Background:Children's Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods:Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results:Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions:RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

The SJMB12 trial used immunohistochemistry (IHC)-based molecular grouping to separate medulloblastoma (MB) into WNT, SHH, and non-WNT/non-SHH (NWNS) groups for risk and treatment stratification. IHC was selected due to its rapid turnaround, cost-effectiveness, and low-tech nature, which allowed its immediate implementation in a prospective clinical trial. Nevertheless, the accuracy and reproducibility of IHC on a prospective cohort were unknown. Here, we compared IHC-based MB molecular group assignment to DNA methylation profiling for 634 evaluable patients from the SJMB12 trial. Robust concordance was observed. All 88 IHC-defined WNT MBs were classified as WNT by methylation. Of 107 IHC-defined SHH MBs, 106 were identified as SHH. Furthermore, 390 (98%) of 398 IHC-defined NWNS cases were identified as Group 3 or Group 4 MBs. Discordant cases were minimal: one IHC-defined SHH tumor was reclassified as glioblastoma by methylation, and 8 IHC-defined NWNS cases were reclassified (SHH (n=4), Pineoblastoma (n=2), WNT (n=1), or unclassified (n=1)). The performance metrics for IHC across MB groups were robust. For WNT, sensitivity was 93.6%, specificity 100%, PPV 100%, and NPV 98.9%. For SHH, sensitivity was 89.1%, specificity 99.8%, PPV 99.1%, and NPV 97.5%. For NWNS (proxy for Group 3/4), sensitivity was 94.9%, specificity 96.4%, PPV 98.0%, and NPV 91.1%. Notably, 41 (6%) tumors could not be grouped by IHC and were placed into an “indeterminate” category. These were assigned by methylation profiling to WNT (n=5), SHH (n=9), Group 3 (n=20), Group 4 (n=1), medullomyoblastoma (n=5), and GBM (n=1). Intriguingly, these cases were not random; they were enriched in MBs belonging to Group 3 subgroup 2, displaying myogenic and/or melanotic differentiation, and TP53-mutated SHH tumors. In conclusion, these findings demonstrate that IHC is a valuable tool for molecular grouping in medulloblastoma. Despite some limitations, it provides accurate results and, even when indeterminate, can reveal intriguing disease characteristics.

Summary of single nucleotide variants.

Summary of genomic variants.

Summary of somatic and de novo germline events.

Supplemental Figures S1-S7, Supplemental Tables S1-S7. Methods and Figures S1-S8; Tables S1-S7. SF1: Heterozygous TP53 deletion in the germline and tumor of patient 1 and expression timelines of DSE. SF2: Mutational signatures in pGBM samples. SF3: Deletions at immune-modulatory loci and their effect on gene expression. SF4: Dynamics of germlines SVs during tumor evolution. SF5: Copy number assays using TaqMan probes confirm the deletion at the ATRX locus. SF6: Genetic heterogeneity at the ATRX locus. SF7: Distribution of allelic frequencies and clonal sizes in pGBM samples. ST1: Calgary pediatric GBM cohort. ST2: Therapeutic approach taken for each pediatric GBM patient in the Calgary cohort. ST3: Toronto pediatric GBM cohort used for WGS with linked reads and bulk RNA-seq. ST4: Features of each sample analyzed by whole-genome sequencing with linked reads. ST5: Genes mutated in diagnostic pGBM samples in more than one patient. ST6: Genes mutated in follow-up resections in more than one patient. ST7: Results of the fits of the first incomplete moment and the negative binomial like distribution to the samples.

Pancreaticoduodenectomy, a procedure rarely performed in children, can lead to significant morbidity. Rhabdomyosarcoma is the most frequent soft tissue sarcoma in pediatrics. Treatment consists of chemotherapy, while local control can be achieved through either surgery, radiotherapy or both. In this brief report, we describe the case of a 15-year-old adolescent who underwent a pancreaticoduodenectomy for a presumed solid pseudopapillary tumor of the head of the pancreas, ultimately diagnosed as a fusion-positive rhabdomyosarcoma. We review the ensuing severe side effects of the treatments, and discuss the role of biopsies for pancreatic tumors in pediatrics.

Abstract BACKGROUND/RATIONAL: Following initial irradiation sparing therapy, many young children with relapsed medulloblastoma can be salvaged with craniospinal irradiation (CSI). However, the interval to relapse is short and neurocognitive sequelae remain a major concern. The contribution of molecular subgrouping may help refine indications and modalities of salvage strategies in this population. METHOD: From a cohort of 151 young children with molecularly characterized relapsed medulloblastoma, subset analysis of the SHH medulloblastoma was conducted to describe the practice of salvage radiotherapy and associated post-relapse survival (PRS). RESULTS: Sixty-seven SHH medulloblastoma patients (46 M0; 54 GTR; 11 non-ND/MBEN) received salvage therapy with curative intent. Before relapse, 54 (80.6%) received conventional chemotherapy (CC), 13 (19.4%) high-dose chemotherapy (HDC), while seven had additional focal radiotherapy (fRT). Median time to relapse was 11.1 months (range 3.8-41.0) and 43.3% were localized. Thirty patients (16 localized relapse) underwent surgery. Forty-seven (71.2%) received salvage radiotherapy (20 with CC; 10 with HDC; 15 alone, two unknown). CSI and fRT accounted for 82% and 18% respectively. CSI median dose was 36Gy (range 18-39Gy). Ten patients (eight with localized relapse) received CSI doses ≤23.4Gy. Nineteen patients (28.8%) did not receive any radiotherapy (nine HDC; 10 CC only). Radiotherapy was associated with better 3-year PRS (73.0% versus 36.1%; p=0.001). All patients treated with CSI ≤ 23.4Gy were alive at median follow-up of 69 months(24-142). Six of nine patients treated with HDC without irradiation were alive at last follow-up. Sixty-three percent of patients received reduced dose CSI(≤23.4Gy), fRT, or no radiotherapy, and their PRS did not significantly differ from those who received CSI ≥ 30.6Gy (p = 0.54). CONCLUSION: While salvage CSI provided PRS benefit in this SHH medulloblastoma cohort, we report the use of reduced salvage radiotherapy and irradiation avoidance in 63% of the patients, with 60% alive at last follow-up.

Abstract INTRODUCTION: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are glioneuronal tumors of early childhood. Surgical resection is usually sufficient to cure these benign tumors. The presence of metastatic seeding is rare and has been reported as an adverse prognostic factor. We present 2 cases of young children with recurrent metastatic DIA/DIG to describe their presentation, therapeutic management and outcome and to highlight the importance of molecular characterization of these rare tumors to guide adjuvant therapy. CASES DESCRIPTION: The first patient developed metastatic recurrence after initial gross total resection (GTR) of a localized DIG. The disseminated relapse was treated with monthly carboplatin and vincristine (CB/VCR). Complete response was achieved after 15 cycles and the patient has remained in continuous complete remission for 5 years. Post hoc molecular analysis of the tumor revealed a BRAF-RDX fusion. The second patient presented with a disseminated intraventricular relapse following an incomplete resection of a DIA associated with a SPECC1L-NTRK2 fusion. The patient received 2 cycles of CB/VCR with minimal response and was then switched to Larotrectinib leading to a very good partial response (VGPR) 3 months into therapy and has remained on treatment since then with significant clinical improvement. DISCUSSION/ CONCLUSION: In our 2 cases, metastatic recurrence was responsive to adjuvant therapy leading to complete response with conventional chemotherapy in the first one and to VGPR with NTRK inhibitor in the second patient. Early molecular characterization of these benign tumors is critical in case of incomplete resection or metastatic seeding to widen therapeutic options and maximize chance of cure. Response with NTRK inhibitor appears rapid and significant but the total duration of treatment and sustainability of response after discontinuation remain unknown.

PURPOSE:Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy.METHODS:We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors.RESULTS:The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007).CONCLUSION:A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Abstract Purpose Intensive multi-modal regimens have improved survival for patients with atypical teratoid rhabdoid tumor, however relapse rates remain high. A better understanding of clinical and pathologic features associated with tumor relapse is critical to risk-stratifying patients. Patients and Methods ACNS0333 treatment consisted of multi-agent chemotherapy, high-dose chemotherapy, and radiation therapy, lasting approximately 6 months. Variables including patient age, sex, tumor location, M-stage, degree of resection, order of therapy, germline status, and molecular subgroup were analyzed. Cumulative incidence (CI) of event free survival due to relapse was evaluated for each variable. Results Thirty-three of 65 evaluable patients had tumor relapse. For the entire cohort, the CI of relapse was 21.8% at 6 months, 40.6% at one year and 50.3% at 4 years. For patients with infratentorial tumors, CI of relapse was 26.3%, 34.2% and 37.2%, at 6 months, 1 and 4 years respectfully compared to 15.3%, 49.9%, and 69.7% for those with supratentorial tumors (p 0.051). Patients with SHH subtype had no relapses in the first 6 months and CI of relapse of 37.5% at 4 years, while those with TYR and MYC subgroups had CI of relapse of 33.3% and 26.7% at 6 months and 46.3% and 73.3% at 4 years respectfully (p 0.088). Patients with germline mutations had a cumulative incidence of relapse of 20% at 6 months and 60% at 12 months compared to 22.6% and 37.7% respectfully for those without. No obvious trends were noted based on other analyzed variables. Conclusions ACNS0333 was not powered to determine prognostic indicators of relapse, however, this data suggest interesting trends based on tumor location, subtype and germline status. Infratentorial location and SHH subtype maybe associated with lower risk of relapse. Larger data sets must be compiled to further investigate these variables, perform multivariate analyses and inform risk-stratification on future trials.

Pediatric Blood & CancerVolume 68, Issue 10 e29074 LETTER TO THE EDITOR Comment on: Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study Nicolas Prud'homme, Corresponding Author Nicolas Prud'homme nicolas.prud-homme.med@ssss.gouv.qc.ca orcid.org/0000-0002-4243-6916 Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Correspondence Nicolas Prud'homme, CHU Sainte-Justine, 3175 chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. Email: nicolas.prud-homme.med@ssss.gouv.qc.caSearch for more papers by this authorGary J. Galante, Gary J. Galante Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorHarmeet Kaur, Harmeet Kaur Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorMarie-Anne Brundler, Marie-Anne Brundler Department of Pathology and Laboratory Medicine and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorPaul Beaudry, Paul Beaudry Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorDouglas Strother, Douglas Strother Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this author Nicolas Prud'homme, Corresponding Author Nicolas Prud'homme nicolas.prud-homme.med@ssss.gouv.qc.ca orcid.org/0000-0002-4243-6916 Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Correspondence Nicolas Prud'homme, CHU Sainte-Justine, 3175 chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. Email: nicolas.prud-homme.med@ssss.gouv.qc.caSearch for more papers by this authorGary J. Galante, Gary J. Galante Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorHarmeet Kaur, Harmeet Kaur Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorMarie-Anne Brundler, Marie-Anne Brundler Department of Pathology and Laboratory Medicine and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorPaul Beaudry, Paul Beaudry Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this authorDouglas Strother, Douglas Strother Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, CanadaSearch for more papers by this author First published: 23 April 2021 https://doi.org/10.1002/pbc.29074Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume68, Issue10October 2021e29074 RelatedInformation

Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon of paradoxical growth of a germ cell tumor (GCT) during treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of iGTS in Western countries. Pediatric patients from 22 North American and Australian institutions diagnosed with iGTS between 2000 and 2017 were retrospectively evaluated. From a total of 777 cases of central nervous system (CNS) GCT, 39 cases of iGTS were identified for an overall frequency of 5%. Pineal region was a more frequent location for iGTS as compared to cases of GCT without iGTS (p < 0.00001). In patients with an initial tissue diagnosis of GCT, immature teratoma was present in 50%. Serum AFP or ßhCG was detectable in 87% of patients (median values 66 ng/mL and 44 IU/L, respectively). iGTS occurred at a median of 2 months (range 0.5–32) from diagnosis, in the majority of patients. All patients underwent surgical resection, leading to gross total resection in 79%. Following surgery, all patients resumed adjuvant therapy or post treatment follow-up for GCT. At a median follow-up of 5.3 years (range 0.2–11.8), 37 (95%) of patients are alive, including 5 with stable residual mass. iGTS occurs in 5% of patients with GCT in Western countries. Tumors of the pineal region and GCT containing immature teratoma appear to be associated with a higher risk of developing iGTS. Complete surgical resection is the mainstay of treatment. Overall survival of patients developing iGTS remains favorable.

Abstract INTRODUCTION CNS tumors are the second most common neoplasm in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors are limited and outdated. We aimed at evaluating the diagnostic interval time(DIT) for Canadian children, and identifying factors possibly associated with prolonged DIT. METHODS Using the CYP-C database, we analyzed data from children <15 years, diagnosed with CNS tumors between 2001–2015. DIT was defined as time in weeks, elapsed from the first contact with a healthcare provider to confirming diagnosis. We described DIT according to patient’s demographics, socioeconomic, geographic factors as well as tumor-related criteria. RESULTS Patients from all Canadian provinces, except Ontario, had available timepoints to calculate DIT. The cohort included 842 patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas had the longest mean DIT and embryonal tumors had the shortest(14.6 and 3.6 weeks p<0.01). ATRT and medulloblastoma had a mean DIT of 1.3 and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4 versus 16.1 weeks, p<0.01). Metastatic disease, infratentorial tumors, or age £36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1 and 8.6). Sex, annual income(QAIPPE), and distance from tertiary center did not influence DIT. CONCLUSION The current diagnostic interval time for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These results only reflect the healthcare system’s contribution toward diagnosis confirmation, but not the patient interval before seeking medical attention.

Problem Compassion has been described as a central construct or essential feature of quality healthcare and is as important to patients' and families' overall healthcare experience as the health interventions and treatments they receive. However, there is little shared understanding of what constitutes compassion, how it is delivered within a pediatric setting, and pediatric patients' and families perspectives and preferences for receiving it. Eligibility criteria Studies that (1) described the nature of the existing literature on compassion in pediatric healthcare; (2) summarized key concepts in the existing evidence base that pertain to compassion in pediatric healthcare; and 3) identified factors that are associated with compassion in pediatric healthcare were eligible for inclusion in this review. Sample Twenty-nine papers were included in the review. Results Findings revealed several factors are associated with compassion in pediatric healthcare, including continuity of care, communication, and coordination of care. Most notably, identified studies treated compassion in a subsidiary fashion, and this review revealed no studies that provided a patient-informed evidence-based definition of compassion in the pediatric healthcare setting. Conclusion Future research is required to generate a comprehensive and accurate understanding of the terms ‘compassion' and ‘compassionate care' when used in the context of pediatric healthcare. Implications This research will inform the therapeutic processes and ultimately enable the development of strategies to improve the delivery of compassionate healthcare to pediatric patients.