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OBJECTIVE Wound complications are a common adverse event following metastatic spine tumor surgery. Some patients with spinal metastases may first undergo radiation but eventually require spinal surgery because of either cord compression or instability. The authors compared wound complication rates in patients who had undergone surgery for metastatic disease and received preoperative radiation treatments, postoperative radiation, or no radiation. METHODS Records from patients treated at the University of California, San Francisco, for metastatic spine disease between 2005 and 2017 were retrospectively reviewed. Baseline characteristics were collected, including preoperative Karnofsky Performance Status (KPS), Spine Instability Neoplastic Score, total radiation dose, indication for surgery, diabetes status, time between radiation and surgery, use of perioperative chemotherapy or steroids, estimated blood loss, extent of fusion, and preoperative albumin level. Wound complication was defined as poor healing, dehiscence, or infection per the Centers for Disease Control and Prevention guidelines, within 6 months of surgery. One-way ANOVA was used to compare means across groups. Cumulative incidence analysis with competing risk methodology was used to adjust for risk of death during follow-up. Statistical analysis was performed using R software. RESULTS Two hundred five patients with adequate medical records were identified. Seventy patients had received preoperative radiation, 74 had received postoperative radiation within 6 months after surgery, and 61 had received no radiation at the surgical site. Wound complication rates were similar across the 3 cohorts: 14.3% (n = 10) in the group with preoperative radiation, 10.8% (n = 8) in the group that received postoperative radiation, and 11.5% (n = 7) in the group with no radiation (p = 0.773). Competing risk analysis showed a higher cumulative incidence of wound complications for the preoperative cohort, though this difference was not significant (p = 0.46). Overall, 89 patients were treated with external beam radiation therapy (EBRT), whereas 55 received stereotactic body radiation therapy (SBRT). There was no significant difference in wound complications for patients treated with EBRT (11.2%, n = 10) versus SBRT (14.5%, n = 8; p = 0.825). KPS was the only factor correlated with wound complications on univariate analysis (p = 0.03). CONCLUSIONS Wound complication rates did not differ across the 3 cohorts: patients treated with preoperative radiation, postoperative radiation within 6 months of surgery, or no radiation. The effect size was small for KPS and likely does not represent a clinically significant predictor of wound complications.

OBJECTIVE The authors previously evaluated risk and time course of adverse radiation effects (AREs) following stereotactic radiosurgery (SRS) for brain metastases, excluding lesions treated after prior SRS. In the present analysis they focus specifically on single-fraction salvage SRS to brain metastases previously treated with SRS or hypofractionated SRS (HFSRS), evaluating freedom from progression (FFP) and the risk and time course of AREs. METHODS Brain metastases treated from September 1998 to May 2019 with single-fraction SRS after prior SRS or HFSRS were analyzed. Serial follow-up magnetic resonance imaging (MRI) and surgical pathology reports were reviewed to score local treatment failure and AREs. The Kaplan-Meier method was used to estimate FFP and risk of ARE measured from the date of repeat SRS with censoring at the last brain MRI. RESULTS A total of 229 retreated brain metastases in 124 patients were evaluable. The most common primary cancers were breast, lung, and melanoma. The median interval from prior SRS/HFSRS to repeat SRS was 15.4 months, the median prescription dose was 18 Gy, and the median duration of follow-up imaging was 14.5 months. At 1 year after repeat SRS, FFP was 80% and the risk of symptomatic ARE was 11%. The 1-year risk of imaging changes, including asymptomatic RE and symptomatic ARE, was 30%. Among lesions that demonstrated RE, the median time to onset was 6.7 months (IQR 4.7–9.9 months) and the median time to peak imaging changes was 10.1 months (IQR 5.6–13.6 months). Lesion size by quadratic mean diameter (QMD) showed similar results for QMDs ranging from 0.75 to 2.0 cm (1-year FFP 82%, 1-year risk of symptomatic ARE 11%). For QMD < 0.75 cm, the 1-year FFP was 86% and the 1-year risk of symptomatic ARE was only 2%. Outcomes were worse for QMDs 2.01–3.0 cm (1-year FFP 65%, 1-year risk of symptomatic ARE 24%). The risk of symptomatic ARE was not increased with tyrosine kinase inhibitors or immunotherapy before or after repeat SRS. CONCLUSIONS RE on imaging was common after repeat SRS (30% at 1 year), but the risk of a symptomatic ARE was much less (11% at 1 year). The results of repeat single-fraction SRS were good for brain metastases ≤ 2 cm. The authors recommend an interval ≥ 6 months from prior SRS and a prescription dose ≥ 18 Gy. Alternatives such as HFSRS, laser interstitial thermal therapy, or resection with adjuvant radiation should be considered for recurrent brain metastases > 2 cm.

OBJECTIVE Resection of brain metastases (BMs) may be associated with increased risk of leptomeningeal disease (LMD). This study examined rates and predictors of LMD, including imaging subtypes, in patients who underwent resection of a BM followed by postoperative radiation. METHODS A retrospective, single-center study was conducted examining overall LMD, classic LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression, Cox proportional hazards, and random forest analyses were performed to identify risk factors associated with LMD. RESULTS Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD, with 19 cases (8.8%) of cLMD and 28 cases (12.9%) of nLMD. Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from the date of LMD diagnosis compared with nLMD (median 2.4 vs 6.9 months, p = 0.02, log-rank test). Cox proportional hazards analysis identified cerebellar/insular/occipital location (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.73–6.11, p = 0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27–4.88, p = 0.008), and ventricle contact (HR 2.82, 95% CI 1.5–5.3, p = 0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an area under the receiver operating characteristic curve of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. CONCLUSIONS Tumor location, absence of extracranial disease at the time of surgery, ventricle contact, and increased tumor volume were associated with LMD. Further work is needed to determine whether escalating therapies in patients at risk of LMD prevents disease dissemination.

OBJECTIVE The authors’ objective was to examine the safety and efficacy of salvage intracranial cesium-131 brachytherapy in combination with resection of recurrent brain tumors. METHODS The authors conducted a retrospective chart review of consecutive patients treated with intraoperative intracranial cesium-131 brachytherapy at a single institution. Permanent suture-stranded cesium-131 seeds were implanted in the resection cavity after maximal safe tumor resection. The primary outcomes of interest were local, locoregional (within 1 cm), and intracranial control, as well as rates of overall survival (OS), neurological death, symptomatic adverse radiation effects (AREs), and surgical complication rate graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS Between 2016 and 2020, 36 patients received 40 consecutive cesium-131 implants for 42 recurrent brain tumors and received imaging follow-up for a median (interquartile range [IQR]) of 17.0 (12.7–25.9) months. Twenty patients (55.6%) with 22 implants were treated for recurrent brain metastasis, 12 patients (33.3%) with 16 implants were treated for recurrent atypical (n = 7) or anaplastic (n = 5) meningioma, and 4 patients (11.1%) were treated for other recurrent primary brain neoplasms. All except 1 tumor (97.6%) had received prior radiotherapy, including 20 (47.6%) that underwent 2 or more prior radiotherapy treatments and 23 (54.8%) that underwent prior resection. The median (IQR) tumor size was 3.0 (2.3–3.7) cm, and 17 lesions (40.5%) had radiographic evidence of ARE prior to salvage therapy. Actuarial 1-year local/locoregional/intracranial control rates for the whole cohort and patients with metastases and meningiomas were 91.6%/83.4%/47.9%, 88.8%/84.4%/45.4%, and 100%/83.9%/46.4%, respectively. No cases of local recurrence of any histology (0 of 27) occurred after gross-total resection (p = 0.012, log-rank test). The 1-year OS rates for the whole cohort and patients with metastases and meningiomas were 82.7%, 79.1%, and 91.7%, respectively, and the median (IQR) survival of all patients was 26.7 (15.6–36.4) months. Seven patients (19.4%) experienced neurological death from progressive intracranial disease (7 of 14 total deaths [50%]), 5 (13.9%) of whom died of leptomeningeal disease. Symptomatic AREs were observed in 9.5% of resection cavities (n = 4), of which 1 (2.4%) was grade 3 in severity. The surgical complication rate was 16.7% (n = 7); 4 (9.5%) of these patients had grade 3 or higher complications, including 1 patient (2.4%) who died perioperatively. CONCLUSIONS Cesium-131 brachytherapy resulted in good local control and acceptable rates of symptomatic AREs and surgical complications in this heavily pretreated cohort, and it may be a reasonable salvage adjuvant treatment for this patient population.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients.

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PDF file - 50K, Tumor Histologies generated from the AI model

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SummaryCell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2–5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.

Brain metastases occur frequently in advanced melanoma and traditionally require surgery and radiation therapy. New evidence demonstrates that systemic therapies are effective for controlling metastatic melanoma brain metastases. This study evaluated outcomes after resection of melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy.All patients received immunotherapy or BRAF/MEK inhibitors preoperatively or in the immediate 3 months postoperatively. Resection cavity failure, distant central nervous system progression, and adverse radiation effects were reported in the presence and absence of focal radiotherapy using the Kaplan-Meier method.Between 2011 and 2020, 37 resection cavities in 29 patients met criteria for analysis. Of lesions, 22 (59%) were treated with focal radiotherapy, and 15 (41%) were treated with targeted therapy or immunotherapy alone. The 12- and 24-month freedom from local recurrence was 64.8% (95% confidence interval [CI] 42.1%-99.8%) and 46.3% (95% CI 24.5%-87.5%), respectively, for systemic therapy alone and 93.3% (95% CI 81.5%-100%) at both time points for focal radiotherapy (P = 0.01). On univariate analysis, focal radiotherapy was the only significant factor associated with reduction of local recurrence risk (hazard ratio 0.10, 95% CI 0.01-0.85; P = 0.04). There were no significant differences in central nervous system progression-free survival or overall survival between patients who received systemic therapy plus focal radiotherapy compared with systemic therapy alone. BRAF mutation status was reviewed for either the brain metastasis (n = 9 patients, 31%) or the primary site (n = 20 patients, 69%), and patients harboring BRAFFocal radiotherapy with systemic therapy for resected melanoma brain metastases significantly decreased resection cavity recurrence compared with systemic therapy alone. BRAF mutation status correlated with poorer outcomes.

We sought to analyze biologic, clinical, and prognostic differences according to pattern of failure at the time of first relapse in neuroblastoma.Children21 years diagnosed with neuroblastoma between 1989 and 2017 with known site of first relapse (isolated local vs. distant only vs. combined local and distant sites) were identified from the International Neuroblastoma Risk Group (INRG) database. Data were compared between sites of relapse according to clinical features, biologic features, initial treatment, time to first relapse, and overall survival (OS) from time of first relapse.Pattern of first relapse among 1833 children was 19% isolated local; 65% distant only; and 16% combined sites. All evaluated clinical and biologic variables with exception of tumor diagnosis differed statistically by relapse pattern, with patients with isolated local failure having more favorable prognostic features. Patients with stage 3 disease were more likely to have isolated local failure compared to all other stages (49% vs. 16%; p .001). OS significantly differed by relapse pattern (5-year OS ± SE): isolated local: 64% ± 3%; distant only: 23% ± 2%; and combined: 26% ± 4% (p .001). After controlling for age, stage, and MYCN status, patients with isolated local failure (adjusted hazard ratio [HR] = 0.46; 95% confidence interval [CI]: 0.33-0.62; p .001) and distant-only failure (adjusted HR = 0.57; 95% CI: 0.45-0.71; p .001) remained at decreased risk for death as compared to patients with combined failure.Patients with distant-only and combined failures have a higher proportion of unfavorable clinical and biological features, and a lower survival than those with isolated local relapse.

Patients with metaiodobenzylguanidine (MIBG)-avid relapsed or refractory neuroblastoma after initial therapy may exhibit transient responses to salvage treatment with iodine-131 metaiodobenzylguanidine (Patients with relapsed or refractory metastatic MIBG-avid neuroblastoma or ganglioneuroblastoma, who received single-agentA total of 84 MIBG-avid metastatic sites were identified immediately prior to MIBG therapy in a cohort of 12 patients. At first progression, a total of 101 MIBG-avid sites were identified, of which 69 (68%) overlapped with pre-treatment disease sites, while 32 (32%) represented anatomically new disease areas. Eight of 12 patients had one or more new MIBG-avid sites at first progression. Of the 69 involved sites at progression that overlapped with pre-treatment disease, 11 represented relapsed sites that had cleared following MIBG therapy, two were persistent but increasingly MIBG-avid, and 56 were stably persistent.Previously involved anatomic disease sites predominate at disease progression following

BACKGROUND Safety of immunotherapy (IO) and targeted therapy (TT) with stereotactic radiosurgery (SRS) in melanoma brain metastases (MBM) treatment remains incompletely understood. We aim to identify whether timing of IO/TT in relation to SRS impacts rates of adverse radiation effect (ARE) in MBM. METHODS Retrospective review of patients with MBM treated with SRS and IO/TT within three months prior and one year after SRS, from 2011-2021 at a single institution with at least two months MRI follow-up, identified 108 patients with 939 unique MBM meeting criteria. ARE was confirmed on independent imaging review. Concurrent IO/TT was defined as receiving IO/TT within 4 weeks before or after SRS. Data analysis was performed with the univariate cox proportional hazard model and Kaplan-Meier method. RESULTS Median radiographic follow-up from time of SRS was 16months. IO/TT was initiated prior to SRS for 681 (72.5%) metastases and after SRS for 258 (27.5%) metastases. 837 (89.1%) metastases received concurrent IO/TT. Most common IO agents were ipilimumab (n=416), nivolumab (n=448), and pembrolizumab (n=203). Most common TT agents were dabrafenib (n=548), trametinib (n=540), and vemurafenib (n=81). 2-year local progression-free survival (PFS), distant intracranial PFS, and overall survival were 94.1%, 33.3%, and 55.2%, respectively. 55 (5.9%) metastases in 33 (30.6%) patients experienced ARE. Median time to ARE was 5mo (IQR 4-9mo). Of those who experienced ARE, 22 (66.7%) patients were symptomatic and treated with steroids; 12 (36.4%) patients underwent surgical intervention. ARE rates were not impacted by concurrent vs nonconcurrent IO/TT (5.5% vs 4.9%, p=0.34) nor IO/TT initiation pre vs post SRS (6.0% vs 5.4%, p=0.61). CONCLUSION IO/TT in conjunction with SRS resulted in low ARE rates as compared to historical controls in the pre-IO/TT era. Timing of IO/TT in relation to SRS may not significantly impact ARE rates in MBM treatment.

The present proof-of-principle study investigated radiobiological effects of redistributing central target dose hot spots across different treatment fractions during hypofractionated stereotactic radiosurgery (HSRS) of large intracranial tumors.Redistribution of central target dose hot spots during HSRS was simulated, and its effects were evaluated in eight cases of brain metastases. To assess dose variations in the target across N number of treatment fractions, a generalized biologically effective dose (gBED) was formulated. The gBED enhancement ratio was defined as the ratio of gBED in the tested treatment plan (with central target dose hot spot redistributions across fractions) to gBED in the conventional treatment plan (without central target dose hot spot redistributions).At a median α value of 0.3/Gy, the tested treatment plans resulted in average gBED increases of 15.6 ± 3.5% and 8.3 ± 1.8% for α/β ratios of 2 and 10 Gy, respectively. In comparison with conventional treatment plans, the differences in the Paddick conformity index and gradient index did not exceed 2%.Redistributing central target dose hot spots across different treatment fractions during HSRS may be considered promising for enhancing gBED in the target. It may be beneficial for management of large intracranial neoplasms; thus, it warrants further clinical testing.

The present study aimed to examine the technical feasibility and effectiveness of adapting the radiation dose distributions with three-dimensional (3D) linear couch translations in contrast to full six-dimensional couch maneuvers to correct for rotational shifts during frameless radiosurgical treatment with the Gamma Knife Icon™ (Elekta AB; Stockholm, Sweden).The original magnetic resonance images used for radiosurgery treatment planning (15 targets) were digitally processed to simulate rotational shifts of ±1, ±2, ±3, ±5, and ±10 degrees in the transverse plane and imported back into Leksell GammaPlanThe "uncorrected" treatment plans resulted in a significant deterioration in target coverage (by 8-72%) and selectivity (by 2-42%), with some targets being missed completely with rotations of ±3 or more degrees. In contrast, in all "corrected" treatment plans, the average decreases in target coverage and selectivity were only 1% (maximum values 4-5%).Applications of 3D linear couch translations successfully overcome gross uncertainties in dose distributions caused by up to ±10 degrees of rotational shifts in a target. As a result, rapid dose adaptation with 3D couch translations is unique and effective for frameless radiosurgery with the Gamma Knife Icon™.

The objective of the present study was evaluation of the interrelationships between changes in the skull size and variations in the normal brain radiation dose during Gamma Knife surgery (GKS).With use of systematic modeling within Leksell GammaPlanWith changes in the skull radius within ±3 cm, the maximum absolute deviation in the mean normal brain radiation dose was 0.8%. As the skull radius increased, the mean normal brain radiation dose also increased linearly (confidence level99%) with a positive slope of 0.2% per centimeter of radius length change. The maximum point dose deviations in all evaluated critical anatomical structures did not exceed 0.5%, with an overall trend toward a dose increase in parallel with an increase in the skull radius.The small skull size of pediatric patients may be associated with dosimetric advantages in terms of normal brain sparing during GKS.

The Radiation Oncology Education Collaborative Study Group (ROECSG) is an international collaborative network of radiation oncology (RO) professionals with the goal of improving RO education. This report summarizes the first two ROECSG annual symposia including an overview of presentations and analysis of participant feedback. One-day symposia were held in June 2018 and May 2019. Programs included oral and poster presentations, RO education leadership perspectives, and keynote addresses. Post-symposia surveys were collected. Research presentations were recorded and made available online. The 2018 symposium was had 36 attendees from 25 institutions in three countries. The 2019 symposium had 76 individuals from 41 institutions in five countries. Attendees represented diverse backgrounds including attending physicians (46%), residents (13%), medical students (14%), physicists (2%), nurses (1%), and program coordinators (1%). Fifty-five oral presentations were given with 53 released online. Ninety percent of attendees rated the symposium as improving their knowledge of RO educational scholarship, 98% felt the symposium provided the opportunity to receive feedback on RO education scholarship, and 99% felt that the symposium fostered the development of collaborative RO education projects. ROECSG was rated higher than professional organizations in fostering educational scholarship (p0.001). All attendees felt that the symposium produced new RO education scholarship ideas and provided unique networking opportunities. The first two ROECSG symposia drew a diverse population of attendees and provided unique opportunities for presentation of RO education scholarship. Future ROECSG symposia will be designed to enhance opportunities to present RO education scholarship and to facilitate networking.

2007 Background: Improvements in risk stratification of meningioma are needed to guide post-operative management and application of adjuvant therapy. Although profiling of DNA methylation, copy number variants (CNVs), RNA sequencing, and exome sequencing have better elucidated meningioma biology, these approaches have not revealed clinically tractable biomarkers for radiotherapy responses. In this study, we develop and validate a targeted gene expression biomarker to predict meningioma outcomes and benefit from radiotherapy. Methods: Targeted gene expression profiling was performed on a development set of 173 meningiomas (median follow-up 8.1 years) and a validation set of 331 consecutive meningiomas (median follow-up 6.1 years) treated at independent institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). All patients underwent surgery (n = 504) with or without postoperative radiotherapy (n = 73 with radiation). Regularized Cox regression within the development set resulted in a continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 genes and 7 housekeeping genes) and thresholds for low, intermediate, and high-risk scores were locked and applied to the validation set. Results: The gene expression risk score outperformed WHO grade (validation 5-year LFFR delta-AUC 0.15, 95% CI 0.076-0.229, p = 0.001) and DNA methylation grouping (delta-AUC 0.075, 95% CI 0.006-0.130, p = 0.01) for LFFR, disease-specific survival, and OS, achieving a negative predictive value for recurrence at 5-years of 93.2%. The biomarker reclassified 35.8% of WHO grade 1 tumors as intermediate or high risk (5-year LFFR/OS 62%/79%), and 18.3% of WHO grade 2-3 tumors as low risk (5-year LFFR/OS 78%/100%). The biomarker was independently prognostic after accounting for WHO grade, extent of resection, primary versus recurrent presentation, CNV status, DNA methylation group, and Ki67 labeling index, and was predictive for LFFR after postoperative radiotherapy, with a hazard ratio of 0.41 for intermediate to high risk propensity-matched meningiomas (95% CI 0.2-0.9, p = 0.0002) versus 0.79 for low risk meningiomas (95% CI 0.1-8.8, p = 0.5182). Conclusions: Targeted gene expression profiling of 504 meningiomas resulted in a biomarker which improved discrimination of meningioma local recurrence, disease-specific survival, and overall survival, and also predicted benefit from radiotherapy.

10003 Background: The addition of dinutuximab (DIN) in the post-consolidation setting led to improved event-free survival rates for patients with high-risk neuroblastoma. Chemoimmunotherapy including irinotecan, temozolomide, DIN and sargramostim (GM-CSF) in patients with recurrent or refractory neuroblastoma results in robust objective clinical responses. Evaluation of chemoimmunotherapy in the induction setting for patients with newly-diagnosed high-risk neuroblastoma (HR-NBL) warrants investigation. Methods: Children’s Oncology Group (COG) ANBL17P1 is a prospective, single arm, limited institution pilot study to assess the tolerability and feasibility of administering DIN (17.5mg/m2/dose, IV Days 2-5) and GM-CSF (250mcg/m2/dose, subcutaneous Days 6-count recovery) with COG Induction chemotherapy Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma. The primary endpoint of tolerability included the number of toxic deaths and number of patients experiencing predefined unacceptable toxicities during Induction Cycles 3-5. Unacceptable toxicities included: hypotension requiring pressors > 24 hours, respiratory toxicity requiring ventilatory support > 24 hours, Grade 4 neuropathy that did not resolve prior to the next cycle, and failure to recover the ANC to > 750 mm3 by day 35. Feasibility was assessed as being able to receive > 75% of planned DIN doses administered during Induction Cycles 3-5. Revised International Neuroblastoma Response Criteria (INRC) were used to assess end of Induction (EOI) response. Results: Forty-two eligible and evaluable patients with newly-diagnosed high-risk neuroblastoma enrolled at 8 sites (22 [52.4%] males; median age 3.3 years at diagnosis) from January 14, 2019 to June 4, 2020. The most common DIN related Grade >3 toxicities observed during Induction Cycles 3-5 included fever (31.0%) and pain (9.5%). None of the patients experienced a toxic death or unacceptable toxicity during Induction Cycles 3-5. Thus, the regimen was deemed tolerable. Patients received 97.4% - 101.8% of the total DIN dose expected to be administered during Induction Cycles 3-5. Therefore, the regimen was deemed feasible. Thirty-eight of 42 patients completed the EOI evaluations, including 11 with complete response, 22 with partial response, 0 with minor response, 3 with stable disease and 2 with progressive disease. The overall EOI objective response rate (CR+PR+MR) was 86.8%. Conclusions: The administration of DIN and GM-CSF to COG Induction Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma was tolerable and feasible. The objective response rate at EOI appears encouraging. This therapeutic regimen will be studied in a randomized phase 3 trial to further evaluate the efficacy of Induction phase chemoimmunotherapy for high-risk neuroblastoma. Clinical trial information: NCT03786783.

SUMMARYMeningiomas arising from the meningothelial central nervous system lining are the most common primary intracranial tumors, and a significant cause of neurologic morbidity and mortality1. There are no effective medical therapies for meningioma patients2,3, and new treatments have been encumbered by limited understanding of meningioma biology. DNA methylation profiling provides robust classification of central nervous system tumors4, and can elucidate targets for molecular therapy5. Here we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, and single-cell approaches to show meningiomas are comprised of 3 epigenetic groups with distinct clinical outcomes and biological features informing new treatments for meningioma patients. Merlin-intact meningiomas (group A, 34%) have the best outcomes and are distinguished by a novel apoptotic tumor suppressor function ofNF2/Merlin. Immune-enriched meningiomas (group B, 38%) have intermediate outcomes and are distinguished by immune cell infiltration,HLAexpression, and lymphatic vessels. Hypermitotic meningiomas (group C, 28%) have the worst outcomes and are distinguished by convergent genetic mechanisms misactivating the cell cycle. Consistently, we find cell cycle inhibitors block meningioma growth in cell culture, organoids, xenografts, and patients. Our results establish a framework for understanding meningioma biology, and provide preclinical rationale for new therapies to treat meningioma patients.

Radiation therapy is an option as a primary treatment for small meningiomas and for treatment of recurrences after surgery. The technology for delivery of treatment has advanced much in the last 15 years, and now image guidance and stereotactic methods are used for defining the target location. There are different forms of treatment that include protons and photons, both delivered using multiple beam paths converging on the target. Currently the most common form of treatment uses photon energy derived from a linear accelerator using intensity modulated techniques. Radiation delivered in multiple sessions, more than five, is termed fractionated treatment, whereas those using five or less have been referred to radiosurgery. This chapter outlines the usefulness of radiation in the management of meningioma.

Purpose The purpose of this retrospective cohort study was to evaluate the effect of tumor location and other major factors on the risk of complications from stereotactic body radiation therapy (SBRT) in non-small cell lung cancer (NSCLC) patients with a history of thoracic surgery and/or radiation therapy. Methods Medical records of patients with recurrent or second primary NSCLC treated with SBRT between 2005 and 2015 were reviewed. All patients had prior thoracic surgery and/or radiation therapy and were treated with image-guided, robotic SBRT. Time to local failure and toxicity was evaluated by using cumulative incidence and competing risk regression analysis. Overall survival was estimated using the Kaplan-Meier method. Results Fifty-six patients with 74 tumors treated with SBRT were included for analysis. Of the 74 tumors, 19 (26%) were centrally located within 2 cm of the proximal bronchial tree. At a median follow-up of 27 months (range = 5–129), the 2-year cumulative incidence of LF was 13% for peripheral tumors and 16% for central tumors (p = 0.95). Neither prior thoracic surgery nor radiation therapy was associated with increased LF or toxicity. Among the 56 patients, eight (14%), three (5%), and one (2%) experienced grade 2, 3, and 4 complications following SBRT. Patients with a ≥ 50 pack-year smoking history were more likely to develop ≥ grade 2 toxicity (HR 5.3; 95% CI 1.4–19.9, p = 0.01). Central tumor location was associated with higher risk of toxicity (HR 3.4; 95% CI 1.1–10.5, p = 0.04) as was planning tumor volume > 30 mL (HR 4.3; 95% CI 1.1–16.3, p = 0.047). In a multivariable model, central location remained significant after adjusting for smoking history and planning tumor volume. Conclusions After prior thoracic surgery and/or radiation, SBRT retreatment for NSCLC provided durable local control and was well tolerated in most patients. Patients with a history of previously operated and/or radiated lung cancer with new central tumors, PTV volume > 30 mL, or smoking history ≥ 50 pack-years were at higher risk of complications from SBRT.