Abstract INTRODUCTION Congenital intracranial neoplasms are a heterogeneous group of lesions that account for <2% of pediatric CNS tumors. Current understanding of histopathologic and survival ...outcomes in this population is limited. METHODS Pediatric patients (<3-years) with congenital neoplasms were retrospectively evaluated across five institutions. Demographic, prenatal care, clinical presentation, histopathologic characteristics, operative and adjuvant therapies, and survival outcomes were collected. RESULTS 323 patients met inclusion. The mean age at diagnosis was 1.5-years. Six patients were conceived through IVF. Eleven families reported abnormal prenatal ultrasounds, although only six were diagnosed prenatally. The most common histopathologies included low-grade astrocytoma (30.6%), ependymoma (15.8%), ATRT (11.5%), medulloblastoma (8.0%), and high-grade astrocytoma (2.8%). 48.9% of patients had low-grade neoplasms, and a third of patients (33.1%) had high-grade tumors. Patients commonly presented with hydrocephalus (59.1%), emesis (34.7%), ocular abnormalities (20.4%), macrocrania (18.0%), lethargy (14.6%), developmental delays (12.7%), and irritability (11.8%). All patients received surgical resection: 55.4% received gross-total (GTR) and 20.4% received subtotal resection. Concurrent treatment with adjuvant therapies occurred in a subset of patients, with 52.9% of patients receiving chemotherapy, 27.2% undergoing radiation, and 6.2% participating in a clinical trial. Patients with low-grade tumors had a rate of 88% progression-free (PFS) at 1-year, 74% PFS at 3-years, and 64% PFS at 5-years post-operative. Patients with high-grade neoplasms had worse PFS, with estimates at 59%, 40%, and 37% at 1-, 3-, and 5-years, respectively. There was statistically significant differences in PFS between patients with high- and low-grade neoplasms (p<0.0001). CONCLUSIONS This series consisted of very young pediatric patients across five participating institutions with diverse histopathologies that vary in frequency relative to the entire pediatric population. Lesions were rarely detected prenatally, despite their young age at diagnosis. GTR occurred in half of patients and subsequent management with adjuvant therapies was common in both sub-totally resected low-grade lesions and high-grade tumors.
Isolated sagittal synostosis is a common form of craniosynostosis affecting roughly 1 in 5,000 children at birth. This results in a scaphocephalic head shape with a characteristically elongated ...anterior-posterior dimension and narrowed biparietal diameter. We present our experience with the correction of scaphocephaly due to sagittal synostosis using cranial vault reconstruction with a novel form of parietal bone fixation in 21 patients over 10 years. The medial fixation results in a hinging effect whereby transverse brain growth at the squamoid suture is enhanced. This results in excellent cosmetic results that are immediate and durable without the need for postoperative molding helmets. Furthermore, the complications associated with this procedure are limited.
The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the ...nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated
-methylguanine DNA methyltransferase (
) promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.
Slit ventricle syndrome (SVS) has been described in hydrocephalus patients who continue to have shunt malfunction-like symptoms in the presence of a functioning shunt system and small ventricles on ...imaging studies. These symptoms usually present years after shunt placement or revision and can consist of headache, nausea and vomiting, lethargy and decreased cognitive skills. Treatments offered range from observation, medical therapy (migraine treatment) and shunt revision to subtemporal decompression or cranial vault expansion. We describe a subset of patients with SVS who were symptomatic with high intracranial pressure (ICP) as measured by sedated lumbar puncture and whose symptoms completely resolved after lumboperitoneal shunt (LPS) placement.
Seven patients with a diagnosis of SVS underwent lumboperitoneal shunting. The age at shunting ranged from 3 to 18 years. Most had undergone recent ventriculoperitoneal shunt (VPS) revisions for presentation of shunt malfunction-like symptoms. Despite this, all remained symptomatic and underwent a sedated lumbar puncture to measure opening pressure (OP). All had high OP in spite of a functional VPS and underwent LPS placement.
All 7 patients had a prolonged period of overdrainage symptoms after lumboperitoneal shunting that resolved completely over several weeks. The initial etiology of hydrocephalus was reported to include trauma, aqueductal stenosis and intraventricular hemorrhage of prematurity. Two patients required revision of their LPS, after which their symptoms again resolved.
In a certain subset of patients with SVS who are symptomatic from increased ICP, placement of an LPS is an effective treatment option. It appears that this subgroup of patients previously treated with ventriculoperitoneal shunting behave in a fashion similar to pseudotumor cerebri patients and respond well to lumboperitoneal shunting.
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults over 55years of age. The median age of diagnosis for patients with GBM is 64years old, with the incidence of patients ...between 75 and 85 increasing. The optimal treatment paradigm for elderly GBM patients continues to evolve due to the higher frequency of age-related and/or medical co-morbidities. Geriatric GBM patients have historically been excluded from larger, controlled clinical trials due to their presumed decreased likelihood of a sustained treatment response and/or a prolonged good outcome. Here, we highlight current treatment considerations of elderly GBM patients with respect to surgical, radiotherapeutic and systemic modalities, with considerations for improving future clinical outcomes for this patient population.
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•A substantial proportion of patients with glioblastoma are elderly, in turn, understanding their optimal management is important for physicians treating these patients.•Radiation alone is associated with longer survival compared to supportive care alone. A shorter course of radiation is often preferable in the elderly population.•Chemotherapy alone can be considered in this patient population.•A combination of short-course radiation and temozolomide chemotherapy is associated with longer overall survival and progression free survival compared to short-course radiation alone.•It will be important to understand the underlying biology of the disease in elderly patients as we investigate future treatment strategies including immunotherapeutic approaches.
Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most ...IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.
Despite aggressive multimodal treatment, survival for patients with glioblastoma remains dismal. One obstacle to improving patient outcomes is the difficulty in delivering adequate therapeutic to the ...central nervous system due to the presence of the blood–brain barrier. Although direct drug infusion by convection-enhanced delivery (CED) can bypass the blood–brain barrier and facilitate delivery to intracranial tumors, determining the distribution of delivered therapeutic remains problematic. Image guidance is a strategy that can optimize the accuracy of therapeutic delivery.
Here we performed an open-label clinical trial in 10 pet dogs with spontaneous intracranial tumors to examine the target coverage accuracy of delivering polymeric magnetite nanoparticles (PMNPs) encapsulating temozolomide (TMZ). A modified small animal frame was applied to the head of each subject, and PMNPs were delivered stereotactically to the center of the tumor. Magnetic resonance imaging (MRI) was performed immediately postoperatively to examine PMNP distribution, and the animals were followed until death.
Nine of the 10 dogs underwent PMNP infusion without complications. No infusate backflow was observed during any procedure. In 70% of the cases, the infusion accurately targeted the tumor mass, as determined by the presence of PMNP signal in the tumor on immediate postoperative MRI.
These data suggest that CED of PMNPs carrying TMZ is safe in dogs with intracranial tumors and can lead to nanoparticle distribution in the region of the target. Image guidance is an important adjunct to CED, because distribution is unpredictable, with the potential for missed target delivery.
•Spontaneous canine gliomas closely resemble human tumors.•Convection-enhanced delivery (CED) of polymeric nanoparticles is safe in dogs with supratentorial tumors.•Distribution of nanoparticles is not predictable following CED.•Following CED, imaging is essential to verify therapeutic agent distribution.
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM ...patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan.
Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy.
Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice.
This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.
•CED's non-uniform distribution geometry characterized using fluorescent nanoparticles.•DTI data of rat brain is used to perform simulations of a 0.5μL/min CED infusion.•Similar infusion parameters ...were used to perform in vivo rat experiments.•Simulations showed large variations in distribution patterns when catheter shifted 1mm.•In vivo infusions exhibited highly irregular distribution geometries despite small flow rates.
Convection-enhanced delivery (CED) has emerged as a promising technique for bypassing the blood–brain barrier to deliver therapeutic agents. However, animal studies and clinical trials that utilize the technique suggest that it may require further optimization before it can be safely used in humans. In particular, while volume of distribution in the target tissue can be controlled, the geometrical spread into a desired target region is highly variable from experiment to experiment. In the present paper we have sought to characterize the non-uniform distribution geometry using fluorescent nanoparticles in both a rat model and computer simulations.
Using diffusion tensor imaging MRI data of the rat brain, we performed computer simulations of a 0.5μL/min CED infusion. A step design catheter targeting the striatum was simulated to infuse 20μL of infusate. Using the same infusion parameters, we then performed in vivo CED experiments where we infused fluorescently labeled polyethylene glycol-polylactide-polycaprolactone nanoparticles (FPNPs) into the rat striatum. Fluorescence microscopy was used to examine the distribution geometry histologically.
The computer simulations demonstrated large variations in distribution patterns when catheter placement was shifted by only 1mm. Animal infusions also exhibited highly irregular and variable distribution geometries despite the use of relatively small flow rates.
Computer simulations and repeated in vivo infusions demonstrate the difficulty of achieving desired drug distribution in target tissue. We have proposed a calculation for sphericity which, along with the ubiquitous volume of distribution measure, may prove helpful in describing distribution geometry. Taken together, our results suggest that CED's limitations must be considered and further optimization may be required before the technique sees widespread use in humans.
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