We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine practice in clinical oncology. Although these sequence alterations are highly informative, sampling tumor tissue has significant inherent limitations; tumor tissue is a single snapshot in time, is subject to selection bias resulting from tumor heterogeneity, and can be difficult to obtain. Cell-free fragments of DNA are shed into the bloodstream by cells undergoing apoptosis or necrosis, and the load of circulating cell-free DNA (cfDNA) correlates with tumor staging and prognosis. Moreover, recent advances in the sensitivity and accuracy of DNA analysis have allowed for genotyping of cfDNA for somatic genomic alterations found in tumors. The ability to detect and quantify tumor mutations has proven effective in tracking tumor dynamics in real time as well as serving as a liquid biopsy that can be used for a variety of clinical and investigational applications not previously possible.

Liquid Biopsies: Genotyping Circulating Tumor DNA

Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensitymodulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike. CA Cancer J Clin 2010;60:166-193. © 2010 American Cancer Society, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/caac.20069

Exciting New Advances in Neuro-Oncology The Avenue to a Cure for Malignant Glioma

In this paper, we describe the state of the art in continuum robot manipulators and systems intended for application to interventional medicine. Inspired by biological trunks, tentacles, and snakes, continuum robot designs can traverse confined spaces, manipulate objects in complex environments, and conform to curvilinear paths in space. In addition, many designs offer inherent structural compliance and ease of miniaturization. After decades of pioneering research, a host of designs have now been investigated and have demonstrated capabilities beyond the scope of conventional rigid-link robots. Recently, we have seen increasing efforts aimed at leveraging these qualities to improve the frontiers of minimally invasive surgical interventions. Several concepts have now been commercialized, which are inspiring and enabling a current paradigm shift in surgical approaches toward flexible access routes, e.g., through natural orifices such as the nose. In this paper, we provide an overview of the current state of this field from the perspectives of both robotics science and medical applications. We discuss relevant research in design, modeling, control, and sensing for continuum manipulators, and we highlight how this work is being used to build robotic systems for specific surgical procedures. We provide perspective for the future by discussing current limitations, open questions, and challenges.

Continuum Robots for Medical Applications: A Survey

Over the past decade, RNA sequencing (RNA-seq) has become an indispensable tool for transcriptome-wide analysis of differential gene expression and differential splicing of mRNAs. However, as next-generation sequencing technologies have developed, so too has RNA-seq. Now, RNA-seq methods are available for studying many different aspects of RNA biology, including single-cell gene expression, translation (the translatome) and RNA structure (the structurome). Exciting new applications are being explored, such as spatial transcriptomics (spatialomics). Together with new long-read and direct RNA-seq technologies and better computational tools for data analysis, innovations in RNA-seq are contributing to a fuller understanding of RNA biology, from questions such as when and where transcription occurs to the folding and intermolecular interactions that govern RNA function.

RNA sequencing: the teenage years

Mechanics-based models of concentric tube continuum robots have recently achieved a level of sophistication that makes it possible to begin to apply these robots to a variety of real-world clinical scenarios. Endonasal skull base surgery is one such application, where their small diameter and tentacle-like dexterity are particularly advantageous. In this paper, we provide the medical motivation for an endonasal surgical robot featuring concentric tube manipulators, and describe our model-based design and teleoperation methods, as well as a complete system incorporating image guidance. Experimental demonstrations using a laparoscopic training task, a cadaver reachability study, and a phantom tumor resection experiment illustrate that both novice and expert users can effectively teleoperate the system, and that skull base surgeons can use the robot to achieve their objectives in a realistic surgical scenario.

/pdf/a-telerobotic-system-for-transnasal-surgery-54an6tad2o.pdf

A Telerobotic System for Transnasal Surgery

New approaches to intracerebral hemorrhage management are motivated by its high incidence and 40% mortality rate. Surgery is sometimes attempted to decompress the brain, although patient outcomes are similar regardless of whether surgery occurs. We hypothesize that surgical decompression is not more effective because current open surgical techniques disrupt healthy brain tissue to access the clot formed by the hemorrhage, offsetting the benefits of surgery. To address this, we propose a less invasive needle-based approach in which the clot is debulked from within using a superelastic, precurved aspiration cannula that is deployed from a needle. The tip of this aspiration cannula is controlled by coordinated insertion and retraction of the cannula and needle, as well as axial rotation of the cannula. We describe the design of a sterilizable and biocompatible robot that can control the three degrees of freedom of the needle and cannula. Image guidance is achieved by adapting an approach originally developed for brain biopsy. We provide an optimization method for the selection of the precurvatures of one or more sequentially used aspiration cannulas to maximize hemorrhage evacuation, based on preoperative medical image data. In vitro experiments demonstrate the feasibility of evacuating 83-92% of hemorrhage volume, depending on the number of tubes and deployment method used.

/pdf/debulking-from-within-a-robotic-steerable-cannula-for-3tesoxbpbn.pdf

Debulking From Within: A Robotic Steerable Cannula for Intracerebral Hemorrhage Evacuation

We describe transnasal skull base surgery, including the current clinical procedure and the ways in which a robotic system has the potential to enhance the current standard of care. The available workspace is characterized by segmenting medical images and reconstructing the available 3D geometry. We then describe thin, “tentacle-like” robotic tools with shafts constructed from concentric tube robots, and an actuation unit designed to robotically control them in a teleoperated setting. Lastly, we discuss the results of a proof-of-concept study in a cadaveric specimen, illustrating the ability of the robot to access clinically relevant skull base targets.

/pdf/a-bimanual-teleoperated-system-for-endonasal-skull-base-48qsesc0vs.pdf

A bimanual teleoperated system for endonasal skull base surgery

This paper reports a novel method to track brain shift using a laser-range scanner (LRS) and nonrigid registration techniques. The LRS used in this paper is capable of generating textured point-clouds describing the surface geometry/intensity pattern of the brain as presented during cranial surgery. Using serial LRS acquisitions of the brain's surface and two-dimensional (2-D) nonrigid image registration, we developed a method to track surface motion during neurosurgical procedures. A series of experiments devised to evaluate the performance of the developed shift-tracking protocol are reported. In a controlled, quantitative phantom experiment, the results demonstrate that the surface shift-tracking protocol is capable of resolving shift to an accuracy of approximately 1.6 mm given initial shifts on the order of 15 mm. Furthermore, in a preliminary in vivo case using the tracked LRS and an independent optical measurement system, the automatic protocol was able to reconstruct 50% of the brain shift with an accuracy of 3.7 mm while the manual measurement was able to reconstruct 77% with an accuracy of 2.1 mm. The results suggest that a LRS is an effective tool for tracking brain surface shift during neurosurgery.

/pdf/a-method-to-track-cortical-surface-deformations-using-a-4lhscvaw2o.pdf

A method to track cortical surface deformations using a laser range scanner

Object The goals of this study were to report the clinical presentation, radiographic findings, operative strategy, and outcomes among patients with temporal bone encephaloceles and cerebrospinal fluid fistulas (CSFFs) and to identify clinical variables associated with surgical outcome. Methods A retrospective case series including all patients who underwent a middle fossa craniotomy or combined mastoid–middle cranial fossa repair of encephalocele and/or CSFF between 2000 and 2012 was accrued from 2 tertiary academic referral centers. Results Eighty-nine consecutive surgeries (86 patients, 59.3% women) were included. The mean age at time of surgery was 52.3 years, and the left side was affected in 53.9% of cases. The mean delay between symptom onset and diagnosis was 35.4 months, and the most common presenting symptoms were hearing loss (92.1%) and persistent ipsilateral otorrhea (73.0%). Few reported a history of intracranial infection (6.7%) or seizures (2.2%). Thirteen (14.6%) of 89 cases had a history...

Temporal bone encephalocele and cerebrospinal fluid fistula repair utilizing the middle cranial fossa or combined mastoid–middle cranial fossa approach

Kyle D. Weaver

Papers

A Telerobotic System for Transnasal Surgery

Debulking From Within: A Robotic Steerable Cannula for Intracerebral Hemorrhage Evacuation

A bimanual teleoperated system for endonasal skull base surgery

A method to track cortical surface deformations using a laser range scanner

Temporal bone encephalocele and cerebrospinal fluid fistula repair utilizing the middle cranial fossa or combined mastoid–middle cranial fossa approach