Asphericity of tumor [123 I]mIBG uptake as a prognostic factor in high-risk neuroblastoma.

BACKGROUND: In recent years, many research groups have attempted to identify a subgroup of "ultra-high risk" patients within the high-risk neuroblastoma (NB) category. The aim of our study was to evaluate the prognostic significance of parameters derived from pretherapeutic 123 I-meta-iodobenzylguanidine ([123 I]mIBG) integrated single photon emission computed tomography and computed tomography in high-risk patients with NB. METHODS: The established parameters metabolic tumor volume (MTV), maximal standardized uptake value (SUVmax ) and the novel parameter tumor asphericity as well as clinical (age, stage) and genetic factors (1p/11q deletions and MYCN amplification) were analyzed in this single-center retrospective study of high-risk patients with newly diagnosed NB. Univariate/multivariable Cox regression and propensity score matching were performed for clinical and radiological parameters. RESULTS: Twenty-eight high-risk patients with NB were included (14 males, median age 28.8 (11.3-41.0), range 3-74 months). Multivariable analysis of "full" cohort identified high asphericity (≥65%, adjusted hazard ratio [HR] 5.32, 95% confidence interval [CI]: 1.18-24.07, p = .03) and MTV (≥50 ml, adjusted HR 4.31, 95% CI: 1.18-15.80, p = .027) as the only factors associated with worse event-free survival. In matched cohort, tumor asphericity was a significant predictor of relapse/progression (HR 3.83, 95% CI: 1.03-14.26, p = .046). CONCLUSION: In this exploratory study, imaging parameters related to tumor metabolic activity, tumor asphericity and MTV, provided prognostic value for event-free survival in high-risk NB patients. Asphericity ≥65% and MTV ≥50 ml may serve as additional prognostic factors to those already used.

Pancreatoblastoma in children: EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm that affects typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological confirmation is mandatory. The mainstay of the treatment is a complete surgical resection. Unresectable and/or metastatic PBL may become amenable to complete delayed surgery after neoadjuvant chemotherapy. This manuscript presents the international consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network - European Registry) project.

Salivary gland carcinoma in children and adolescents: The EXPeRT/PARTNER diagnosis and treatment recommendations.

Salivary gland carcinomas (SGCs) are rare during childhood and adolescence. Consequently, no standardized recommendations for the diagnosis and therapeutic management of pediatric SGC are available, and pediatric oncologists and surgeons generally follow adult guidelines. Complete surgical resection with adequate margins constitutes the cornerstone of treatment. However, the indications and modalities of adjuvant therapy remain controversial and may be challenging in view of the potential long-term toxicities in the pediatric population. This paper presents the consensus recommendations for the diagnosis and treatment of children and adolescents with SGCs, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER project (Paediatric Rare Tumours Network - European Registry).

Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are exceptionally rare neoplasms, which are often driven by rearranged tyrosine kinases. METHODS: This study considered 33 consecutive patients with IMT (median age, 6.6; age range, 0.6-15.8 years). RNA and cDNA were successfully obtained in 29 cases. The molecular analysis included sequential tests for 5'/3'-end unbalanced gene expression, variant-specific PCR, and next-generation sequencing (NGS). RESULTS: 5'/3'-end unbalanced ALK expression was revealed in 15/29 (52%) IMTs. Strikingly, all these tumors demonstrated high amount of ALK protein detected by immunohistochemistry. Variant-specific PCR was capable of identifying the type of ALK rearrangement in 11/15 IMTs with 5'/3'-end unbalanced ALK expression. The remaining four tumors were analyzed by NGS; two known and two novel (CLTC-ins6del84-ALK and EEF1G-ALK) ALK rearrangements were detected. Five IMTs demonstrated 5'/3'-end unbalanced ROS1 expression, and all these tumors carried TFG-ROS1 fusion. Nine tumors, which were negative for 5'/3'-end unbalanced ALK/ROS1 expression, were subjected to further analysis. Variant-specific PCR revealed two additional tumors with gene rearrangements (TFG-ROS1 and ETV6-NTRK3). The remaining seven IMTs were tested by NGS; single instances of TFG-ROS1 and novel SRF-PDGFRb translocations were detected. CONCLUSIONS: Twenty-four of 29 IMTs (83%) were shown to have druggable rearrangements involving tyrosine kinases, 20 of these 24 gene fusions were detectable by simple and inexpensive PCR assay, which is based on the detection 5'/3'-end unbalanced gene expression.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A safe treatment option for intraperitoneal rhabdomyosarcoma in children below 5 years of age.

Advanced and relapsed intraperitoneal rhabdomyosarcomas in young children represent an oncological challenge and options for local tumor control are limited. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is commonly used in advanced peritoneal tumors in adults. However, no studies are available regarding CRS and HIPEC in young children. We report our experiences treating six patients with intraperitoneal rhabdomyosarcoma with CRS and HIPEC using cisplatin and doxorubicin focusing on safety and outcomes. No procedure-associated mortalities occurred and no major short- or long-term toxicities were recorded. All patients showed no evidence of disease after 12-month median (7-41) follow-up.

The extraordinary challenge of treating patients with congenital rhabdoid tumors-a collaborative European effort.

BACKGROUND: Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach. METHODS: A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU-RHAB), France and Moscow (2006-2016) diagnosed within the first 28 days of life was evaluated. Genetic and clinical reference evaluation included SMARCB1 and/or SMARCA4 (fluorescence-in-situ-hybridization, multiplex ligation-dependent probe amplification, and sequencing) mutation analysis and immunohistochemistry. Forty-eight percent (20/42) of patients were treated according to the EU-RHAB therapy, 7% (3/42) according to the pilot approach Rhabdoid 2007, 33% (14/42) with individual schedules, and 12% (5/42) received no chemotherapy at all. RESULTS: Forty point five percent (17/42) of patients presented with extracranial rhabdoid tumors, 33.5% (14/42) with rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor), and the remainder 26% (11/42) demonstrated synchronous tumors. Metastases at diagnosis were present in 52% (22/42) of patients. A germline mutation was detected in 66% (25/38) and was associated with a poor prognosis (4.2 ± 4.1% vs. 48 ± 16.4%, P < 0.00005). A gross total resection (GTR) was realized in 17%. A GTR (42.9 ± 18.7% vs. 4.9 ± 4.3%, P = 0.04), therapy according to a standardized approach (20.9 ± 8.7% vs. 7.1 ± 6.9 %, P = 0.0018), and a complete remission (CR) (23.6 ± 9.8% vs. 1.3 ± 3.6%, P = 0.04) were significant prognostic factors. CONCLUSIONS: The management of patients with congenital rhabdoid tumors requires a major multidisciplinary effort. In many instances, cure is not possible and a palliative approach is warranted. Our data indicate a positive impact of standardized therapeutic approaches on survival, making a tailored approach toward affected patients and their families mandatory.

DICER1-Related Tumor Predisposition: Identification of At-risk Individuals and Recommended Surveillance Strategies.

BACKGROUND: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the Registry's goals is to continue to refine these guidelines as additional data becomes available. EXPERIMENTAL DESIGN: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the National Cancer Institute Natural History of DICER1 Syndrome study. RESULTS: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor (SLCT) at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed under age 8 years, the current age of onset of pelvic surveillance. Additionally, 4% of SLCTs were diagnosed before the age of 4 years. CONCLUSION: Ongoing data collection highlights the role of lung surveillance in the detection of early PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before age 8 years, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

Childhood leukemia and lymphoma: time trends and factors affecting survival in five Southern and Eastern European Cancer Registries.

PURPOSE: Within Europe, incidence and mortality rates of childhood leukemia and lymphoma are rather heterogeneous. The present study comprising data from five Southern and Eastern European Cancer Registries aims to compare time trends and examine whether sociodemographic variables, clinical parameters, and proxies of efficient care affect survival. METHODS: Data spanning 1996-2010 were obtained for a total of 3,041 newly diagnosed childhood leukemia and 1,183 lymphoma cases reported by the Greek Nationwide Registry for Childhood Hematological Malignancies, Bulgarian National Cancer Registry, Moscow Region and Turkey (Antalya and Izmir) Cancer Registries. Poisson modeling for the evaluation of time trends and multivariate Cox regression analysis for the assessment of prognostic factors were performed. RESULTS: The incidence of leukemia was increasing in all cases, with Bulgaria and Greece presenting statistically significant annual changes (+3.5, and +1.7 %, respectively), followed by marginally increasing trends in Izmir and Moscow; by contrast, there was a remarkable, statistically significant, decreasing mortality trend for leukemia. Rates for lymphoma remained flat. Greece experienced almost twofold better survival rates for both leukemia and lymphoma, probably due to its higher socioeconomic status during the study period. Overall, patients with leukemia living in rural areas had a 28 % lower prognosis (RR: 1.28, 95 % CI 1.03-1.59), pointing to effects of remoteness, when the most privileged country (Greece) was excluded from the analysis. CONCLUSIONS: The favorable mortality trends highlight the progress in Southern-Eastern European countries along their trajectory to converge with Northern-Western EU counterpart states. Socioeconomic status may act as a multipotent factor underlying the study findings.

Primary Neuroblastoma of the Thymus.

ABSTRACT: Primary neuroblastoma is the most common extracranial solid tumor in children and may occur anywhere along the sympathetic chain, but most commonly occur in abdominal/retroperitoneal region including the adrenal glands, followed by the thorax. In children, the most primary neuroblastomas in the thorax are in the posterior mediastinum. We present herein an extremely rare case of primary neuroblastoma of thymus in pediatric patient.

Survival patterns of childhood neuroblastoma: an analysis of clinical data from Southern-Eastern European countries.

The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009-2018) were collected from Greece, Slovenia and Russia. Kaplan-Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5-4.9 years: 61%; EFS 5-year; 1.5-4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year; <1.5 years: 91%; EFS 5-year; <1.5 years: 78%). Predictors of poor OS included stage 4 (hazard ratio, HR OS : 18.12, 95% confidence intervals, CI: 3.47-94.54), N-myc amplification (HR OS : 2.16, 95% CI: 1.40-3.34), no surgical excision (HR OS : 3.27, 95% CI: 1.91-5.61) and relapse/progression (HR OS : 5.46, 95% CI: 3.23-9.24). Similar unfavorable EFS was found for the same subsets of patients. By contrast, treatment with anti-GD2 antibody in high-risk patients was associated with decreased risk of death or unfavorable events (HR OS : 0.11, 95% CI: 0.02-0.79; HR EFS : 0.19, 95% CI: 0.07-0.52). Our results confirm the outstanding prognosis of the early NBL stages, especially in children <1.5 years, and the improved outcomes of the anti-GD2 treatment in high-risk patients. Ongoing high-quality clinical cancer registration is needed to ensure comparability of survival across Europe and refine our understanding of the NBL biology.

Presenting features of neuroblastoma with spinal canal invasion. A prospective study of the International Society of Pediatric Oncology Europe - Neuroblastoma (SIOPEN).

Introduction: Between 5 and 15% of children with neuroblastoma (NB) present with or develop spinal canal invasion (SCI). The majority of these children have symptoms of epidural compression of spinal cord and/or spinal nerves. Treatment of NB-SCI is considered an emergency but its modalities are not yet well-established. Independently of treatment, NB-SCI may result in significant long-term disabilities. We report on the first prospective study of NB-SCI focused on presenting characteristics of both symptomatic and asymptomatic patients and correlation between SCI-related symptoms and imaging features. Materials and methods: This SIOPEN prospective NB-SCI study opened in June 2014. Patient data including SCI symptoms evaluated by standardized measures and spinal cord imaging studies were collected for each patient. For the purpose of this study data entry was locked on July 2021. Results: Of the 208 NB-SCI patients registered, 196 were evaluable for this analysis of whom 67% were symptomatic and 33% asymptomatic. Median age was 11 months. The thorax was the commonest primary tumor site. The median intervals between initial symptoms and diagnosis and between first medical visit and diagnosis were 14 and 3 days, respectively. The was no statistical difference in frequency of presenting characteristics between symptomatic and asymptomatic patients. Presenting features of NB-SCI patients differed from other NBs for older median age, prevalence of thoracic vs. abdominal primary site, prevalence of localized vs. metastatic disease and lower incidence of MYCN gene amplification. The most common SCI features were motor deficit in the younger and pain in the older patients that correlated on imaging with both transverse and longitudinal extent but not with the level of intraspinal tumor. Spinal cord T2-hyperintensity was more frequently detected in symptomatic patients (not significant). Conclusion: This prospective study confirms that children with NB-SCI differ from NBs without SCI. Compared to previous studies, it provides more detailed information regarding presenting symptoms, time intervals between SCI symptoms, medical visit and diagnosis, and correlations between symptoms and imaging features.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Survival and prognostic factors for childhood malignant liver tumors: analysis of harmonized clinical data.

BACKGROUND: Despite overall striking advances in survival of childhood liver tumors, outcomes remain poor for specific patient segments. We aimed to assess overall survival (OS) of this rare disease and evaluate the generalizability of prognostic variables included in international collaborative systems using, for the first time, harmonized clinical data from two geographically different cohorts (Greece and Moscow). METHODS: Data for children (0-14 years) with liver tumors were retrieved from two Southern-Eastern European areas (Greece; 2001-2019 and Moscow; 2012-2019). Kaplan-Meier curves were constructed, and OS values were derived from Cox proportional models controlling for study variables. RESULTS: A total of 171 newly diagnosed cases (54.4% males) were included. The OS5-year exceeded 80% in patients <5 years, reaching 85% among 133 patients with hepatoblastoma (HBL). By contrast, children with other than HBL histology, especially hepatocellular carcinoma (HCC) had significantly worse prognosis (hazard ratio [HR] HCC: 7.09, 95% confidence intervals [CI]: 2.56-19.65; HR other liver tumors: 5.18; 95%CI: 2.15-12.49). The OS5-year was poorer (40%-60%) in patients with extensive local, metastatic or relapsed disease. By contrast, a significantly lower risk of death was shown in case of microscopically margin-negative resection (HR: 0.06, 95%CI: 0.02-0.17) and liver transplantation (HR: 0.12, 95% CI: 0.02-0.63) compared to the non- operated group. CONCLUSIONS: Outcomes of patients with liver tumors registered in two SEE areas were comparable to those reported by major collaborative trials. Ongoing clinical cancer registration could facilitate comparison of outcomes between different study groups in order to shape state of the art of treatment.

Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).

INTRODUCTION: Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework. METHODS: We evaluated 100 patients recruited within EU-RHAB (2009-2018). Tumours and matching blood samples were examined for SMARCB1 mutations by sequencing and cytogenetics. RESULTS: A total of 70 patients presented with extracranial, extrarenal tumours (eMRT) and 30 with renal rhabdoid tumours (RTK). Nine patients demonstrated synchronous tumours. Distant metastases at diagnosis (M+) were present in 35% (35/100), localised disease (M0) with (LN+) and without (LN-) loco-regional lymph node involvement in 65% (65/100). SMARCB1 germline mutations (GLM) were detected in 21% (17/81 evaluable) of patients. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.8 ± 5.4% and 35.2 ± 5.1%, respectively. On univariate analyses, age at diagnosis (≥12 months), M0-stage, absence of synchronous tumours, absence of a GLM, gross total resection (GTR), radiotherapy and achieving a CR were significantly associated with favourable outcomes. In an adjusted multivariate model presence of a GLM, M+ and lack of a GTR were the strongest significant negative predictors of outcome. CONCLUSIONS: We suggest to stratify patients with localised disease (M0), GTR+ and without proof of a GLM (5-year OS 72.2 ± 9.9%) as 'standard risk'. Patients presenting with one of the features M+ and/or GTR- and/or GLM+ belong to a high risk group (5-year, OS 32.5 ± 6.2%). These patients need novel therapeutic strategies such as combinations of targeted agents with conventional chemotherapy or novel experimental approaches ideally within international phase I/II trials.

A minimally invasive first stage of ALPPS for hepatoblastoma in a child.

Large and giant tumors, especially hepatoblastomas, are more frequently presented in pediatric patients. At about two-third of hepatoblastomas at the time of diagnosis are unresectable and liver transplantation is considered as a treatment of choice because of insufficient future liver remnant volume. In selected cases, 2-staged hepatectomy may be the unique chance for curative resection except hepatectomy followed by liver replacement. Despite the overwhelming spread of minimally invasive liver surgery, the laparoscopic approach remains uncommon in children. A case of successful partial associating liver partition with portal vein ligation for staged hepatectomy firstly accomplished pure laparoscopically on the first stage in an infant is presented. Described experience suggests both: the feasibility of laparoscopic procedures and the effectiveness of partial in situ liver splitting to reach appropriate future liver remnant volume and to avoid liver transplantation and its disadvantages.

Malignant rhabdoid tumor of the liver presented with initial tumor rupture.

Malignant rhabdoid tumor (MRT) of the liver is a rare, highly aggressive tumor of early childhood. We report a 6-month-old boy who was diagnosed with MRT of the liver and presented with spontaneous tumor rupture. The patient underwent intensified chemotherapy and a radical surgical procedure. Twenty four months from the time of the diagnosis, he is alive without evidence of disease. This is the second report of prolonged survival after initial rupture of hepatic MRT.