Daniels, David J.

OBJECTIVE Intracranial germ cell tumors (iGCTs) often arise at the neurohypophysis, their second most common origination, following the pineal region. Neurohypophyseal iGCTs present with stereotypical symptoms, including pituitary dysfunction and visual field deficit, due to their suprasellar location. The goal of this study was to present a large, longitudinal single-institution experience with neurohypophyseal iGCTs to better understand their natural history and identify opportunities for further improvement in treatment outcomes. METHODS This is a retrospective, single-institution cohort study of neurohypophyseal iGCTs treated between 1988 and 2017, with a focus on the epidemiology, presentation, natural history, and treatment. RESULTS Thirty-five neurosurgically managed patients met inclusion criteria; the median age was 18 years (3 months to 49 years), and 74% of patients were male (n = 26). Thirty-one tumors were germinomas, and 4 were nongerminomatous iGCTs. Presenting symptoms included pituitary insufficiency in 76% (n = 25), visual deficit in 45% (n = 15), and diabetes insipidus (DI) in 61% (n = 20) of patients. Index symptoms included isolated DI in 10 (36%), isolated hormone deficiency in 14 (50%), and concomitant DI and hormone deficiency symptoms in 4 (14%). Radiographic diagnostic latency was common, occurring at a median of 363 days (range 9–2626 days) after onset of the first symptoms and was significantly associated with both DI and hormone deficiency as the index symptoms (no DI vs DI: 360 vs 1083 days, p = 0.009; no hormone deficiency vs hormone deficiency: 245 vs 953 days, p = 0.004). Biochemical abnormalities were heterogeneous; each pituitary axis was dysfunctional in at least 1 patient, with most patients demonstrating at least 2 abnormalities, and pretreatment dysfunction demonstrating a nonsignificant trend toward association with long-term posttreatment hormone supplementation. Among germinomas, whole-brain or whole-ventricle radiotherapy demonstrated significantly improved progression-free and overall survival compared with local therapy (p = 0.009 and p = 0.004, respectively). CONCLUSIONS Neurohypophyseal iGCTs are insidious tumors that may pose a diagnostic dilemma, as evidenced by the prolonged latency before radiographic confirmation. Serial imaging and close endocrine follow-up are recommended in patients with a characteristic clinical syndrome and negative imaging, due to the propensity for radiographic latency. Pretreatment biochemical abnormalities may indicate higher risk of posttreatment pituitary insufficiency, and all patients should receive careful endocrine follow-up. Local radiotherapy is prone to treatment failure, while whole-ventricle treatment is associated with improved survival in germinomas.

Abstract Background Successful management of pediatric low-grade glioma (pLGG) can be complicated by eloquent anatomical location, as well as specific pathologic and molecular features. Some authors have proposed using the VEGF inhibitor bevacizumab to improve disease control, but its safety and efficacy are poorly defined. Correspondingly, our aim was to pool systematically identified clinical data in the literature to assess the clinical utility of bevacizumab for pLGG at progression. Methods A systematic search of 7 electronic databases from inception to June 2019 was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Articles were screened against prespecified criteria. Outcomes were then pooled by random-effects meta-analyses of proportions. Results Seven pertinent studies described the outcomes of 110 progressive pLGG patients managed with bevacizumab in largely multiagent regimens. While on treatment, the rate of clinical response was 58% (95% CI, 43%-72%), and the rate of response on imaging was 80% (95% CI, 58%-96%). The rate of grade 3 or higher toxicity was 8% (95% CI, 2%-17%), with proteinuria the most commonly described. In the off-treatment period up to median 1 year, the rate of progression was estimated to be 51% (95% CI, 28%-74%). Conclusions Bevacizumab has the potential to control clinical and radiographic disease with relatively low grade 3 or higher toxicity risk in progressive pLGG patients. However, the long-term off-treatment benefits of this therapy are not yet well defined. Heterogeneity in the literature precludes any formal recommendations regarding its use until larger, more standardized investigations can be performed.

OBJECTIVE Central nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms that arise predominantly in adolescents and young adults. CNS GCTs demonstrate characteristic trends in national associations, with implications for both tumor incidence and genetics. Although the incidence of CNS GCTs is markedly higher in East Asia than Western countries, direct comparative analyses between these CNS GCT populations are limited. METHODS In Japan, to facilitate the genomic analyses of CNS GCTs, the Intracranial Germ Cell Tumor Genome Analysis Consortium was established in 2011, and more than 200 cases of GCTs are available for both tumor tissue and clinical data, which is organized by the National Cancer Center (NCC) Japan. At the Mayo Clinic, there have been 98 cases of intracranial GCTs treated by the Department of Neurologic Surgery since 1988. In this paper, the authors compared the epidemiology, clinical presentation including location and histology, and prognosis between cases treated in the US and Japan. RESULTS There was no significant difference in age and sex distributions between the databases. However, there was a significant difference in the tumor locations; specifically, the frequency of basal ganglia was higher in the NCC database compared with the Mayo Clinic (8.4% vs 0%, p = 0.008), and bifocal location (neurohypophysis and pineal gland) was higher at the Mayo Clinic than at the NCC (18.8% vs 5.8%, p = 0.002). There was no difference in histological subdivisions between the databases. There was no difference in progression-free survival (PFS) and overall survival (OS) of germinoma cases and OS of nongerminomatous GCT (NGGCT) cases treated with chemotherapy and radiation therapy covering whole ventricles. However, PFS of NGGCTs differed significantly, and was better in the NCC cohorts (p = 0.04). CONCLUSIONS There appears to be a differential distribution of GCTs by neuroanatomical location between major geographic and national groups. Further study is warranted to better characterize any underlying genomic, epigenetic, or environmental factors that may be driving the phenotypic differences.

OBJECTIVE Convection-enhanced delivery (CED) and osmotic pump delivery both have been promoted as promising techniques to deliver drugs to pediatric diffuse intrinsic pontine gliomas (DIPGs). Correspondingly, the aim of this study was to understand how infusate molecular weight (MW), duration of delivery, and mechanism of delivery (CED or osmotic pump) affect volume of distribution (V d ) in the brainstem, to better inform drug selection and delivery in future DIPG investigations. METHODS A series of in vivo experiments were conducted using rat models. CED and osmotic pump delivery systems were surgically implanted in the brainstem, and different MW fluorescent dextran beads were infused either once (acute) or daily for 5 days (chronic) in a volume infused (V i ). Brainstems were harvested after the last infusion, and V d was quantified using serial sectioning and fluorescence imaging. RESULTS Fluorescence imaging showed infusate uptake within the brainstem for both systems without complication. A significant inverse relationship was observed between infusate MW and V d in all settings, which was distinctly exponential in nature in the setting of acute delivery across the 570-Da to 150-kDa range. Chronic duration and CED technique resulted in significantly greater V d compared to acute duration or osmotic pump delivery, respectively. When accounting for V i , acute infusion yielded significantly greater V d /V i than chronic infusion. The distribution in CED versus osmotic pump delivery was significantly affected by infusate MW at higher weights. CONCLUSIONS Here the authors demonstrate that infusate MW, duration of infusion, and infusion mechanism all impact the V d of an infused agent and should be considered when selecting drugs and infusion parameters for novel investigations to treat DIPGs.

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG. METHODS Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies. RESULTS A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8–14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78–95%) and 69% (95% CI, 52–84%) respectively. The incidence of acute serious toxicity was 0% (95% CI, 0–4%). Pooled overall survivals from initial diagnosis, and time of reRT, were 18.0 months (95% CI, 14.2–21.7) and 6.2 months (95% CI, 5.5–7.0) respectively. CONCLUSIONS Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely a sub-cohort of all DIPG diagnoses will be most amenable to improved prognosis with reRT, and greater investigation is required to identify their characteristics.

Abstract Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors without cure. One of the major challenge sin DIPG treatment is the effective delivery of therapeutic agents across the blood-brain barrier (BBB) to the tumor and surrounding infiltrating cells. Therefore, strategies that enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a technique that bypasses the BBB and increases drug distribution by applying hydraulic pressure to deliver compounds directly and evenly into a target region. However, knowledge in CED pharmacology and convective kinetics is still lacking. In an effort to characterize the feasibility, safety, and distribution in the brain based on molecular size of the delivered agent, we performed infusions of FITC-dextran (range 3,000 Da–150,000 Da) comparing CED and osmotic pump-based delivery into the brainstem of rodents. We calculated the area and volume of distribution (Vd) of the FITC-dextran throughout the brain. Our data showed that the Vd decreased exponentially with increased molecular weight of the FITC-dextran. Interestingly, the Vdcan maintain linearity at lower molecular weights. Maximal cross-sectional area and craniocaudal extension of fluorescence also decreased when lowering the infusate size. In addition, we developed a patient-derived DIPG orthotopic xenograft model and performed an image-guided CED cannula installation in the tumor bed. Using 3D bioluminescence imaging and computed tomography, we determined the tumor volume and the positioning of the cannula in the bulk tumor. The summation of these results supports CED as a promising technique for treating DIPG tumors. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens and, ultimately, offers hope to patients and families with this devastating disease.

Abstract BACKGROUND Diffuse midline gliomas harboring the H3K27M mutation, previously known as diffuse intrinsic pontine gliomas (DIPG), are rare and aggressive pediatric brain tumors. Over 100 clinical trials with different chemotherapeutics have failed to show any therapeutic benefit. One reason for failure is likely due to poor delivery of these agents to the brainstem. Convection-enhanced delivery (CED) is an emerging delivery technique used to directly inject the agent of interest into the brainstem under pressure. While there is evidence that this may be an effective delivery method, little work has been done to understand the optimal physical properties of these drugs. We sought characterize volume of distribution in the brain based on molecular size of the agent delivered via CED. METHODS Sprague- Dawley rats underwent a single injection of FITC-dextran (3,000 Da, 10,000 Da, 20,000 Da, 70,000 Da, 150,000 Da) via CED into the pons. Post-injection, animals were sacrificed and their brains harvested. Fluorescent microscopy imaging was used to calculate the volume of distribution of the FITC-dextran throughout the brain. RESULTS The volume of distribution (Vd) decreased exponentially according to a two-phase delay (r2= 0.94) as the molecular size of the FITC-dextran increased. The highest mean Vd (107.87mm3) was at a molecular weight of 3,000 Da, and lowest mean Vd (26.48 mm3) was at a molecular weight of 150,000 Da. ANOVA analysis was statistically significant (p= 0.0017). CONCLUSIONS As the molecular size of the FITC-dextran increased, the volume of distribution within the brain following a single injection via CED into the pons decreased. A better understanding of how drugs distribute by convection will allow us to optimize treatment regimens for DIPG tumors.

Abstract BACKGROUND Diffuse intrinsic pontine gliomas (DIPG), known today as diffuse midline gliomas with the H3K27M mutation, are inoperable and aggressive brain tumors found predominantly in children. Despite extensive research no treatment or cure has been elucidated. Studies in 2012 showed that the majority of DIPG tumors have the H3K27M mutation, but the development of novel therapeutics has been hindered by lack of good laboratory models. Although patient derived cell lines with the H3K27M mutation have increased, the development of good murine xenografts are lagging, requiring extensive time and money. Previous studies have shown that the chicken embryo Chorioallantoic Membrane (CAM) model is an affordable and time-efficient method of studying tumor biology and response to treatment. We sought to develop this in H3K27M tumors to bridge the gap between in vitro—in vivo studies. METHODS Three patient-derived H3K27M cell lines were cultured and implanted on the chick embryo CAM on day 9 post-fertilization. Tumors underwent multiple drug treatment with 0.5uM or 2.0uM Alisertib (days 11, 13, 15) or a single targeted radiation treatment at 2 Grey (day 13). Tumor volume was assessed via ultrasound on day 16. The tumor specimens were harvested and analyzed by immunohistochemistry. RESULTS Patient-derived DIPG cells implanted on the CAM maintain their molecular characteristics and form tumors on the surface of the CAM as evidenced by H&E and H3K27M status. Statistically significant differences in volume were found in three H3K27M DIPG lines in Alisertib treated tumors compared to the control (p< 0.001, p< 0.001, p= 0.005). Statistically significant differences in tumor volume were found when treating two DIPG lines with targeted radiation therapy compared to controls (p= 0.01, p= 0.02). CONCLUSIONS These results validated the CAM assay as a reliable xenograft model for studying DIPG tumor biology and determining efficacy of drug and radiation treatment.