Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy1,2, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease3-10. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging11,12, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost13,14. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH21,2, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.

Hypofractionated re-irradiation for diffuse intrinsic pontine glioma.

BACKGROUND: Re-irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation (CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF). METHODS: We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF. Outcomes included steroid use, and overall survival (OS) was measured from both diagnosis and start of reRT. RESULTS: Of 22 patients who received reRT for DIPG, two did not complete their course due to clinical decline. Of the 20 who completed reRT, the dose was 20-30 Gy in 2-Gy fractions (n = 6) and 30-36 Gy in 3-Gy fractions (n = 14). Median age was 5 years (range: 3-14), median interval since initial RT was 8 months (range: 3-20), and 12 received concurrent bevacizumab. Median OS from diagnosis was 18 months [95% confidence interval: 17-24]. Median OS from start of reRT for HF versus CF was 8.2 and 7.5 months, respectively (p = .20). Thirteen (93%) in the HF group and three (75%) in the CF group tapered pre-treatment steroid dose down or off within 2 months after reRT due to clinical improvement. There was no significant difference in steroid taper between HF and CF (p = .4). No patients developed radionecrosis. CONCLUSION: reRT with HF achieved survival duration comparable to published outcomes and effectively palliated symptoms. Future investigation of this regimen in the context of new systemic therapies and upfront HF is warranted.

Treatment of Pediatric Low-Grade Gliomas.

PURPOSE OF REVIEW: Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy. Chemotherapy remains the preferred first-line therapy for adjuvant treatment of the majority of recurrent or progressive pLGG. RECENT FINDINGS: Technologic advances offer the potential to limit volume of normal brain exposed to low doses of radiation when treating pLGG with either conformal photon or proton RT. Recent neurosurgical techniques such as laser interstitial thermal therapy offer a "dual" diagnostic and therapeutic treatment modality for pLGG in specific surgically inaccessible anatomical locations. The emergence of novel molecular diagnostic tools has enabled scientific discoveries elucidating driver alterations in mitogen-activated protein kinase (MAPK) pathway components and enhanced our understanding of the natural history (oncogenic senescence). Molecular characterization strongly supplements the clinical risk stratification (age, extent of resection, histological grade) to improve diagnostic precision and accuracy, prognostication, and can lead to the identification of patients who stand to benefit from precision medicine treatment approaches. The success of molecular targeted therapy (BRAF inhibitors and/or MEK inhibitors) in the recurrent setting has led to a gradual and yet significant paradigm shift in the treatment of pLGG. Ongoing randomized trials comparing targeted therapy to standard of care chemotherapy are anticipated to further inform the approach to upfront management of pLGG patients.

Comparative Analysis of 2D and 3D Metrics for Evaluation of Postoperative Outcomes Following Endoscopic Suturectomy for Sagittal Craniosynostosis.

To assess whether 3-dimensional (3D) volumetrics can be used to track and evaluate postoperative course of patients treated with endoscopic suturectomy for nonsyndromic sagittal synostosis, we compared changes in 2-dimensional (2D) measurements along with 3D volumetric correlates throughout the period of helmet therapy. Forty-six patients treated at our institution with endoscopic suturectomy for sagittal synostosis were retrospectively reviewed. Head circumference (HC), cephalic index (CI), and total cranial volumes (TCVs) were measured at 3 timepoints following surgery using optical surface scans obtained for helmet orthotics. All measurements showed significant differences between timepoints on the analysis of variance ( P <0.001). There was a significant correlation between CI and TCV (r=0.35, P =0.004) and between HC and TCV (r=0.81, P <0.001). The normalized rate of change over the course of treatment was significantly higher for TCV (36.7%) than for CI (8.8%) and HC (8.4%, P <0.001), with no difference between HC and CI. The authors conclude that 3D metrics were able to reliably follow the course of postoperative 2D metrics. There was a direct and linear correlation between HC and CI with TCV. Total cranial volumes showed the highest rate of sustained change at every timepoint. Although CI and HC plateau after the first measurement, TCV continues to adapt over the course of treatment. These results demonstrate the feasibility and value of volumetrics from 3D imaging to provide a more comprehensive evaluation of postoperative surgical outcomes than traditional 2D metrics without the ionizing radiation traditionally utilized for CT to obtain 3D metrics.

Quantifying intraventricular drug delivery utilizing programmable ventriculoperitoneal shunts as the intraventricular access device.

PURPOSE: Programmable ventriculoperitoneal shunts (pVP shunts) are increasingly utilized for intraventricular chemotherapy, radioimmunotherapy, and/or cellular therapy. Shunt adjustments allow optimization of drug concentrations in the thecal space with minimization in the peritoneum. This report assesses the success of the pVP shunt as an access device for intraventricular therapies. Quantifying intrathecal drug delivery using scintigraphy by pVP shunt model has not been previously reported. METHODS: We performed a single-institution, retrospective analysis on patients with CNS tumors and pVP shunts from 2003 to 2020, noting shunt model. pVP flow was evaluated for consideration of compartmental radioimmunotherapy (cRIT) using In-111-DTPA scintigraphy. Scintigraphy studies at 2-4 h and at 24 h quantified ventricular-thecal and peritoneal drug activity. RESULTS: Twenty-two CSF flow studies were administered to 15 patients (N = 15) with diagnoses including medulloblastoma, metastatic neuroblastoma, pineoblastoma, and choroid plexus carcinoma. Six different types of pVP models were noted. 100% of the studies demonstrated ventriculo-thecal drug activity. 27% (6 of 22) of the studies had no peritoneal uptake visible by imaging. 73% (16 of 22) of the studies had minimal relative peritoneal uptake (< 12%). 27% (6 of 22) of the studies demonstrated moderate relative peritoneal uptake (12-37%). No studies demonstrated peritoneal uptake above 37%. CONCLUSIONS: All patients had successful drug delivery of In-111-DTPA to the ventriculo-thecal space. 73% of the patients had minimal relative (< 12%) peritoneal drug uptake. Though efficacy varies by shunt model, low numbers preclude conclusions regarding model superiority. CSF flow scintigraphy studies assesses drug distribution of In-111-DTPA, informing CSF flow for delivery of intraventricular therapies.

Familial colloid cysts: not a chance occurrence.

PURPOSE: Colloid cysts are rare, benign brain tumors of the third ventricle with an estimated population prevalence of 1 in 5800. Sudden deterioration and death secondary to obstructive hydrocephalus are well-described presentations in patients with a colloid cyst. Although historically conceptualized as driven by sporadic genetic events, a growing body of literature supports the possibility of an inherited predisposition. METHODS: A prospective registry of patients with colloid cysts was maintained between 1996 and 2021. Data pertaining to a family history of colloid cyst was collected retrospectively; self-reporting was validated in each case by medical record or imaging review. Frequency of patients with a documented first-degree family member with a colloid cyst based on self-reporting was calculated. The rate of familial co-occurrence within our series was then compared to a systematic literature review and aggregation of familial case studies, as well as population-based prevalence rates of sporadic colloid cysts. RESULTS: Thirteen cases with affected first-degree relatives were identified in our series. Of the entire cohort, 19/26 were symptomatic from the lesion (73%), 12/26 (46.2%) underwent resection, and 2/26 (7.7%) had sudden death from presumed obstructive hydrocephalus. The majority of transmission patterns were between mother and child (9/13). Compared with the estimated prevalence of colloid cysts, our FCC rate of 13 cases in 383 (3.4%) estimates a greater-than-chance rate of co-occurrence. CONCLUSION: Systematic screening for FCCs may facilitate early recognition and treatment of indolent cysts, thereby preventing the rapid deterioration that can occur with an unrecognized third ventricular tumor. Furthermore, identifying a transmission pattern may yield more insight into the molecular and genetic underpinnings of colloid cysts.

Examining the Role of Early Diagnostic Imaging for Craniosynostosis in the Era of Endoscopic Suturectomy: A Single Institution Experience.

ABSTRACT: Endoscopic suturectomy is a minimally invasive surgical treatment for single-suture craniosynostosis in children between 1 and 4 months of age. This study sought to characterize the role played by diagnostic imaging in facilitating early surgical management with endoscopic suturectomy. The authors also characterized the overall diagnostic utility of imaging in patients assessed for abnormal head shape at their institution, regardless of surgical status. A retrospective cohort of children diagnosed with singlesuture synostosis undergoing either primary endoscopic suturectomy or open calvarial reconstruction at the authors' institution from 1998 to 2018 was first reviewed. Of 132 surgical patients, 53 underwent endoscopic suturectomy and 79 underwent open repair. There was no difference in the proportion of endoscopic and open surgery patients imaged preoperatively before (24.5% versus 35.4%; P = 0.24) or after (28.3% versus 25.3%; P = 0.84) craniofacial assessment. Stratifying by historical epoch (1998-2010 versus 2011-2018), there was also no difference found between preoperative imaging rates (63.6% versus 56.4%; P = 0.35). In another cohort of 175 patients assessed for abnormal head shape, 26.9% were imaged to rule out craniosynostosis. Positive diagnostic imaging rates were recorded for suspected unicoronal (100%), metopic (87.5%), lambdoidal (75.0%), sagittal (63.5%), multisuture (50%), and bicoronal (0%) synostosis. The authors conclude that the use of diagnostic imaging at their institution has not increased despite higher utilization of endoscopic suturectomy and need for expedient identification of surgical candidates.However, their results suggest that imaging may play a greater diagnostic role for suspected bicoronal, sagittal, and multi-sutural synostosis among sutural subtypes of synostosis.

Analysis of the Sonopet Ultrasonic Bone Aspirator to Traditional Instrumentation for Endoscopic Suturectomy for Craniosynostosis.

OBJECTIVE: The goal of endoscopic treatment for craniosynostosis is to remove the fused suture and achieve calvarial remodeling with external orthosis. To reduce the need for secondary surgery and to minimize blood loss, instruments that maximize bone removal while minimizing blood loss and risk of dural injury are evolving. The authors therefore assess the safety and efficacy of the Sonopet Ultrasonic Bone Aspirator (UBA) (Stryker, Kalamazoo, MI) for endoscopic suturectomy compared to traditional instrumentation at our institution. METHODS: Retrospective chart review of consecutive endoscopic suturectomies performed from 2011 to 2019 at Weill Cornell Medical Center was conducted, including demographics, cephalic index, surgical indications, operative time, cosmetic and functional results, complications, estimated blood loss (EBL), re-operation rate, length of stay, and length of helmet therapy. These variables were then compared between the Sonopet and non-Sonopet cohorts. RESULTS: Of the 60 patients who underwent endoscopic suturectomy, 16 cases (26.7%) utilized the Sonopet. Mean operative time was 2.8 ±â€Š0.4 hours in the Sonopet group, compared to 3.2 ±â€Š1.2 hours (P = 0.05) without the Sonopet. EBL was 17.8 ±â€Š23.9 cc versus 34.7 ±â€Š75.5 cc (P = 0.20) with versus without the Sonopet respectively. Length of stay and duration of helmet therapy were similar in both groups, ranging from 1 to 3 days (P = 0.68) and 7.25 to 12 months (P = 0.30) respectively. There were no reoperations in the Sonopet group with a mean follow up of 9.18 months. There were 3 reoperations in the non-Sonopet group with a mean follow up of 11.3 months. Among the cases utilizing the Sonopet, 13 (81%) were metopic and three (19%) were coronal synostoses. Of the non-Sonopet cases, 27 (61%) were sagittal, 8 (18%) were metopic, 7 (16%) were coronal, and 2 (5%) were lambdoid synostoses. CONCLUSIONS: The use of the Sonopet resulted in a mean decrease in operative time at our institution (P = 0.18). Lower EBL and reoperation rates with comparable LOS and helmet therapy duration were also seen. This modality should be considered a safe and effective adjunct in appropriate endoscopic craniosynostosis cases.

A Potential Role For Apparent Diffusion Coefficient in the Diagnosis of Trilateral Retinoblastoma.

We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (>1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.

Deformational changes after convection-enhanced delivery in the pediatric brainstem.

OBJECTIVE: In the brainstem, there are concerns regarding volumetric alterations following convection-enhanced delivery (CED). The relationship between distribution volume and infusion volume is predictably greater than one. Whether this translates into deformational changes and influences clinical management is unknown. As part of a trial using CED for diffuse intrinsic pontine glioma (DIPG), the authors measured treatment-related volumetric alterations in the brainstem and ventricles. METHODS: Enrolled patients underwent a single infusion of radioimmunotherapy. Between 2012 and 2019, 23 patients with volumetric pre- and postoperative day 1 (POD1) and day 30 (POD30) MRI scans were analyzed using iPlan® Flow software for semiautomated volumetric measurements of the ventricles and pontine segment of the brainstem. RESULTS: Children in the study had a mean age of 7.7 years (range 2-18 years). The mean infusion volume was 3.9 ± 1.7 ml (range 0.8-8.8 ml). Paired t-tests demonstrated a significant increase in pontine volume immediately following infusion (p < 0.0001), which trended back toward baseline by POD30 (p = 0.046; preoperative 27.6 ± 8.4 ml, POD1 30.2 ± 9.0 ml, POD30 29.5 ± 9.4 ml). Lateral ventricle volume increased (p = 0.02) and remained elevated on POD30 (p = 0.04; preoperative 23.5 ± 15.4 ml, POD1 26.3 ± 16.0, POD30 28.6 ± 21.2). Infusion volume had a weak, positive correlation with pontine and lateral ventricle volume change (r2 = 0.22 and 0.27, respectively). Four of the 23 patients had an increase in preoperative neurological deficits at POD30. No patients required shunt placement within 90 days. CONCLUSIONS: CED infusion into the brainstem correlates with immediate but self-limited deformation changes in the pons. The persistence of increased ventricular volume and no need for CSF diversion post-CED are inconsistent with obstructive hydrocephalus. Defining the degree and time course of these deformational changes can assist in the interpretation of neuroimaging along the DIPG disease continuum when CED is incorporated into the treatment algorithm.

An [18F]-Positron Emitting Fluorophore Allows Safe Evaluation of Small Molecule Distribution in the CSF, CSF Fistulas, and CNS Device Placement.

The small molecule fluorescein is commonly used to guide the repair of cerebral spinal fluid leaks (CSFLs) in the clinic. We modified fluorescein so that it is also visible by positron emission tomography (PET). This probe was used to quantitatively track the fast distribution of small molecules in the CSF of rats. We tested this probe in models relevant to the clinical diagnosis and treatment of central nervous system (CNS) diseases that affect CSF flow. In this study, fluorescein was radiolabeled with fluorine-18 to produce Fc-AMBF3. [18/19F]-Fc-AMBF3 was introduced at trace quantities (13.2 nmols, 100 µCi) intrathecally (between L5 and L6) in rats to observe the dynamic distribution and clearance of small molecules in the CSF by both [18F]-PET and fluorescence (FL) imaging. Murine models were used to demonstrate the following utilities of Fc-AMBF3: (1) utility in monitoring the spontaneous CSFL repair of a compression fracture of the cribriform plate and (2) utility in quantifying CSF flow velocity during neurosurgical lumboperitoneal shunt placement. Fc-AMBF3 clearly delineated CSF-containing volumes based on noninvasive PET imaging and in ex vivo FL histology. In vivo morbidity (n = 16 rats, <2.7 mg/kg, 77 times the PET dose) was not observed. The clearance of the contrast agent from the CNS was rapid and quantitative (t1/2 = 33.8 ± 0.6 min by FL and t1/2 = 26.0 ± 0.5 min by PET). Fc-AMBF3 was cleared from the CSF through the vasculature and/or lymphatic system that supplies the cribriform plate and the temporal bone. Fc-AMBF3 can be used to diagnose CSFLs, image CSFL repair, and determine the CSF flow velocity in the CNS or through lumboperitoneal shunts by PET/FL imaging. In conclusion, Fc-AMBF3 PET imaging has been demonstrated to safely and dynamically quantitate CSF flow, diagnose fistulas associated with the CSF space, and approximate the clearance of small molecules in the CSF.

Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial.

BACKGROUND: Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma. METHODS: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort. FINDINGS: From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200. INTERPRETATION: Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma. FUNDING: National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Patterns of relapse for children with localized intracranial ependymoma.

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.

Long-term outcomes of adult medulloblastoma patients treated with radiotherapy.

Medulloblastoma (MB) is rare in adults and treatment guidelines are consequently not well-established. Few modern series have reported long-term follow-up and treatment sequelae. We examined long-term outcomes of adult MB patients at one institution. Records of 29 consecutive patients (18 male, 11 female) aged ≥ 18 years who received radiotherapy (RT) for primary MB from 1990 to 2016 were reviewed. Median age at diagnosis was 28 years (range 18-72 years). Seventeen patients were standard risk and 12 were high risk. Nineteen patients had gross total resection, seven had subtotal resection, and three had biopsy only. Median craniospinal irradiation and boost doses were 36 Gy (range 23.4-39.6 Gy) and 55.8 Gy (range 54-59.4 Gy), respectively. Of 24 patients receiving chemotherapy, 20 received concurrent + adjuvant and 4 received adjuvant only. At median follow-up of 9.0 years (range 1.1-20.5 years), five patients recurred: four in the posterior fossa and one in both the posterior fossa and above the tentorium. Five patients died: two of disease progression and three after possible treatment complications (seizure, lobar pneumonia, and multifactorial sepsis). At last follow-up, 23 patients were alive with no evidence of disease. Long-term effects include executive dysfunction (n = 17), weakness/ataxia (n = 16), and depression/anxiety (n = 13). Kaplan-Meier estimates of 10-year overall survival and failure-free survival are 83% (95% confidence interval [CI] 59-93%) and 79% (CI 55-91%), respectively. Despite encouraging disease control in this cohort, long-term sequelae may limit quality of life. Multimodality pediatric regimens using lower RT doses may be considered to reduce treatment-related morbidity.

A phase II study of radioimmunotherapy with intraventricular 131 I-3F8 for medulloblastoma.

BACKGROUND: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6-12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3-55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024). CONCLUSIONS: cRIT with 131 I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.

Twenty-Year Outcome Experience With Open Craniosynostosis Repairs: An Analysis of Reoperation and Complication Rates.

BACKGROUND: Surgical intervention during infancy for both syndromic and nonsyndromic patients with craniosynostosis remains the criterion standard of treatment with the 2 main options being open vault remodeling versus minimally invasive surgery. Although open cranial vault remodeling was initially considered a high-risk procedure, many advances have improved its safety. Despite this, there is a paucity of literature on the long-term outcomes of contemporary open craniosynostosis repair. METHODS: A retrospective review of all patients who underwent primary open cranial vault repair for craniosynostosis by a single surgeon (J.A.A.) at New York-Presbyterian Hospital from 1995 to 2015 was performed. RESULTS: For primary open repair, 81 patients (46 males, 35 females) were analyzed, and affected sutures included unicoronal (28), bicoronal (7), metopic (24), sagittal (11), lambdoid (2), and multisuture (9). Fourteen patients (17.3%) were syndromic. Mean (SD) operative patient age was 13.81 (16.24) months: 34 (42%) were 0 to 6 months; 26 (32%), 7 to 12 months; and 21 (26%), 12 months of age or older. There were no intraoperative complications. Mean (SD) estimated blood loss for the plastic surgery portion of all cases was 74.53 (72.34) mL, and total estimated blood loss was 174.93 (182.23) mL. Mean (SD) hospital length of stay was 4.31 (1.59) days. One syndromic patient was readmitted for a wound infection (1.2%) that was successfully treated with antibiotics, and 2 syndromic patients (2.5%) had reoperation for fronto-orbital readvancement. CONCLUSIONS: This 20-year experience demonstrates the safety of modern open craniosynostosis repairs at a large academic medical center with low rates of mortality (0%), complications (1.2%), and reoperations (2.5%).

Reduced-volume radiotherapy for patients with localized intracranial nongerminoma germ cell tumors.

Craniospinal irradiation is standard radiotherapy (RT) for localized intracranial nongerminoma germ cell tumors (NGGCT). Given its toxicity, there is interest in using smaller fields. We examined outcomes of NGGCT patients receiving reduced-volume RT at a single institution. Records of 16 patients who received reduced-volume RT as part of definitive treatment between 1996 and 2016 were reviewed. Median age at presentation was 10.8 years (range 4.6-41.0 years). Ten patients had pineal tumors and 6 had suprasellar tumors. All received chemotherapy and 9 patients received second-look surgery thereafter. RT volume was tumor-only to a median of 54 Gy (range 50.4-54 Gy) in 3 patients and whole-ventricle irradiation to a median of 30.6 Gy (range 30.6-36 Gy) with a boost to 54 Gy in 13 patients. Median follow-up was 4.1 years (range 1.9-19.3 years). Three patients recurred locally at a median 9.9 months (range 9.6-10.6 months) after diagnosis, and one of these developed leptomeningeal relapse after 30 months. One patient expired from disease 2.6 years post-diagnosis and another due to stroke 19.3 years post-diagnosis. Fourteen patients are alive with no evidence of disease. Kaplan-Meier estimates of the 4-year overall survival and failure-free survival are 92% (95% confidence interval [CI], 57-99%) and 81% (95% CI 53-94%), respectively. Excellent disease control was observed in these patients with no initial relapses outside of these RT fields. The results of ACNS1123 may better delineate patterns of failure and identify subgroups likely to benefit from this approach.

Glioblastoma spheroids produce infiltrative gliomas in the rat brainstem.

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is universally fatal without proven therapy other than radiation therapy for palliation. Representative animal models will play an essential role in the preclinical stage of future therapy development. To address the shortage of representative models, we created a novel infiltrative brainstem glioma model in rats based on glioblastoma spheroids. METHODS: Cells dissociated from glioblastoma spheroids grown from surgical specimens were implanted into the brainstem of NIH nude rats. Animals were serially assessed clinically and radiographically with magnetic resonance imaging (MRI). Tumors were further characterized using histology, immunohistochemistry, and cytogenetics. RESULTS: Tumor generation was successful in all animals receiving glioblastoma spheroid cells. The rats survived 17-25 weeks before severe symptoms developed. The tumors showed as diffuse hyperintense lesions on T2-weighted images. Histologically, they demonstrated cellular heterogeneity, and infiltrative and invasive features, with cells engorging vascular structures. The tumors were shown to comprise immature human origin glial tumor cells, with human epidermal growth factor receptor (EGFR) gene amplification and gain. CONCLUSIONS: This study showed that cells from glioblastoma spheroids produced infiltrative gliomas in rat brainstem. The rat brainstem gliomas are radiographically and histologically accurate compared to DIPG. These tumors develop over several months that would allow sequential clinical and radiographic assessments of therapeutic interventions. This study demonstrated in principle the feasibility of developing patient-specific animal models based on putative cancer stem cells from biopsy or resection samples.

Advances in Molecular Imaging of Locally Delivered Targeted Therapeutics for Central Nervous System Tumors.

Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood-brain barrier (BBB) renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED)) to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a "wait-and-see" approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS) malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents.

Low incidence of radionecrosis in children treated with conventional radiation therapy and intrathecal radioimmunotherapy.

Radionecrosis is a potentially devastating complication of external beam radiotherapy (XRT). Intraventricular compartmental radioimmunotherapy (cRIT) using (131)I-3F8 or (131)I-8H9 can eradicate malignant cells in the CSF. The incidence of radionecrosis using cRIT (131)I based intraventricular radioimmunotherapy, when used alone or in combination with conventional craniospinal CSI-XRT is unknown. We retrospectively analyzed the incidence of radionecrosis in two cohorts of pediatric patients treated with both CSI-XRT and cRIT at MSKCC since 2003: patients with metastatic CNS neuroblastoma (NB) and medulloblastoma (MB). 94 patients received both CSI-XRT and cRIT, two received cRIT alone, median follow up 41.5 months (6.5-124.8 months). Mean CSI-XRT dose was 28 Gy (boost to the primary tumor site up to 54 Gy) in the MB cohort, and CSI XRT dose 18-21 Gy (boost to 30 Gy for focal parenchymal mass) in the NB cohort. For MB patients, 20 % had focal re-irradiation for a second or more subsequent relapse, mean repeat-XRT dose was 27.5 Gy; seven patients with NB had additional focal XRT. Median CSF cRIT dose was 18.6 Gy in the MB cohort and 32.1 in the NB cohort. One asymptomatic patient underwent resection of 0.6-cm hemorrhagic periventricular white-matter lesion confirmed to be necrosis and granulation tissue, 2.5 years after XRT. The risk of radionecrosis in children treated with XRT and cRIT appears minimal (~1 %). No neurologic deficits secondary to radionecrosis have been observed in long-term survivors treated with both modalities, including patients who underwent re-XRT. Administration of cRIT may safely proceed in patients treated with conventional radiotherapy without appearing to increase the risk of radionecrosis.