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Key Points The clinical, neuroradiological and surgical definition of hypothalamic involvement is a fundamental factor related to poor postoperative outcome, progressive obesity and neuropsychological impairment in children after surgical removal of craniopharyngioma The previously assumed 'gold-standard' objective of a primary radical removal of the lesion in all cases needs to be replaced with the new paradigm of a limited resection plus focused radiotherapy in patients with craniopharyngioma and hypothalamic lesions Hypothalamic involvement and treatment-related hypothalamic lesions are associated with the highest risk of postoperative sequelae and impaired quality of survival 3D intensity-modulated proton beam radiotherapy has potential advantages over photon beam methods to focus and limit the radiation effects to optic and hypothalamic structures Preclinical, in vivo mouse models can be used to investigate the pathogenesis of adamantinomatous craniopharyngioma and to test novel treatments Childhood-onset craniopharyngioma is a rare embryonic tumour of low-grade malignancy that has traditionally been treated by radical resection. Here, Müller and colleagues review recent advances in the molecular pathogenesis of the disease and treatment strategies that could lead to novel targeted therapies and more-limited surgeries. Childhood-onset craniopharyngiomas are rare embryonic tumours of low-grade histological malignancy. Novel insights into the molecular pathogenesis of human adamantinomatous craniopharyngioma have started to unveil the possibility of testing novel treatments targeting pathogenic pathways. Hypothalamic involvement and/or treatment-related lesions result in impaired physical and social functionality and in severe neuroendocrine sequelae. Quality of survival in patients with craniopharyngioma with hypothalamic involvement is impaired by severe obesity, physical fatigue and non-optimal psychosocial development. Patients with craniopharyngioma involving hypothalamic structures have reduced 20-year overall survival, but overall and progression-free survival are not related to the degree of surgical resection. Irradiation is effective in the prevention of tumour progression and recurrence. For favourably localized craniopharyngiomas, the preferred treatment of choice is to attempt complete resection with preservation of visual, hypothalamic and pituitary function. For unfavourably localized tumours in close proximity to optic and/or hypothalamic structures, a radical neurosurgical strategy attempting complete resection is not recommended owing to potential severe sequelae. As expertise has been shown to have an impact on post-treatment morbidity, medical societies should establish criteria for adequate professional expertise for the treatment of craniopharyngioma. On the basis of these criteria, health authorities should organize the certification of centres of excellence that are authorized to treat and care for patients with this chronic disease.

Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity. In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0–21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067. Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39–13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28–8·53) for patients who did not have progression and 7·62 years (IQR 6·48–8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4–99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3–4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff. Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared. American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness.

Therapy for ependymoma includes aggressive surgical intervention and radiotherapy administered by use of methods that keep the risk of side-effects to a minimum. We extended this treatment approach to include children under the age of 3 years with the aim of improving tumour control. Between July 11, 1997, and Nov 18, 2007, 153 paediatric patients (median age 2·9 years [range 0·9–22·9 months]) with localised ependymoma were treated. 85 patients had anaplastic ependymoma; the tumours of 122 were located in the infratentorial region, and 35 had received previous chemotherapy. Patients received conformal radiotherapy after definitive surgery (125 patients had undergone gross total, 17 near total, and 11 subtotal resection). Doses of 59·4 Gy (n=131) or 54·0 Gy (n=22) were prescribed to a 10 mm margin around the target volume. Disease control, patterns of failure, and complications were recorded for patients followed over 10 years. Overall survival, event-free survival (EFS), cumulative incidence of local recurrences, and cumulative incidence of distant recurrences were assessed. Variables considered included tumour grade, tumour location, ethnic origin, sex, age when undergoing conformal radiotherapy, total radiotherapy dose, number of surgical procedures, surgery extent, and preradiotherapy chemotherapy. After a median follow-up of 5·3 years (range 0·4–10·4), 23 patients had died and tumour progression noted in 36, including local (n=14), distant (n=15), and combined failure (n=7). 7-year local control, EFS, and overall survival were 87·3% (95% CI 77·5–97·1), 69·1% (56·9–81·3), and 81·0% (71·0–91·0), respectively. The cumulative incidences of local and distant failure were 16·3% (9·6–23·0) and 11·5% (5·9–17·1), respectively. In the 107 patients treated with immediate postoperative conformal radiotherapy (without delay or chemotherapy), 7-year local control, EFS, and overall survival were 88·7% (77·9–99·5), 76·9% (63·4–90·4), and 85·0% (74·2–95·8), respectively; the cumulative incidence of local and distant failure were 12·6% (5·1–20·1), and 8·6% (2·8–14·3), respectively. The incidence of secondary malignant brain tumour at 7 years was 2·3% (0–5·6) and brainstem necrosis 1·6% (0–4·0). Overall survival was affected by tumour grade (anaplastic vs differentiated: HR 3·98 [95% CI 1·51–10·48]; p=0·0052), extent of resection (gross total vs near total or subtotal: 0·16 [0·07–0·37]; p<0·0001), and ethnic origin (non-white vs white: 3·0 [1·21–7·44]; p=0·018). EFS was affected by tumour grade (anaplastic vs differentiated: 2·52 [1·27–5·01]; p=0·008), extent of resection (gross total vs near total or subtotal: 0·20 [0·11–0·39]; p<0·0001]), and sex (male vs female: 2·19 [1·03–4·66]; p=0·042). Local failure was affected by extent of resection (gross total vs near total or subtotal: 0·16 [0·067–0·38]; p<0·0001), sex (male vs female: 3·85 [1·10–13·52]; p=0·035), and age (<3 years vs ≥3 years: 3·25 [1·30–8·16]; p=0·012). Distant recurrence was only affected by tumour grade (anaplastic vs differentiated: 4·1 [1·2–14·0]; p=0·017). Treatment of ependymoma should include surgery with the aim of gross-total resection and conformal, high-dose, postoperative irradiation. Future trials might consider treatment stratification based on sex and age. American Cancer Society and American Lebanese Syrian Associated Charities (ALSAC).

Perivascular spaces (PVS) are fluid filled compartments surrounding the small blood vessels in the brain. The impact of radiotherapy and chemotherapy on PVS remains unclear. The aim of this study is to investigate treatment effects of radiotherapy and chemotherapy at four time points (TPs) in pediatric medulloblastoma (MB) patients. We examined 778 scans from 241 MB patients at baseline (0M), after 12 weeks (about 3 months) of radiotherapy and rest (3M), after chemotherapy completion (12M), and a follow-up (FollowUp) at 18- or 21-months post-baseline. PVS was segmented by applying Frangi filter on the white matter regions on T1 weighted images acquired at 3T Siemens MRI scanner using MPRAGE. PVS volume and ratio, defined as the ratio of PVS volume to the white matter volume, were measured at the four TPs. The data was first statistically analyzed using a full model where all data were included, then a paired model, which included only patients who completed consecutive measurements under the same anesthesia and shunt conditions. Both the full model and paired model showed that PVS (including ratio and volume) increased at 3M post-radiotherapy compared to baseline. During chemotherapy, PVS decreased significantly from 3M to 12M. Subsequently, from 12M to FollowUp, PVS increased again. MRI exams under anesthesia exhibited significantly lower PVS than those without anesthesia. Patients who had undergone a shunt procedure exhibited a significantly reduced PVS compared to those who had not undergone the procedure. We concluded that craniospinal irradiation led to an elevated PVS. Conversely, chemotherapy or time post-irradiation decreased PVS. Anesthesia and shunt procedures can also influence perivascular space ratio or volume.

Craniospinal irradiation (CSI) is a vital therapeutic approach utilized for young patients suffering from central nervous system disorders such as medulloblastoma. The task of accurately outlining the treatment area is particularly time-consuming due to the presence of several sensitive organs at risk (OAR) that can be affected by radiation. This study aimed to assess two different methods for automating the segmentation process: an atlas technique and a deep learning neural network approach. Additionally, a novel method was devised to prospectively evaluate the accuracy of automated segmentation as a knowledge-based quality assurance (QA) tool. Involving a patient cohort of 100, ranging in ages from 2 to 25 years with a median age of 8, this study employed quantitative metrics centered around overlap and distance calculations to determine the most effective approach for practical clinical application. The contours generated by two distinct methods of atlas and neural network were compared to ground truth contours approved by a radiation oncologist, utilizing 13 distinct metrics. Furthermore, an innovative QA tool was conceptualized, designed for forthcoming cases based on the baseline dataset of 100 patient cases. The calculated metrics indicated that, in the majority of cases (60.58%), the neural network method demonstrated a notably higher alignment with the ground truth. Instances where no difference was observed accounted for 31.25%, while utilization of the atlas method represented 8.17%. The QA tool results showed that the two approaches achieved 100% agreement in 39.4% of instances for the atlas method and in 50.6% of instances for the neural network auto-segmentation. The results indicate that the neural network approach showcases superior performance, and its significantly closer physical alignment to ground truth contours in the majority of cases. The metrics derived from overlap and distance measurements have enabled clinicians to discern the optimal choice for practical clinical application.

Cranial radiation can impact the cerebral vasculature in many ways, with a wide range of clinical manifestations. The incidence of these late effects including cerebrovascular accidents (CVAs), lacunar lesions, vascular occlusive disease including moyamoya syndrome, vascular malformations, and hemorrhage is not well known. This article reviews the preclinical findings regarding the pathophysiology of late radiation-induced vascular damage, and discusses the clinical incidence and risk factors for each type of vasculopathy. The pathophysiology is complex and dependent on the targeted blood vessels, and upregulation of pro-inflammatory and hypoxia-related genes. The risk factors for adult CVAs are similar to those for patients not exposed to cranial radiotherapy. For children, risks for late vascular complications include young age at radiotherapy, radiotherapy dose, NF1, tumor location, chemotherapy, and endocrine abnormalities. The incidence of late vascular complications of radiotherapy may be impacted by improved technology, therapeutic interventions, and appropriate follow up.

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array ( n  = 43), whole-exome sequencing ( n  = 26), and RNA-sequencing ( n  = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% ( P  = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% ( P  = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B–like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1 , DROSHA , and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B–like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

Purpose/Objective(s) To describe a log file–based patient‐specific quality assurance (QA) method and develop an in‐house tool for system performance tracking and dose reconstruction in pencil‐beam scanning proton therapy that can be used for pre‐treatment plan review. Materials/Methods The software extracts beam‐specific information from the treatment delivery log file and automatically compares the monitor units (MU), lateral position, and size of each spot against the intended values in the treatment plan to identify any discrepancies in the beam delivery. The software has been used to analyze 992 patients, 2004 plans, 4865 fields, and more than 32 million proton spots from 2016 to 2021. The composite doses of 10 craniospinal irradiation (CSI) plans were reconstructed based on the delivered spots and compared with the original plans as an offline plan review method. Results Over the course of 6 years, the proton delivery system has proved stable in delivering patient QA fields with proton energies of 69.4–221.3 MeV and an MU range of 0.003–1.473 MU per spot. The planned mean and standard deviation (SD) of the energy and spot MU were 114.4 ± 26.4 MeV and 0.010 ± 0.009 MU, respectively. The mean and SD of the differences in MU and position between the delivered and planned spots were 9.56 × 10−8 ± 2.0 × 10−4 MU and 0.029/−0.007 ± 0.049/0.044 mm on the X/Y‐axis for random differences and 0.005/0.125 ± 0.189/0.175 mm on the X/Y‐axis for systematic differences. The mean and SD of the difference between the commissioning and delivered spot sizes were 0.086/0.089 ± 0.131/0.166 mm on the X/Y‐axis. Conclusion A tool has been developed to extract crucial information about the performance of the proton delivery and monitor system and provide a dose reconstruction based on delivered spots for quality improvement. Each patient's plan was verified before treatment to ensure accurate and safe delivery within the delivery tolerance of the machine.

No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas ( n  = 146) from children treated on the RT1 trial at St. Jude Children’s Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q ( EXO1 ), 6q ( LATS1 ) and 9, including 9p21 ( CDKN2A ). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas ( n  = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas ( n  = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.

Background Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen. Methods In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy. Results The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72–98) and 88% (95% CI: 67–96); ≥ CR2 were 81% (95% CI: 61–92) and 68% (95% CI: 47–82) and refractory disease were 32% (95% CI: 11–54) and 20% (95% CI: 6–40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64–87) with no difference amongst recipients with or without minimal residual disease ( P  = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors ( P  = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors ( P  = 0.035). Conclusion The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611).