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Purpose: The extent of brain tumor resection (EOR) is a fundamental prognostic factor in pediatric neuro-oncology in association with the histology. In general, resection aims at gross total resection (GTR). Intraoperative imaging like intraoperative US (iOUS) and MRI have been developed in order to find any tumoral remnant but with different costs. Aim of our work is to review the current literature in order to better understand the differences between costs and efficacy of MRI and iOUS to evaluate tumor remnants intraoperatively. Methods: We reviewed the existing literature on PubMed until 31st December 2021 including the sequential keywords “intraoperative ultrasound and pediatric brain tumors”, “iUS and pediatric brain tumors”, “intraoperative magnetic resonance AND pediatric brain tumors”, and “intraoperative MRI AND pediatric brain tumors. Results: A total of 300 papers were screened through analysis of title and abstract; 254 were excluded. After selection, a total of 23 articles were used for this systematic review. Among the 929 patients described, a total of 349(38%) of the cases required an additional resection after an iMRI scan. GTR was measured on 794 patients (data of 69 patients lost), and it was achieved in 552(70%) patients. In case of iOUS, GTR was estimated in 291 out of 379 (77%) cases. This finding was confirmed at the post-operative MRI in 256(68%) cases. Conclusions: The analysis of the available literature demonstrates that expensive equipment does not always mean better. In fact, for the majority of pediatric brain tumors, iOUS is comparable to iMRI in estimating the EOR.

Introduction: Posterior fossa syndrome (PFS) is a set of debilitating complications that can occur after surgery for posterior fossa tumors. This study aimed to assess the preoperative radiological and surgical risk factors for the onset of PFS in a histologically homogeneous population of children with medulloblastoma and compare it to a similar population of young adults. Methods: Included patients underwent posterior fossa surgery for medulloblastoma at 11 Italian neurosurgical wards (2003–2019) and were referred to Fondazione IRCCS Istituto Nazionale dei Tumori in Milan (INT) for postoperative treatments. We collected patients’ pre- and post-operative clinical, surgical and radiological data from the INT charts. To compare the distribution of variables, we used the Mann–Whitney and Fisher tests for continuous and categorical variables, respectively. Results: 136 patients (109 children and 27 young adults) were included in the study. Among children, 29 (27%) developed PFS, and all of them had tumors at midline site with invasion of the fourth ventricle. Radiological evidence of involvement of the right superior (39% versus 12%; p = 0.011) or middle cerebellar peduncles (52% versus 18%; p = 0.002) seemed more common in children who developed PFS. Young adults showed an expected lower incidence of PFS (4 out of 27; 15%), that may be due to anatomical, physiological and oncological elements. Conclusions: This study confirmed some factors known to be associated with PFS onset and shed light on other debated issues. Our findings enhance an already hypothesized role of cerebellar language lateralization. The analysis of a population of young adults may shed more light on the often-neglected existence of PFS in non-pediatric patients.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4 Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36 Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients. Methods: We gathered non-metastatic patients over 18 years old (median age 28 years, range 18–48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996–2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison. Results: Forty-four adults were considered (median follow-up 101 months): 36 had 23.4 Gy of CSI, and 8 had 30.6 Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4 Gy did not influence PFS. Female adult patients tended to have a better outcome than males. Conclusion: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.

Purpose: There is no consensus in the literature about the impact of hydrocephalus on clinical course and overall survival of diffuse intrinsic pontine gliomas (DIPG) patients as well as about its specific treatment. Authors reviewed a series of DIPG patients to investigate factors related to the onset of hydrocephalus, its treatment, and its impact on clinical course and prognosis. Methods: A retrospective observational study was performed enrolling pediatric patients affected by DIPG from 2008 to 2018. Clinical and radiological charts were reviewed to find patients’ demographic, pathologic and radiologic features in hydrocephalic and non-hydrocephalic patients. In the hydrocephalus cohort, treatment strategy and its effectiveness and complications were analyzed. Results: Ninety-four pediatric patients were enrolled in the study. Patients who developed hydrocephalus showed significantly lesser maximum axial tumor areas than patients without hydrocephalus (respectively 6.5 cm2 vs 16.45 cm2, p < 0.005). Hydrocephalus developed in 33 patients (35%) with an onset interval of 5.24 ± 1.21 months (range 3.2–7.3). The majority of hydrocephalic patients (28 cases, 90%) were treated by ventriculoperitoneal shunt, the remaining 3 patients being treated by endoscopic third ventriculostomy. Mean overall survival was 16.6 months ± 20 months without significative difference between the groups. Conclusion: The onset of hydrocephalus occurs in the first moths of the disease story and found a negative correlation with tumor maximal axial diameter. Early treatment of hydrocephalus presents a very low complications rate with satisfying clinical outcome, as it allows the patients to continue the neurooncological therapies being a part of the treatment armamentarium instead of a palliative solution.

BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHOD(S): We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULT(S): Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0-17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSION(S): We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Item does not contain fulltext, AIMS: Studies implicated a role for a genetic variant in CEP72 in vincristine-induced peripheral neuropathy. This study aims to evaluate this association in a cohort of brain tumour patients, to perform a cross-disease meta-analysis and explore the protein-coding region of CEP72. METHODS: In total, 104 vincristine-treated brain tumour patients were genotyped for CEP72 rs924607, and sequenced for the protein-coding region. Data regarding patient and treatment characteristics, and peripheral neuropathy, were collected. Logistic regression and meta-analysis were performed for rs924607 replication. A weighted burden analysis was applied to evaluate impact of overall genetic variation in CEP72. RESULTS: Analysis of 24 cases and 80 controls did not show a significant association between CEP72 rs924607 and neuropathy (odds ratio, OR [95% confidence interval, CI] 2.076 [0.359-11.989], P = .414). When combined with 8 cohorts (1095 cancer patients), a significant increase in risk for neuropathy was found for patients with a TT genotype (OR [95% CI] 2.15 [1.35-3.43], P = .001). Additionally, a missense variant (rs12522955) was significantly associated (OR [95% CI] 2.3 [1.2-4.4], P = .041) and patients with severe neuropathy carried more impactful variants in CEP72 coding regions (P = .039). CONCLUSION: The association of CEP72 rs924607 in vincristine-induced neuropathy was not confirmed in a cohort of brain tumour patients, but did contribute to its suggested effect when combined in a cross-disease meta-analysis. The importance of other genetic variations in CEP72 on vincristine-induced neuropathy was demonstrated. This study contributes to evidence of the importance of genetic variants in CEP72 in development of vincristine-induced toxicity, and provides guidance for future prospective studies.

BACKGROUND: TRK fusions are detected in less than 3% of CNS tumors. Given their rarity, there are limited data on the clinical course of these patients. METHODS: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, NTRK gene fusion, treatment modalities and outcomes. Patients less than 18 years of age at diagnosis were included in this analysis. RESULTS: Seventy-three pediatric patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 2.4 years (range 0.0–17.8) and 60.2 % were male. NTRK2 gene fusions were found in 37 patients (50.7%), NTRK1 and NTRK3 aberrations were detected in 19 (26.0%) and 17 (23.3%), respectively. Tumor types included 38 high-grade gliomas (HGG; 52.1%), 20 low-grade gliomas (LGG; 27.4%), 4 embryonal tumors (5.5%) and 11 others (15.1%). Median follow-up was 46.5 months (range 3-226). During the course of their disease, a total of 62 (84.9%) patients underwent surgery with a treatment intent, 50 (68.5%) patients received chemotherapy, 35 (47.9%) patients received radiation therapy, while 34 (46.6%) patients received NTRK inhibitors (3 as first line treatment). Twenty-four (32.9%) had no progression including 9 LGG (45%) and 9 HGG (23.6%). At last follow-up, only one (5.6%-18 evaluable) patient with LGG died compared to 11 with HGG (35.5%-31 evaluable). For LGG the median progression-free survival (PFS) after the first line of treatment was 17 months (95% CI: 0.0-35.5) and median overall survival (OS) was not reached. For patients with HGG the median PFS was 30 months (95% CI: 11.9-48.1) and median OS was 182 months (95% CI 20.2-343.8). CONCLUSIONS: We report the largest cohort of pediatric patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.

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 salva

Background: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods: We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results: The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

Introduction: Cervicomedullary gliomas (CMGs) are usually low-grade tumors often found in the pediatric age. Histological findings, treatments, and classification have been much the same for 40 years, although histological and molecular classifications have largely been developed for other pediatric CNS tumors. The management and treatment of pediatric CMG are still conducted by many authors according to their anatomical location and characteristics, independently from histology. Methods: We conducted a literature review in PubMed (Medline) to identify relevant contributions about pediatric CMG published until December 31, 2021. We also analyzed a series of 10 patients with CMG treated from 2006 to 2021 at IRCCS Istituto Nazionale dei Tumori. The aim of the present review was to see whether and how the diagnosis, treatment, and classification of CMGs in children have developed over time, especially in the context of molecular advancements, and to analyze our single-center experience in the last 15 years. Results: Thirty articles have been included in the review. Articles have been divided into two historical periods (1981-2000 and 2001-2021) and data from different series were analyzed to see how much the management and treatment of pediatric CMG have changed during years. Analysis of our series of 10 patients affected by CMG was also performed to compare it with the literature. Discussion: Management and classification of CMG in children have not dramatically changed during years. However, new insight from molecular diagnostics and target therapies and the development of radiological, neurophysiological, and radiotherapy techniques have updated treatment modalities in the last 20 years. Treatment modalities and their innovations have been reviewed and discussed. Further studies are needed to standardize and customize treatment protocols for these tumors.

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Medulloblastoma and central nervous system (CNS) germ cell tumors are very rare in adults, while they account for 25% and 5% of brain tumors in children, respectively (Pastore et al. Eur J Cancer 42:2064–208, 2006). Pediatric experiences, mostly from randomized and controlled clinical trials, have led to different tailored treatments, based on various risk factors, including histology, and extent of disease. For medulloblastoma, biological features have recently emerged that enable therapies to be scaled down in some cases, or pursued more aggressively in the event of chromosomal and/or genetic alterations (Massimino et al. Crit Rev Oncol Hematol 105:35–51, 2016). Such refinements are still impossible for adult patients due to the lack of similar clinical trials that might provide the same or a different understanding regarding patients’ prognosis, long-term survival, quality of life, and acute and late toxicities. This review aims to contribute to the debate on the treatment of adults with these two diseases and promote the creation of broad-based, national and international trials to advance our knowledge in this area and to share the skills between pediatric and adult oncologists as adolescent and young adults (AYA) brain tumor national boards are currently requiring.

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.