, Clinique de La Source, Lausanne, Switzerland; Jed G. Nuchtern, Texas Children's Hospital and Baylor College of Medicine, Houston, TX; Wendy B. London, Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Harvard Medical School, Boston, MA; Nita L. Seibel and O. Wolf Lindwasser, National Cancer Institute, Bethesda, MD; Gudrun Schleiermacher, Institut Curie, Paris; Dominique Valteau-Couanet, Gustave Roussy, Villejuif, France; and Ruth Ladenstein, Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria.

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 (I) -metaiodobenzylguanidine (MIBG) scans or [F]fluorodeoxyglucose-positron emission tomography scans if the tumor is MIBG nonavid. I-MIBG scans, or [F]fluorodeoxyglucose-positron emission tomography scans for MIBG-nonavid disease, replace technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ≤ 5% tumor involvement will be classified as minimal disease. Urinary catecholamine levels will not be included in response assessment. Overall response will be defined as complete response, partial response, minor response, stable disease, or progressive disease. Conclusion These revised criteria will provide a uniform assessment of disease response, improve the interpretability of clinical trial results, and facilitate collaborative trial designs.
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http://dx.doi.org/10.1200/JCO.2016.72.0177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676955PMC
August 2017
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