Three-Dimensional Printed Modeling of Diffuse Low-Grade Gliomas and Associated White Matter Tract Anatomy.

BACKGROUND: Diffuse low-grade gliomas (DLGGs) represent several pathological entities that infiltrate and invade cortical and subcortical structures in the brain. OBJECTIVE: To describe methods for rapid prototyping of DLGGs and surgically relevant anatomy. METHODS: Using high-definition imaging data and rapid prototyping technologies, we were able to generate 3 patient DLGGs to scale and represent the associated white matter tracts in 3 dimensions using advanced diffusion tensor imaging techniques. RESULTS: This report represents a novel application of 3-dimensional (3-D) printing in neurosurgery and a means to model individualized tumors in 3-D space with respect to subcortical white matter tract anatomy. Faculty and resident evaluations of this technology were favorable at our institution. CONCLUSION: Developing an understanding of the anatomic relationships existing within individuals is fundamental to successful neurosurgical therapy. Imaging-based rapid prototyping may improve on our ability to plan for and treat complex neuro-oncologic pathology.

3D printing in neurosurgery: A systematic review.

BACKGROUND: The recent expansion of three-dimensional (3D) printing technology into the field of neurosurgery has prompted a widespread investigation of its utility. In this article, we review the current body of literature describing rapid prototyping techniques with applications to the practice of neurosurgery. METHODS: An extensive and systematic search of the Compendex, Scopus, and PubMed medical databases was conducted using keywords relating to 3D printing and neurosurgery. Results were manually screened for relevance to applications within the field. RESULTS: Of the search results, 36 articles were identified and included in this review. The articles spanned the various subspecialties of the field including cerebrovascular, neuro-oncologic, spinal, functional, and endoscopic neurosurgery. CONCLUSIONS: We conclude that 3D printing techniques are practical and anatomically accurate methods of producing patient-specific models for surgical planning, simulation and training, tissue-engineered implants, and secondary devices. Expansion of this technology may, therefore, contribute to advancing the neurosurgical field from several standpoints.

Management of Giant Cervical Teratoma with Intracranial Extension Diagnosed in Utero.

Cervical teratomas are rare germ cell tumors affecting the fetus that are associated with significant morbidity and mortality due to an increased risk of airway obstruction at delivery. These tumors can commonly produce polyhydramnios that results from the fetus' impaired ability to swallow amniotic fluid. Improved rates of prenatal diagnosis through comprehensive evaluations and imaging have dramatically impacted the perinatal management of infants with this condition. Here, we report a patient diagnosed with polyhydramnios whose fetus was discovered to have a giant cervical teratoma on imaging studies. The child underwent surgical resection after having the airway secured under the uteroplacental support as part of an ex utero intrapartum treatment procedure performed at 37 weeks. The following gross pathological and magnetic resonance images demonstrate this condition and its currently accepted treatment.

Three-Dimensional Printed Modeling of an Arteriovenous Malformation Including Blood Flow.

BACKGROUND: Arteriovenous malformations (AVMs) represent a complex pathologic entity in terms of their associated angioarchitecture and blood flow dynamics. METHODS: Using existing imaging data, we generated a patient's giant AVM to scale. RESULTS: A series of 3-dimensional (3D) models were generated and blood flow dynamics were represented. Faculty and resident surveys were positive regarding the technology. CONCLUSIONS: This report represents a novel application of 3D printing in neurosurgery and a means to model dynamic blood flow in 3 dimensions. The 3D printed models may improve on our ability to plan for and treat complex vascular pathologies.

Individualized Map of White Matter Pathways: Connectivity-Based Paradigm for Neurosurgical Planning.

BACKGROUND: Advances in white matter tractography enhance neurosurgical planning and glioma resection, but white matter tractography is limited by biological variables such as edema, mass effect, and tract infiltration or selection biases related to regions of interest or fractional anisotropy values. OBJECTIVE: To provide an automated tract identification paradigm that corrects for artifacts created by tumor edema and infiltration and provides a consistent, accurate method of fiber bundle identification. METHODS: An automated tract identification paradigm was developed and evaluated for glioma surgery. A fiber bundle atlas was generated from 6 healthy participants. Fibers of a test set (including 3 healthy participants and 10 patients with brain tumors) were clustered adaptively with this atlas. Reliability of the identified tracts in both groups was assessed by comparison with 2 experts with the Cohen κ used to quantify concurrence. We evaluated 6 major fiber bundles: cingulum bundle, fornix, uncinate fasciculus, arcuate fasciculus, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus, the last 3 tracts mediating language function. RESULTS: The automated paradigm demonstrated a reliable and practical method to identify white mater tracts, despite mass effect, edema, and tract infiltration. When the tumor demonstrated significant mass effect or shift, the automated approach was useful for providing an initialization to guide the expert with identification of the specific tract of interest. CONCLUSION: We report a reliable paradigm for the automated identification of white matter pathways in patients with gliomas. This approach should enhance the neurosurgical objective of maximal safe resections. ABBREVIATIONS: AF, arcuate fasciculusDTI, diffusion tensor imagingIFOF, inferior fronto-occipital fasciculusILF, inferior longitudinal fasciculusROI, region of interestWM, white matter.

Generation and characterization of an analog-sensitive PERK allele.

Restriction of nutrients and oxygen in the tumor microenvironment disrupts ER homeostasis and adaptation to such stress is mediated by the key UPR effector PERK. Given its pro-tumorigenic activity, significant efforts have been made to elucidate the molecular mechanisms that underlie PERK function. Chemical-genetic approaches have recently proven instrumental in pathway mapping and interrogating kinase function. To enable a detailed study of PERK signaling we have generated an analog-sensitive PERK allele that accepts N(6)-alkylated ATP analogs. We find that this allele can be regulated by bulky ATP-competitive inhibitors, confirming the identity of the PERK gatekeeper residue as methionine 886. Furthermore, this analog-sensitive allele can be used to specifically label substrates with thiophosphate both in vitro and in cells. These data highlight the potential for using chemical-genetic techniques to identify novel PERK substrates, thereby providing an expanded view of PERK function and further definition of its signaling networks.

PERK utilizes intrinsic lipid kinase activity to generate phosphatidic acid, mediate Akt activation, and promote adipocyte differentiation.

The endoplasmic reticulum (ER) resident PKR-like kinase (PERK) is necessary for Akt activation in response to ER stress. We demonstrate that PERK harbors intrinsic lipid kinase, favoring diacylglycerol (DAG) as a substrate and generating phosphatidic acid (PA). This activity of PERK correlates with activation of mTOR and phosphorylation of Akt on Ser473. PERK lipid kinase activity is regulated in a phosphatidylinositol 3-kinase (PI3K) p85α-dependent manner. Moreover, PERK activity is essential during adipocyte differentiation. Because PA and Akt regulate many cellular functions, including cellular survival, proliferation, migratory responses, and metabolic adaptation, our findings suggest that PERK has a more extensive role in insulin signaling, insulin resistance, obesity, and tumorigenesis than previously thought.