Early-phase clinical trial eligibility and response evaluation criteria for refractory, relapsed, or progressive neuroblastoma: A consensus statement from the National Cancer Institute Clinical Trials Planning Meeting

Consensus criteria; Early phase; NeuroblastomaCriteris de consens; Fase inicial; NeuroblastomaCriterios de consenso; Fase inicial; NeuroblastomaBackground International standardized criteria for eligibility, evaluable disease sites, and disease response assessment in patients with refractory, progressive, or relapsed high-risk neuroblastoma enrolled in early-phase clinical trials are lacking. Methods A National Cancer Institute–sponsored Clinical Trials Planning Meeting was convened to develop an international consensus to refine the tumor site eligibility criteria and evaluation of disease response for early-phase clinical trials in children with high-risk neuroblastoma. Results Standardized data collection of patient and disease characteristics (including specified genomic data), eligibility criteria, a definition of evaluable disease, and response evaluations for primary and metastatic sites of disease were developed. Eligibility included two distinct patient groups: progressive disease and refractory disease. The refractory disease group was subdivided into responding persistent disease and stable persistent disease to better capture the clinical heterogeneity of refractory neuroblastoma. Requirements for defining disease evaluable for a response assessment were provided; they included requirements for biopsy to confirm viable neuroblastoma and/or ganglioneuroblastoma in those patients with soft tissue or bone disease not avid for iodine-123 meta-iodobenzylguanidine. Standardized evaluations for response components and time intervals for response evaluations were established. Conclusions The use of international consensus eligibility, evaluability, and response criteria for early-phase clinical studies will facilitate the collection of comparable data across international trials and promote more rapid identification of effective treatment regimens for high-risk neuroblastoma.National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee; Alex's Lemonade Stand Foundation for Childhood Cancer; Ben Towne Foundation; EVAN Foundation; Cancer Research UK Institute of Cancer Research, Grant/Award Number C347/A15403; National Institute for Health Research Research Methods Programme/Institute of Cancer Research Biomedical Research Centre

Anti-ALK Antibodies in Patients with ALK-Positive Malignancies Not Expressing NPM-ALK.

Patients with Nucleophosmin (NPM)- Anaplastic Lymphoma Kinase (ALK) fusion positive Anaplastic Large Cell Lymphoma produce autoantibodies against ALK indicative of an immune response against epitopes of the chimeric fusion protein. We asked whether ALK-expression in other malignancies induces specific antibodies. Antibodies against ALK were detected in sera of one of 50 analysed ALK-expressing neuroblastoma patients, 13 of 21 ALK positive non-small cell lung carcinoma (NSCLC) patients, 13 of 22 ALK translocation-positive, but NPM-ALK-negative lymphoma patients and one of one ALK-positive rhabdomyosarcoma patient, but not in 20 healthy adults. These data suggest that boosting a pre-existent anti-ALK immune response may be more feasible for patients with ALK-positive NSCLC, lymphomas and rhabdomyosarcomas than for tumours expressing wild-type ALK.This work was supported by a grant from the Deutsche Jose Carreras Leukämie-Stiftung (DJCLS08/ 09) to WW, and RS. CDW and WW are additionally supported by the von behring röntgen stiftung (60-0011) and the Forschungshilfe Peiper, IO and RS by the Kinderkrebsinitiative Buchholz/HolmSeppensen and KP by Bloodwise, the Julian Starmer-Smith Memorial Fund and the Sam Foye Fund. SDT is a Bloodwise University Senior Lecturer and is also supported by the Alex Hulme Foundation and the Sam Foye Fund. MH is supported by a PhD studentship from the Wellcome Trust.This is the final version of the article. It first appeared from Ivyspring International via http://dx.doi.org/10.7150/jca.1523

Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

Differences in MYCN/c-MYC target gene expression are associated with distinct neuroblastoma subtypes and clinical outcome

Adrenocortical tumors and pheochromocytoma/paraganglioma initially mistaken as neuroblastoma — experiences from the GPOH-MET registry

In children and adolescents, neuroblastoma (NBL), pheochromocytoma (PCC), and adrenocortical tumors (ACT) can arise from the adrenal gland. It may be difficult to distinguish between these three entities including associated extra-adrenal tumors (paraganglioma, PGL). Precise discrimination, however, is of crucial importance for management. Biopsy in ACT or PCC is potentially harmful and should be avoided whenever possible. We herein report data on 10 children and adolescents with ACT and five with PCC/PGL, previously mistaken as NBL. Two patients with adrenocortical carcinoma died due to disease progression. Two (2/9, missing data in one patient) patients with a final diagnosis of ACT clearly presented with obvious clinical signs and symptoms of steroid hormone excess, while seven patients did not. Blood analyses indicated increased levels of steroid hormones in one additional patient; however, urinary steroid metabolome analysis was not performed in any patient. Two (2/10) patients underwent tumor biopsy, and in two others tumor rupture occurred intraoperatively. In 6/10 patients, ACT diagnosis was only established by a reference pediatric pathology laboratory. Four (4/5) patients with a final diagnosis of PCC/PGL presented with clinical signs and symptoms of catecholamine excess. Urine tests indicated possible catecholamine excess in two patients, while no testing was carried out in three patients. Measurements of plasma metanephrines were not performed in any patient. None of the five patients with PCC/PGL received adrenergic blockers before surgery. In four patients, PCC/PGL diagnosis was established by a local pathologist, and in one patient diagnosis was revised to PGL by a pediatric reference pathologist. Genetic testing, performed in three out of five patients with PCC/PGL, indicated pathogenic variants of PCC/PGL susceptibility genes. The differential diagnosis of adrenal neoplasias and associated extra-adrenal tumors in children and adolescents may be challenging, necessitating interdisciplinary and multidisciplinary efforts. In ambiguous and/or hormonally inactive cases through comprehensive biochemical testing, microscopical complete tumor resection by an experienced surgeon is vital to preventing poor outcome in children and adolescents with ACT and/or PCC/PGL. Finally, specimens need to be assessed by an experienced pediatric pathologist to establish diagnosis

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

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

Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective

MIBG scans in patients with stage 4 neuroblastoma reveal two metastatic patterns, one is associated with MYCN amplification and in MYCN-amplified tumours correlates with a better prognosis

Methods: Diagnostic 123I-MIBG scans from 249 patients (123 from a European and 126 from the COG cohort) were assessed for metastatic spread in 14 body segments and the form of the lesions: “focal” (clear margins distinguishable from adjacent background) or “diffuse” (indistinct margins, dispersed throughout the body segment). The total numbers of diffuse and focal lesions were recorded. Patients were then categorized as having lesions exclusively focal, lesions more focal than diffuse, lesions more diffuse than focal, or lesions exclusively diffuse.Results: Diffuse lesions affected a median of seven body segments and focal lesions a median of two body segments (P < 0.001, both cohorts). Patients with a focal pattern had a median of 2 affected body segments and those with a diffuse pattern a median of 11 affected body segments (P < 0.001, both cohorts). Thus, two MIBG-avid metastatic patterns emerged: “limited-focal” and “extensive-diffuse”. The median numbers of affected body segments in MYCN-amplified (MNA) tumours were 5 (European cohort) and 4 (COG cohort) compared to 9 and 11, respectively, in single-copy MYCN (MYCNsc) tumours (P < 0.001). Patients with exclusively focal metastases were more likely to have a MNA tumour (60 % and 70 %, respectively) than patients with the other types of metastases (23 % and 28 %, respectively; P < 0.001). In a multivariate Cox regression analysis, focal metastases were associated with a better event-free and overall survival than the other types of metastases in patients with MNA tumours in the COG cohort (P < 0.01).Conclusion: Two metastatic patterns were found: a “limited and focal” pattern found mainly in patients with MNA neuroblastoma that correlated with prognosis, and an “extensive and diffuse” pattern found mainly in patients with MYCNsc neuroblastoma.Purpose: The aim of this study was to find clinically relevant MIBG-avid metastatic patterns in patients with newly diagnosed stage 4 neuroblastoma

Update on Pediatric Opsoclonus Myoclonus Syndrome

Opsoclonus myoclonus syndrome (dancing eye syndrome) is a rare paraneoplastic syndrome characterized by opsoclonus, myoclonus, and ataxia, usually accompanied by behavioral abnormalities. In adults, opsoclonus myoclonus syndrome has been reported in association with different types of cancer; whereas in children, the syndrome may be associated with neuroblastic tumors. Although a direct proof is lacking, the syndrome is assumed to be of autoimmune origin. The treatment is corticosteroid based with the addition of other immunosuppressive or immunomodulating drugs if intensification seems necessary. Because of the rarity of the disease, international collaborations as well on research as on therapeutic strategies are urgently needed. A European consortium just started a trial for this rare condition

I-131-mIBG therapy in neuroblastoma: established role and prospective applications

The following review aims to summarise contemporary information on I-131-meta-iodobenzylguanidine (I-131-mIBG) therapy in neuroblastoma being the most common paediatric extracranial solid cancer characterized by mIBG avidity in >= 90 % of patients. Pathophysiologic basis for mIBG uptake is the expression of the norepinephrine transporter on the tumor cell membrane. Meta-iodobenzylguanidine was introduced in 1979 by Dr. Donald Wieland for imaging the adrenal medulla. Uptake in neuroblastoma cells is known since 1984 and mIGB has been in use as diagnostic and therapeutic tool in neuroblastoma patients for more than 30 years. A European guideline published by the European Association of Nuclear Medicine is available. Most therapy studies report about the use of I-131-mIBG in refractory or relapsed neuroblastoma. More recent studies combine I-131-mIBG with non-myeloablative or myeloablative chemotherapy regimens and stem cell transplantation. Response rates are in the range of 30-40 %. In Germany, I-131-mIBG therapy is scheduled in the first-line treatment at the end of induction chemotherapy in patients with residual non-progressing mIBG-avid lesions present before myeloablative chemotherapy and autologous stem cell transplantation using 444 MBq (12 mCi) I-131-mIBG/kg body weight. In The Netherlands, I-131-mIBG therapy is also integrated upfront in first-line neuroblastoma treatment protocols. I-131-mIBG is also widely used in case of recurrent disease. Monotherapy with low activities of I-131-mIBG can achieve good pain reduction in the terminal ill patient. Ongoing efforts aim to optimise I-131-mIBG treatment by better patient selection, using no-carrier-added I-131mIBG, increasing norepinephrine transporter expression or increasing radiosensitivity of neuroblastoma cells by combining radionuclide with chemotherapy. Further efforts include a more standardized approach including patient and tumour dosimetry. Despite more than 30 years of experience with I-131-mIBG therapy there no definite conclusion about its optimal clinical use and there is a definite lack of prospective randomized clinical trials. Nuclear medicine can deliver I-131-mIBG treatment. However, the implementation of a prospective trial with I-131-mIBG needs crucial input from pediatric oncologists and a solid infrastructure allowing to perform investigator-initiated trials. New radionuclide treatment options include peptide receptor radionuclide therapy