A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma.

PURPOSE: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. PATIENTS AND METHODS: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. RESULTS: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7). CONCLUSIONS: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

Incidental brain tumors in children: an international neurosurgical, oncological survey.

PURPOSE: Incidental pediatric brain tumors (IPBT) are increasingly being diagnosed. Currently, there is no consensus regarding the need and timing of their treatment. In the current study, we identify trends among pediatric neurosurgeons and oncologists with regard to IPBT management and approval of growth hormone replacement therapy (GHRT). METHODS: A questionnaire presenting six different cases of IPBT was emailed to all members of several leading societies in pediatric neurosurgery and oncology. Collected data included basic information concerning the responders (profession, experience, continent of practice), as well as responses to multiple questions regarding treatment of the lesion, permission to supply GHRT, and free text for comments. RESULTS: One hundred forty-three responses were eligible for analysis (92 neurosurgeons, 51 oncologists, from a total of 6 continents). Initial recommendations for each case were heterogeneous. However, a few consistent trends were identified: Lesions that were stable over time lead to a common shift in treatment recommendation to a more conservative one. Growing lesions were commonly treated more aggressively. Neither profession nor experience had a consistent impact on recommendations. CONCLUSIONS: Management recommendations for IPBT varied among the responders and seem to be influenced by many factors. However, stable lesions lead to a shift in management towards a "watch and wait" approach, while in growing lesions responders tended towards a "biopsy" or "resection" approach. This highlights the need for better understanding of the natural course of incidental brain tumors in children, as well as evaluating the potential risk for malignant transformation.

The use of a stent-retriever to cause mechanical dilatation of a vasospasm secondary to iatrogenic subarachnoid haemorrhage.

Objective To report the use of a stent-retriever in the management of vasospasm secondary to craniopharyngioma resection. Postoperative improvement was seen both clinically and on perfusion imaging. Methods A patient was admitted for resection of a large craniopharygioma. On day 6 postoperatively the patient had an acute hemiparesis. A computed tomography angiogram and perfusion scan demonstrated acute right-sided cerebral vasospasm and a perfusion defect in the territory of the middle cerebral artery (MCA). Results A pREset 4 × 20 mm stent-retriever was used to dilate the M1 and proximal M2 segments of the right MCA mechanically. This resulted in immediate dilatation of the spastic segment and improvement in the transit time on the angiogram. There was an improvement in the clinical status post-procedure and a computed tomography perfusion performed 24 hours after the procedure showed symmetrical perfusion. A computed tomography angiogram and magnetic resonance imaging performed 1 week later showed a symmetrical appearance to the MCA and no evidence of restricted diffusion. Conclusion The use of commercially available stent-retrievers can cause mechanical dilatation of vasospastic vessels. The stents do not need to be deployed for a prolonged period nor do they need to be implanted to have a prolonged dilatory effect on the spastic vessels.

The Assessment of Distortion in Neurosurgical Image Overlay Projection.

BACKGROUND: Numerous studies have demonstrated the superiority of neuronavigation during neurosurgical procedures compared to non-neuronavigation-based procedures. Limitations to neuronavigation systems include the need for the surgeons to avert their gaze from the surgical field and the cost of the systems, especially for hospitals in developing countries. Overlay projection of imaging directly onto the patient allows localization of intracranial structures. A previous study using overlay projection demonstrated the accuracy of image coregistration for a lesion in the temporal region but did not assess image distortion when projecting onto other anatomical locations. Our aim is to quantify this distortion and establish which regions of the skull would be most suitable for overlay projection. METHODS: Using the difference in size of a square grid when projected onto an anatomically accurate model skull and a flat surface, from the same distance, we were able to calculate the degree of image distortion when projecting onto the skull from the anterior, posterior, superior, and lateral aspects. Measuring the size of a square when projected onto a flat surface from different distances allowed us to model change in lesion size when projecting a deep structure onto the skull surface. RESULTS: Using 2 mm as the upper limit for distortion, our results show that images can be accurately projected onto the majority (81.4%) of the surface of the skull. CONCLUSION: Our results support the use of image overlay projection in regions with ≤2 mm distortion to assist with localization of intracranial lesions at a fraction of the cost of existing methods.