Late-onset lymphopenia during radiation is associated with an increased risk of tumor recurrence in newly diagnosed pediatric medulloblastoma.

BACKGROUND: Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy-naïve. PROCEDURE: We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2-21 years) treated between 1997 and 2013 with craniospinal RT. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk. RESULTS: Eighty-three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty-four of 79 (30%) patients developed disease recurrence at an average 27.0 months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log-rank p = .016; Cox p = .03) and Week 5 (log-rank p = .024; Cox p = .032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p = .04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0-3) or absolute lymphocyte count (ALC) below the median at any time during RT. CONCLUSIONS: Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.

Comparing the effects of irradiation with protons or photons on neonatal mouse brain: Apoptosis, oncogenesis and hippocampal alterations.

BACKGROUND AND PURPOSE: Medulloblastoma (MB) is a common primary brain cancer in children. Proton therapy in pediatric MB is intensively studied and widely adopted. Compared to photon, proton radiations offer potential for reduced toxicity due to the characteristic Bragg Peak at the end of their path in tissue. The aim of this study was to compare the effects of irradiation with the same dose of protons or photons in Patched1 heterozygous knockout mice, a murine model predisposed to cancer and non-cancer radiogenic pathologies, including MB and lens opacity. MATERIALS AND METHODS: TOP-IMPLART is a pulsed linear proton accelerator for proton therapy applications. We compared the long-term health effects of 3 Gy of protons or photons in neonatal mice exposed at postnatal day 2, during a peculiarly susceptible developmental phase of the cerebellum, lens, and hippocampus, to genotoxic stress. RESULTS: Experimental testing of the 5 mm Spread-Out Bragg Peak (SOBP) proton beam, through evaluation of apoptotic response, confirmed that both cerebellum and hippocampus were within the SOBP irradiation field. While no differences in MB induction were observed after irradiation with protons or photons, lens opacity examination confirmed sparing of the lens after proton exposure. Marked differences in expression of neurogenesis-related genes and in neuroinflammation, but not in hippocampal neurogenesis, were observed after irradiation of wild-type mice with both radiation types. CONCLUSION: In-vivo experiments with radiosensitive mouse models improve our mechanistic understanding of the dependence of brain damage on radiation quality, thus having important implications in translational research.

The pivotal role of irradiation-induced apoptosis in the pathogenesis and therapy of medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is a rare primitive neuroectodermal tumors originating from the cerebellum. MB is the most common malignant primary brain tumor of childhood. MB originates from neural precursor cells in distinctive regions of the rhombic lip, and their maturation occurs in the cerebellum or the brain stem during embryonal development. Also, apoptosis is a programmed cell death associated with numerous physiological as well as pathological regulations. RECENT FINDINGS: Irradiation (IR)-induce apoptosis triggers cell death, with or without intervening mitosis within a few hours of IR and these share different morphologic alteration such as, loss of normal nuclear structure as well as degradation of DNA. Moreover, MB is strikingly sensitive to DNA-damaging therapies and the role of apoptosis a key treatment modality. Furthermore, in MB, the apoptotic pathways are made up of several triggers, modulators, as well as effectors. Notably, IR-induced apoptotic mechanisms in MB therapy are very complex and they either induce radiosensitivity or inhibit radioresistance leading to potential effective treatment strategies for MB. CONCLUSION: This review explicitly explores the pivotal roles of IR-induced apoptosis in the pathogenesis and therapy of MB.

Adaptive, behavioral, and emotional outcomes following postoperative pediatric cerebellar mutism syndrome in survivors treated for medulloblastoma.

OBJECTIVE: Patients who experience postoperative pediatric cerebellar mutism syndrome (CMS) during treatment for medulloblastoma have long-term deficits in neurocognitive functioning; however, the consequences on functional or adaptive outcomes are unknown. The purpose of the present study was to compare adaptive, behavioral, and emotional functioning between survivors with and those without a history of CMS. METHODS: The authors examined outcomes in 45 survivors (15 with CMS and 30 without CMS). Comprehensive neuropsychological evaluations, which included parent-report measures of adaptive, behavioral, and emotional functioning, were completed at a median of 2.90 years following craniospinal irradiation. RESULTS: Adaptive functioning was significantly worse in the CMS group for practical and general adaptive skills compared with the group without CMS. Rates of impairment in practical, conceptual, and general adaptive skills in the CMS group exceeded expected rates in the general population. Despite having lower overall intellectual functioning, working memory, and processing speed, IQ and related cognitive processes were uncorrelated with adaptive outcomes in the CMS group. No significant group differences or increased rates of impairment were observed for behavioral and emotional outcomes. CONCLUSIONS: Survivors with CMS, compared with those without CMS, are rated as having significant deficits in overall or general adaptive functioning, with specific weakness in practical skills several years posttreatment. Findings from this study demonstrate the high risk for ongoing functional deficits despite acute recovery from symptoms of CMS, highlighting the need for intervention to mitigate such risk.

Postradiation platinum-etoposide in adult medulloblastomas: retrospective analysis of hematological toxicity.

Aim: Adult medulloblastomas (MB) are rare, and optimal post-craniospinal irradiation (CSI) chemotherapy is not yet defined. We investigated hematological toxicity in patients treated with platinum-etoposide (EP) post-CSI. Methods: Retrospective, single-institution study to determine hematological toxicity in adult MB patients treated with EP (1995-2022). Results: Thirteen patients with a median follow-up of 50 months (range, 10-233) were analyzed. Four discontinued treatment due to toxicity, one after 1, 3 after 3 cycles. Hematological toxicities included grade 3 (5 patients) and grade 4 (6 patients). Two patients experienced post-treatment progression and died 16 and 37 months from diagnosis. Conclusion: Post-CSI EP demonstrates acceptable hematological toxicity in adult MB. However, the small cohort precludes definitive survival outcome conclusions. Prospective studies for comprehensive comparisons with other regimens are needed in this context.

Our study aimed to understand the effect of a chemotherapy combination (platinum and etoposide) on blood counts in adult patients with medulloblastoma after craniospinal radiation. Medulloblastoma is a rare brain cancer in adults. We analyzed data from 13 adult patients with medulloblastoma. The results show that the treatment leads to significant blood count-related side effects. Four of the patients discontinued their treatment early. Blood counts improved again after completion of treatment. Two patients had the tumor grow back after treatment and died later. Overall, the effect from this chemotherapy combination on blood counts was felt to be acceptable. The number of patients in this study was small, and more research is needed to determine the overall effectiveness of this treatment.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review.

PURPOSE: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. METHODS AND MATERIALS: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. RESULTS: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/ß value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

Predictive Factors Associated With Radiation Myelopathy in Pediatric Patients With Cancer: A PENTEC Comprehensive Review.

PURPOSE: Radiation myelitis (RM) is a rare complication of radiation therapy (RT). The Pediatric Normal Tissue Effects in the Clinic spinal cord task force aimed to identify RT dose effects and assess risk factors for RM in children. Through systematic review, we analyzed RT dose, fraction size, latency between completion of RT and toxicity, chemotherapy use, age when irradiated, and sex. METHODS AND MATERIALS: We conducted literature searches of peer-reviewed manuscripts published from 1964 to June 2017 evaluating RM among children. Normality of variables was assessed with Kolmogorov-Smirnov or Shapiro-Wilk tests. Spearman's rank correlation coefficients were used to test correlations between RT dose/fraction size and latency between RT and development of toxicity. RESULTS: Of 1329 identified and screened reports, 144 reports were fully reviewed and determined to have adequate data for analysis; 16 of these reports had a total of 33 cases of RM with a median age of 13 years (range, 0.2-18) at the time of RT. The most common primary tumor histologies were rhabdomyosarcoma (n = 9), medulloblastoma (n = 5), and Hodgkin lymphoma (n = 2); the most common chemotherapy agents given were vincristine (n = 15), intrathecal methotrexate (n = 12), and intrathecal cytarabine (n = 10). The median RT dose and fraction size were 40 Gy (range, 24-57.4 Gy) and 1.8 Gy (range, 1.3-2.6 Gy), respectively. RT dose resulting in RM in patients who also received chemotherapy was lower than in those not receiving chemotherapy (mean 39.6 vs 49.7 Gy; P = .04). There was no association of age with RT dose. The median latency period was 7 months (range, 1-29). Higher RT dose was correlated with longer latency periods (P = .03) to RM whereas sex, age, fraction size, and chemotherapy use were not. Two of 17 patients with adequate follow-up recovered from RM; unfortunately, it was fatal in 6 of 15 evaluable patients. Complication probability modeling was not possible because of the rarity of events. CONCLUSIONS: This report demonstrates a relatively short latency from RT (with or without chemotherapy) to RM and a wide range of doses (including fraction sizes) associated with RM. No apparent association with age at the time of RT could be discerned. Chemotherapy appears to reduce spinal cord tolerance. Recovery from RM is rare, and it is often fatal.

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis.

Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

Dosimetric impact of adding non-coplanar arcs for scalp-avoidance whole-brain irradiation with volumetric-modulated arc radiotherapy on scalp dose reduction in pediatric patients with medulloblastomas.

PURPOSE: We performed scalp-avoidance whole-brain irradiation with volumetric-modulated arc therapy (SAWB-VMAT) as a component of craniospinal irradiation. In SAWB-VMAT with two coplanar arcs, radiation oncologists and medical physicists sometimes experience difficulty in reducing the dose to the scalp to below the cut-off equivalent dose in 2 Gy per fraction (assuming α/ß = 2) to 50% (EQD50%scalp ). To investigate the advantage of adding coplanar or non-coplanar arcs in reducing the dose to the scalp in SAWB-VMAT, we conducted a planning study to compare the EQD50%scalp , the dose to other organs at risk (OARs), and target coverage in VMAT with two coplanar arcs (Co2arcVMAT), VMAT with three coplanar arcs (Co3arcVMAT), and VMAT with two coplanar and two non-coplanar arcs (NcVMAT). METHODS: Co2arcVMAT, Co3arcVMAT, and NcVMAT plans were created for 10 pediatric patients with medulloblastoma. The planned target volume (PTV) included the regions of the whole brain, cervical spinal cord, cerebrospinal fluid space, and intervertebral foramen. The EQD50%scalp was evaluated separately for four areas (top, back, left, and right) in each case. The prescribed dose for the PTV was 35.2 Gy in 22 fractions. RESULTS: The median EQD50%scalp of the top area was 21.9 , 22.1 , and 18.3 Gy for Co2arcVMAT, Co3arcVMAT, and NcVMAT, respectively. The EQD50%scalp of the top area was significantly reduced in NcVMAT compared to those in Co2arcVMAT and Co3arcVMAT (p < 0.05). The median EQD50%scalp of the top area for NcVMAT was < 19.9 Gy, which is the cut-off dose for severe permanent alopecia. There were no significant differences in EQD50%scalp in the three other areas, the dose to other OARs, or the dose coverage of PTV among the three techniques. CONCLUSION: NcVMAT could reduce the EQD50%scalp of the top area below the cut-off dose of 19.9 Gy. NcVMAT appears to be a promising treatment technique for SAWB-VMAT.

Single-fraction Radiation Treatment Dose Response in a Genetically Engineered Mouse Model of Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of children. Although standard of care radiotherapy for pediatric medulloblastoma (PM) can lead to long-term remission or cure in many patients, it can also cause life-long cognitive impairment and other adverse effects. The pathophysiological mechanisms involved in radiation-induced cerebral damage are incompletely understood, and their elucidation may lead to interventions that mitigate radiation toxicity. To explore the mechanisms of radiation-induced cerebral damage, transgenic mouse models of PM and non-tumor-bearing controls were exposed to radiation doses that ranged from 0 to 30 Gy. Between 0-20 Gy, a significant dose-dependent reduction in tumor-associated hydrocephalus and increase in overall survival were observed. However, at 30 Gy, hydrocephalus incidence increased and median overall survival fell to near-untreated levels. Immunohistochemistry revealed that both tumor-bearing and non-tumor-bearing mice treated with 30 Gy of radiation had significantly more reactive astrocytes and microvascular damage compared to untreated controls. This effect was persistent across mice that were given 1 and 2 weeks of recovery time after irradiation. Our data suggest that radiation therapy promotes neural death by inducing long-term neuroinflammation in PM, suggesting radiation delivery methods that limit inflammation may be effective at widening the therapeutic window of radiation therapy in PM patients.

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study.

BACKGROUND: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. RESULTS: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival). CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

A Pilot Study Omitting Radiation in the Treatment of Children with Newly Diagnosed Wnt-Activated Medulloblastoma.

PURPOSE: Treatment of wingless (WNT)-activated medulloblastoma (WNT+MB) with surgery, irradiation (XRT), and chemotherapy results in excellent outcomes. We studied the efficacy of therapy de-intensification by omitting XRT entirely in children with WNT+MB. PATIENTS AND METHODS: Tumors were molecularly screened to confirm the diagnosis of WNT+MB. Eligible children were treated within 31 days following surgery with nine cycles of adjuvant chemotherapy per ACNS0331. No XRT was planned. The primary endpoint was the occurrence of relapse, progression, or death in the absence of XRT within the first two years after study enrollment. Four events in the first 10 evaluable patients would result in early study closure. RESULTS: Fourteen children were prescreened, and nine met the protocol definition of WNT+MB. Six of the nine eligible patients consented to protocol therapy, and five completed planned protocol therapy. The first two children enrolled relapsed shortly after therapy completion with local and leptomeningeal recurrences. The study was closed early due to safety concerns. Both children are surviving after XRT and additional chemotherapy. A third child relapsed at completion of therapy but died of progressive disease 35 months from diagnosis. Two children finished treatment but immediately received post-treatment XRT to guard against early relapse. The final child's treatment was aborted in favor of a high-dose therapy/stem cell rescue approach. Although OS at 5 years is 83%, no child received only planned protocol therapy, with all receiving eventual XRT and/or alternative therapy. CONCLUSIONS: Radiotherapy is required to effectively treat children with WNT-altered medulloblastoma. See related commentary by Gottardo and Gajjar, p. 4996.

In Vivo Radiobiological Investigations with the TOP-IMPLART Proton Beam on a Medulloblastoma Mouse Model.

Protons are now increasingly used to treat pediatric medulloblastoma (MB) patients. We designed and characterized a setup to deliver proton beams for in vivo radiobiology experiments at a TOP-IMPLART facility, a prototype of a proton-therapy linear accelerator developed at the ENEA Frascati Research Center, with the goal of assessing the feasibility of TOP-IMPLART for small animal proton therapy research. Mice bearing Sonic-Hedgehog (Shh)-dependent MB in the flank were irradiated with protons to test whether irradiation could be restricted to a specific depth in the tumor tissue and to compare apoptosis induced by the same dose of protons or photons. In addition, the brains of neonatal mice at postnatal day 5 (P5), representing a very small target, were irradiated with 6 Gy of protons with two different collimated Spread-Out Bragg Peaks (SOBPs). Apoptosis was visualized by immunohistochemistry for the apoptotic marker caspase-3-activated, and quantified by Western blot. Our findings proved that protons could be delivered to the upper part while sparing the deepest part of MB. In addition, a comparison of the effectiveness of protons and photons revealed a very similar increase in the expression of cleaved caspase-3. Finally, by using a very small target, the brain of P5-neonatal mice, we demonstrated that the proton irradiation field reached the desired depth in brain tissue. Using the TOP-IMPLART accelerator we established setup and procedures for proton irradiation, suitable for translational preclinical studies. This is the first example of in vivo experiments performed with a "full-linac" proton-therapy accelerator.

Re-irradiation in Paediatric Tumours of the Central Nervous System: National Guidelines from the Swedish Workgroup of Paediatric Radiotherapy.

There is a lack of clinical protocols for re-irradiation in paediatric central nervous system (CNS) tumours. To fill this void, the Swedish Workgroup of Paediatric Radiotherapy (SBRTG) compiled national guidelines on re-irradiation in paediatric CNS tumours (diffuse intrinsic pontine glioma, ependymoma, germinoma and medulloblastoma). These have been in clinical practice since 2019 in all paediatric radiotherapy centres in Sweden. Since the implementation, the guidelines have been complemented with a yearly review on clinical outcome and toxicities in all paediatric patients treated according to the guidelines. This article presents the Swedish national guidelines on re-irradiation in paediatric CNS tumours.

Molecular characterization of long-term survivors of metastatic medulloblastoma treated with reduced-dose craniospinal irradiation.

BACKGROUND AND AIMS: Current standard treatment for metastatic medulloblastoma consists of 36 Gray (Gy) of craniospinal irradiation (CSI) supplemented with local irradiation and adjuvant chemotherapy after surgery. Although contemporary protocols have been designed to limit a radiation dose using risk-adapted CSI dosing to reduce neurocognitive morbidity, high-dose CSI remains the standard of care. Recently, the molecular classification of medulloblastoma has been emerging but its clinical significance has not been established particularly in patients with metastatic medulloblastoma treated with lower dose of CSI. METHODS: We molecularly analyzed three cases of metastatic medulloblastoma treated with 24.0 Gy of CSI by DNA methylation analysis using the Illumina EPIC array. RESULTS: All three patients had spinal metastases at the time of diagnosis. Postoperative treatment included multiple courses of chemotherapy, 24 Gy of CSI with focal boost to primary and metastatic sites, and high-dose chemotherapy. There was no disease progression observed during the 9.0, 7.7, and 5.7　years post-diagnosis follow-up. The molecular diagnosis was Group 3/4 in all three cases. Cases 1 and 2 belonged to Subtypes 7 and 4, both of which were reported to be good prognostic subtypes among the group. Case 3 belonged to Subtype 5 with MYC amplification. CONCLUSIONS: The present cases suggest that the novel subtype classification in Group 3/4 medulloblastoma may be useful for risk stratification of patients with metastatic medulloblastoma who received lower dose of CSI than standard treatment.

Resection cavity auto-contouring for patients with pediatric medulloblastoma using only CT information.

PURPOSE: Target delineation for radiation therapy is a time-consuming and complex task. Autocontouring gross tumor volumes (GTVs) has been shown to increase efficiency. However, there is limited literature on post-operative target delineation, particularly for CT-based studies. To this end, we trained a CT-based autocontouring model to contour the post-operative GTV of pediatric patients with medulloblastoma. METHODS: One hundred four retrospective pediatric CT scans were used to train a GTV auto-contouring model. Eighty patients were then preselected for contour visibility, continuity, and location to train an additional model. Each GTV was manually annotated with a visibility score based on the number of slices with a visible GTV (1 = < 25%, 2 = 25-50%, 3 = > 50-75%, and 4 = > 75-100%). Contrast and the contrast-to-noise ratio (CNR) were calculated for the GTV contour with respect to a cropped background image. Both models were tested on the original and pre-selected testing sets. The resulting surface and overlap metrics were calculated comparing the clinical and autocontoured GTVs and the corresponding clinical target volumes (CTVs). RESULTS: Eighty patients were pre-selected to have a continuous GTV within the posterior fossa. Of these, 7, 41, 21, and 11 were visibly scored as 4, 3, 2, and 1, respectively. The contrast and CNR removed an additional 11 and 20 patients from the dataset, respectively. The Dice similarity coefficients (DSC) were 0.61 ± 0.29 and 0.67 ± 0.22 on the models without pre-selected training data and 0.55 ± 13.01 and 0.83 ± 0.17 on the models with pre-selected data, respectively. The DSC on the CTV expansions were 0.90 ± 0.13. CONCLUSION: We successfully automatically contoured continuous GTVs within the posterior fossa on scans that had contrast > ± 10 HU. CT-Based auto-contouring algorithms have potential to positively impact centers with limited MRI access.

Quality of life in survivors of pediatric medulloblastoma: a systematic review and meta-analysis.

INTRODUCTION: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The mainstay of treatment is maximum surgical resection and craniospinal radiation, which may be followed by chemotherapy. The debilitating effect of the tumor and the intensive treatment approaches in MB lead to long-term neuropsychological, physical, and chronic medical problems. We conducted a systematic review to assess the quality of life (QoL) in the long-term survivors of MB and the factors leading to compromised QoL. METHODS: We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our review. A comprehensive literature search was performed using PubMed, Cochrane Library, Digital Commons Network, and Wiley Online Library databases to search for articles having quality of life, medulloblastoma, and pediatric survivors in title or abstract. We removed duplicates and screened through titles, and full texts. Twelve articles were included in our study. Articles using and reporting all domains of PaedsQL were included in the meta-analysis. The PaedsQL scores of survivors and their caregivers were compared. Subgroup analysis was conducted for craniospinal and proton radiotherapy groups. RESULTS: As compared to other posterior fossa tumors, MB survivors have the lowest QoL scores. There is a difference in the perception of QoL of survivors between caregivers and survivors themselves with survivors rating themselves higher in several domains. The overall PaedsQL scores were significantly different for both groups (p < 0.001). Subgroup analysis showed that the difference between those who were treated with craniospinal or proton radiation was not significant (p = 0.76). For the subscales, physical (p = 0.005), psychosocial (p = 0.0003), and school (p = 0.03) perceptions were significantly different for the survivors and their caregivers; however, psychosocial (p = 0.80) and emotional (p = 0.93) scales were not different for the survivors or caregivers. Patient characteristics related to a worse QoL included disease severity, metastatic disease, lesser family income, smaller current ventricle size, need for permanent hydrocephalus treatment, and lesser age at diagnosis. CONCLUSION: An analysis of various studies, using different measures of QoL, concludes that QoL is compromised in all pediatric survivors of MB; however, the perception of QoL of the survivors is better than objective or caretaker-rated QoL.