Convection-enhanced delivery (CED) is a technique designed to deliver
drugs directly into the brain or tumors. Its ability to bypass the blood-brain barrier
(BBB), one of the major hurdles in ...delivering drugs to the brain, has made it a
promising drug delivery method for the treatment of primary brain tumors. A number
of clinical trials utilizing CED of various therapeutic agents have been conducted to
treat patients with supratentorial high-grade gliomas. Significant responses have been
observed in certain patients in all of these trials. However, the insufficient ability to
monitor drug distribution and pharmacokinetics hampers CED from achieving its
potentials on a larger scale. Brainstem CED for diffuse intrinsic pontine glioma
(DIPG) treatment is appealing because this tumor is compact and has no definitive
treatment. The safety of brainstem CED has been established in small and large animals, and recently in
early stage clinical trials. There are a few current clinical trials of brainstem CED in treating DIPG patients
using targeted macromolecules such as antibodies and immunotoxins. Future advances for CED in DIPG
treatment will come from several directions including: choosing the right agents for infusion; developing
better agents and regimen for DIPG infusion; improving instruments and technique for easier and accurate
surgical targeting and for allowing multisession or prolonged infusion to implement optimal time sequence;
and better understanding and control of drug distribution, clearance and time sequence. CED-based
therapies for DIPG will continue to evolve with new understanding of the technique and the disease.
Neuroendoscopy has progressed remarkably in the past few decades. Ventriculoscopy, skull base endoscopy, and spinal endoscopy are now part of routine practice in the neurosurgical treatment of ...numerous pathologies. Like other developing fields, however, it faces numerous challenges and obstacles that must be overcome for the field to continue to evolve and expand. This brief review of new and exciting developments in neuroendoscopy describes some of the most interesting directions the field is starting to steer towards.
OBJECTIVE Craniopharyngiomas can be difficult to remove completely based on their intimate relationship with surrounding visual and endocrine structures. Reoperations are not uncommon but have been ...associated with higher rates of complications and lower extents of resection. So radiation is often offered as an alternative to reoperation. The endonasal endoscopic transsphenoidal approach has been used in recent years for craniopharyngiomas previously removed with craniotomy. The impact of this approach on reoperations has not been widely investigated. METHODS The authors reviewed a prospectively acquired database of endonasal endoscopic resections of craniopharyngiomas over 11 years at Weill Cornell Medical College, NewYork-Presbyterian Hospital, performed by the senior authors. Reoperations were separated from first operations. Pre- and postoperative visual and endocrine function, tumor size, body mass index (BMI), quality of life (QOL), extent of resection (EOR), impact of prior radiation, and complications were compared between groups. EOR was divided into gross-total resection (GTR, 100%), near-total resection (NTR, > 95%), and subtotal resection (STR, < 95%). Univariate and multivariate analyses were performed. RESULTS Of the total 57 endonasal surgical procedures, 22 (39%) were reoperations. First-time operations and reoperations did not differ in tumor volume, radiological configuration, or patients' BMI. Hypopituitarism and diabetes insipidus (DI) were more common before reoperations (82% and 55%, respectively) compared with first operations (60% and 8.6%, respectively; p < 0.001). For the 46 patients in whom GTR was intended, rates of GTR and GTR+NTR were not significantly different between first operations (90% and 97%, respectively) and reoperations (80% and 100%, respectively). For reoperations, prior radiation and larger tumor volume had lower rates of GTR. Vision improved equally in first operations (80%) compared with reoperations (73%). New anterior pituitary deficits were more common in first operations compared with reoperations (51% vs 23%, respectively; p = 0.08), while new DI was more common in reoperations compared with first-time operations (80% vs 47%, respectively; p = 0.08). Nonendocrine complications occurred in 2 (3.6%) first-time operations and no reoperations. Tumor regrowth occurred in 6 patients (11%) over a median follow-up of 46 months and was not different between first versus reoperations, but was associated with STR (33%) compared with GTR+NTR (4%; p = 0.02) and with not receiving radiation after STR (67% vs 22%; p = 0.08). The overall BMI increased significantly from 28.7 to 34.8 kg/m
over 10 years. Six months after surgery, there was a significant improvement in QOL, which was similar between first-time operations and reoperations, and negatively correlated with STR. CONCLUSIONS Endonasal endoscopic transsphenoidal reoperation results in similar EOR, visual outcome, and improvement in QOL as first-time operations, with no significant increase in complications. EOR is more impacted by tumor volume and prior radiation. Reoperations should be offered to patients with recurrent craniopharyngiomas and may be preferable to radiation in patients in whom GTR or NTR can be achieved.
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 therapy
, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease
. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging
, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost
. 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 IDH2
, 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.
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.
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.
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.
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.
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.
Convection-enhanced delivery (CED) has been introduced into contemporary therapeutic strategies for incurable brain neoplasms as diffuse intrinsic pontine glioma. Therapeutic benefit in part is ...predictably dependent on drug distribution within tumors. However, therapeutics can rarely be detected through conventional imaging techniques. Coinfusion of the tracer gadolinium-diethylenetriaminepentacetate (Gd-DTPA) has been advocated to monitor drug distributive features including volume, tumor coverage, and efflux during and after administration. The kinetics of Gd-DTPA are unclear as longitudinal magnetic resonance imaging is rarely performed. Understanding these changes would have important implications related to the timing of diagnostic imaging and reliance on tracers as surrogates of pharmacokinetic drug monitoring.
The behavior of Gd-DTPA as a surrogate is presented in a time-dependent fashion as measured by repeated magnetic resonance imaging based on the case of a child with recurrent diffuse intrinsic pontine glioma treated with an oncolytic virus (ICOVIR-5) delivered by CED with coinfused Gd-DTPA (1 mM, for a volume of 2000 μL). Initial Vd/Vi was 1.46. Gd-DTPA was observed up to 18 hours post CED but not thereafter.
This longitudinal imaging assessment provides a rare opportunity to better characterize the kinetics of surrogate tracers delivered by CED to the brainstem, highlighting the importance of immediate and longitudinal monitoring.
Leptomeningeal disease (LMD) in pediatric brain tumors (PBTs) is a poorly understood and categorized phenomenon. LMD incidence rates, as well as diagnosis, treatment, and screening practices, vary ...greatly depending on the primary tumor pathology. While LMD is encountered most frequently in medulloblastoma, reports of LMD have been described across a wide variety of PBT pathologies. LMD may be diagnosed simultaneously with the primary tumor, at time of recurrence, or as primary LMD without a primary intraparenchymal lesion. Dissemination and seeding of the cerebrospinal fluid (CSF) involves a modified invasion-metastasis cascade and is often the result of direct deposition of tumor cells into the CSF. Cells develop select environmental advantages to survive the harsh, nutrient poor and turbulent environment of the CSF and leptomeninges. Improved understanding of the molecular mechanisms that underlie LMD, along with improved diagnostic and treatment approaches, will help the prognosis of children affected by primary brain tumors.
Diffuse intrinsic pontine glioma (DIPG) is a childhood brainstem tumor with a universally poor prognosis. Here, we characterize a positron emission tomography (PET) probe for imaging DIPG
In human ...histological tissues, the probes target, PARP1, was highly expressed in DIPG compared to normal brain. PET imaging allowed for the sensitive detection of DIPG in a genetically engineered mouse model, and probe uptake correlated to histologically determined tumor infiltration. Imaging with the sister fluorescence agent revealed that uptake was confined to proliferating, PARP1-expressing cells. Comparison with other imaging technologies revealed remarkable accuracy of our biomarker approach. We subsequently demonstrated that serial imaging of DIPG in mouse models enables monitoring of tumor growth, as shown in modeling of tumor progression. Overall, this validated method for quantifying DIPG burden would serve useful in monitoring treatment response in early phase clinical trials.
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Neuroendoscopy: The State of the Art Tosi, Umberto; Guadix, Sergio W.; Souweidane, Mark M.
World neurosurgery,
October 2023, 2023-10-00, 20231001, Volume:
178
Journal Article
Peer reviewed
Open access
Over the past century, neuroendoscopy developed into a mainstay of neurosurgical practice, allowing for minimally invasive approaches to the ventricles, skull base, and spine. Its development, ...however, is far from over. Current challenges are inherent in the very feature that renders neuroendoscopy appealing—the small channels of the modern endoscope allow surgery to be performed with minimal tissue retraction, but they also make hemostasis and resection of large masses difficult. New optics allow for significantly improved image quality; yet open craniotomy often allows for 3-dimensional visualization and bimanual dissection and is part of everyday neurosurgical training. Finally, the utilization of neuroendoscopy remains limited, presenting ongoing challenges for neurosurgical teaching and achievement of technical mastery.
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