Lola B. Chambless

Intertumoral Heterogeneity within Medulloblastoma Subgroups

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Single cell analysis of human tissues and solid tumors with mass cytometry

Mass cytometry measures 36 or more markers per cell and is an appealing platform for comprehensive phenotyping of cells in human tissue and tumor biopsies. While tissue disaggregation and fluorescence cytometry protocols were pioneered decades ago, it is not known whether established protocols will be effective for mass cytometry and maintain cancer and stromal cell diversity.

Multi-institutional validation of a preoperative scoring system which predicts survival for patients with glioblastoma

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. Average survival is approximately 1 year, but individual survival is heterogeneous. Using a single institutional experience, we have previously identified preoperative factors associated with survival and devised a prognostic scoring system based on these factors. The aims of the present study are to validate these preoperative factors and verify the efficacy of this scoring system using a multi-institutional cohort. Of the 334 patients in this study from three different institutions, the preoperative factors found to be negatively associated with survival in a Cox analysis were age >60 years (p<0.0001), Karnofsky Performance Scale score ≤80 (p=0.03), motor deficit (p=0.02), language deficit (p=0.04), and periventricular tumor location (p=0.04). Patients possessing 0-1, 2, 3, and 4-5 of these variables were assigned a preoperative grade of 1, 2, 3, and 4, respectively. Patients with a preoperative grade of 1, 2, 3, and 4 had a median survival of 17.9, 12.3, 10, and 7.5 months, respectively. Survival of each of these grades was statistically significant (p<0.05) in log-rank analysis. This grading system, based only on preoperative variables, may provide patients and physicians with prognostic information that may guide medical and surgical therapy before any intervention is pursued.

Porous polyethylene implant reconstruction of the orbit after resection of spheno-orbital meningiomas: A novel technique

BACKGROUND Spheno-orbital meningiomas (SOM) are complex tumors involving the middle cranial fossa and orbit. Following resection of these tumors, reconstruction of the orbit can be challenging. Inadequate reconstruction may lead to cosmetic deformities and functional complications. OBJECTIVE The development of a technique for orbital reconstruction which is technically straightforward, cost-effective, with an excellent functional and cosmetic outcome. TECHNIQUE Twelve patients with SOM each underwent a modified orbital-zygomatic craniotomy with osteotomies based on individual tumor location. After tumor resection, the lateral orbit and orbital roof, where necessary, were reconstructed using a 1 mm porous polyethylene sheet, customized to reconstruct the bony anatomy of the lateral and superior orbit and secured with 1.5×4 mm titanium screws into the orbital roof and rim. RESULTS All patients demonstrated stabilization or improvement of vision and satisfactory cosmetic outcomes. One complication (surgical site infection) was noted. Follow-up imaging was obtained at regular intervals. The resection cavity was easily visualized without interference from the implant in each case. One patient developed tumor recurrence requiring re-operation 20 months after the initial procedure. CONCLUSIONS Use of a 1mm porous polyethylene sheet for reconstruction of the lateral orbit offers an excellent functional and cosmetic outcome, does not interfere with postoperative imaging, is technically straightforward, and is cost-effective.

Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis

The ventricular-subventricular zone (V-SVZ), which lies in the walls of the lateral ventricles (LV), is the largest neurogenic niche within the adult brain. Whether radiographic contact with the LV influences survival in glioblastoma (GBM) patients remains unclear. We assimilated and analyzed published data comparing survival in GBM patients with (LV+GBM) and without (LV-GBM) radiographic LV contact. PubMed, EMBASE, and Cochrane electronic databases were searched. Fifteen studies with survival data on LV+GBM and LV-GBM patients were identified. Their Kaplan–Meier survival curves were digitized and pooled for generation of median overall (OS) and progression free (PFS) survivals and log-rank hazard ratios (HRs). The log-rank and reported multivariate HRs after accounting for the common predictors of GBM survival were analyzed separately by meta-analyses. The calculated median survivals (months) from pooled data were 12.95 and 16.58 (OS), and 4.54 and 6.25 (PFS) for LV+GBMs and LV-GBMs, respectively, with an overall log-rank HRs of 1.335 [1.204–1.513] (OS) and 1.387 [1.225–1.602] (PFS). Meta-analysis of log-rank HRs resulted in summary HRs of 1.58 [1.35–1.85] (OS, 10 studies) and 1.41 [1.22–1.64] (PFS, 5 studies). Meta-analysis of multivariate HRs resulted in summary HRs of 1.35 [1.14–1.58] (OS, 6 studies) and 1.64 [0.88–3.05] (PFS, 3 studies). Patients with GBM contacting the LV have lower survival. This effect may be independent of the common predictors of GBM survival, suggesting a clinical influence of V-SVZ contact on GBM biology.

Type 2 Diabetes Mellitus is an Independent Risk Factor for PostoperativeComplications in Patients Surgically Treated for Meningioma

Objectives: Increased risk of perioperative complications in patients with type 2 diabetes mellitus (DM) has previously been noted with regard to a number of different operations. We sought to study the relative rates of postoperative complications after the surgical resection of an intracranial meningioma based on a pre-existing diagnosis of diabetes. Methods: We conducted a retrospective cohort study on 259 patients who underwent a primary meningioma resection at our institution between 2001-2013. The medical record was reviewed to identify a pre-existing diagnosis of type 2 DM and any postoperative complications prior to discharge. The duration of postoperative hospital stay, intensive care unit (ICU) stay, perioperative changes in Karnofsky Performance Status (KPS) scores, and any postoperative emergency department (ED) presentation within 90 days of the operation were also recorded for each patient. Multivariable logistic regression models were built to determine the impact of a history of diabetes on postoperative complications and post-discharge presentation to the ED. Multivariable linear regression models were designed to assess the predictors of lengthier hospitalization and ICU stays in addition to differential postoperative changes in KPS scores. Results: Forty-one (16%) patients had diagnoses of type 2 DM prior to clinical presentation. In multivariate analyses, patients with a pre-existing history of diabetes had a higher risk of postoperative complications, postoperative ED presentation, and deterioration in functional status in addition to lengthier durations of hospitalization and ICU stay (p<0.001, p=0.008, p<0.001, p=0.007, p<0.001). Conclusions: Patients with pre-existing diagnoses of type 2 DM have a significantly increased risk of immediate postoperative complications following the resection of an intracranial meningioma. Type 2 DM also predicts increased lengths of postoperative hospital stay, decreased postoperative performance status, and increased risk of postoperative ED presentation.

Functional and Structural Traumatic Brain Injury in Equestrian Sports: A Review of the Literature.

OBJECTIVE Sports-related concussions and traumatic brain injury (TBI) represent a growing public health concern. We reviewed the literature regarding equestrian-related brain injury, ranging from concussion to severe TBI. METHODS A literature review was performed to address the epidemiology of sports-related concussion and TBI in equestrian-related sports. MEDLINE and PUBMED databases were searched to identify all studies pertaining to brain injury in equestrian-related sports. We included two broad types of brain injury using a distinction established in the literature: 1) TBI with functional impairment, including concussion, or mild TBI, with negative imaging findings; and 2) TBI with structural impairment, with positive imaging and at least one of the following pathologies identified: subdural hemorrhage, epidural hemorrhage, subarachnoid hemorrhage, intraparenchymal hemorrhage, cerebral contusions, and skull fractures. RESULTS Our literature search yielded 199 results. We found 26 studies describing functional TBI and 25 mentioning structural TBI, and 8 including both. Of all modern sporting activities, equestrian sports were found to cause some of the highest rates of total bodily injury, severe brain injury, and mortality. Concussions comprise 9.7%-15% of all equestrian-related injuries brought to hospitals for evaluation. Structural TBI was rare, and documentation of these injuries was poor. Although demographic risk factors like age and sex are minimally discussed in the literature, two studies identified a protective effect of increasing rider experience on all forms of bodily injury. However, it remains unclear whether increasing rider experience protects specifically against head injury. Finally, rates of helmet use in horseback riding remain dismally low-ranging from 9%-25%, depending on the activity. These low rates have persisted over time, despite evidence in this literature that helmets lead to an absolute risk reduction for head injury of 40%-50% in equestrian sports. CONCLUSIONS Equestrian-related functional and structural TBI represent a significant public health burden. Rider and horse characteristics make the sport uniquely dangerous, as the athlete has limited control over an animal weighing a thousand pounds. Helmet use rates remain very low despite clear evidence of risk reduction. Health care providers are strongly urged to lobby professional and governmental organizations for mandatory helmet use in all equestrian sports.

Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study.

Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.

Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma.

BACKGROUND Improved therapies for high-grade glioma (HGG) are urgently needed as the median survival for grade IV gliomas is only 15 months. Bone morphogenetic protein (BMP) signaling plays critical and complex roles in many types of cancer, including glioma, with most of the recently published work focusing on BMP-mediated regulation of glioma stem cells (GSCs). We hypothesized that BMP signaling may be an important modulator of tumorigenic properties in glioma cells outside of the GSC compartment. METHODS We used a human HGG tissue microarray and performed immunohistochemistry for phospho-Smads1,5,8. To examine the role of BMP signaling in tumorigenic astrocytes, transgenic mice were used to delete the BMP type IA receptor (Bmpr1a) and generate astrocytes transformed with oncogenic Ras and homozygous deletion of p53. The cells were transplanted orthotopically into immunocompetent adult host mice. RESULTS First we established that BMP signaling is active within the vast majority of HGG tumor cells. Mice implanted with BMPR1a-knockout transformed astrocytes showed an increase in median survival compared with mice that received BMPR1a-intact transformed astrocytes (52.5 vs 16 days). In vitro analysis showed that deletion of BMPR1a in oncogenic astrocytes resulted in decreased proliferation, decreased invasion, decreased migration, and increased expression of stemness markers. In addition, inhibition of BMP signaling in murine cells and astrocytoma cells with a small molecule BMP receptor kinase inhibitor resulted in similar tumor suppressive effects in vitro. CONCLUSION BMP inhibition may represent a viable therapeutic approach in adult HGG.

Persistent and automatic intraoperative 3D digitization of surfaces under dynamic magnifications of an operating microscope

One of the major challenges impeding advancement in image-guided surgical (IGS) systems is the soft-tissue deformation during surgical procedures. These deformations reduce the utility of the patients preoperative images and may produce inaccuracies in the application of preoperative surgical plans. Solutions to compensate for the tissue deformations include the acquisition of intraoperative tomographic images of the whole organ for direct displacement measurement and techniques that combines intraoperative organ surface measurements with computational biomechanical models to predict subsurface displacements. The later solution has the advantage of being less expensive and amenable to surgical workflow. Several modalities such as textured laser scanners, conoscopic holography, and stereo-pair cameras have been proposed for the intraoperative 3D estimation of organ surfaces to drive patient-specific biomechanical models for the intraoperative update of preoperative images. Though each modality has its respective advantages and disadvantages, stereo-pair camera approaches used within a standard operating microscope is the focus of this article. A new method that permits the automatic and near real-time estimation of 3D surfaces (at 1 Hz) under varying magnifications of the operating microscope is proposed. This method has been evaluated on a CAD phantom object and on full-length neurosurgery video sequences (∼1 h) acquired intraoperatively by the proposed stereovision system. To the best of our knowledge, this type of validation study on full-length brain tumor surgery videos has not been done before. The method for estimating the unknown magnification factor of the operating microscope achieves accuracy within 0.02 of the theoretical value on a CAD phantom and within 0.06 on 4 clinical videos of the entire brain tumor surgery. When compared to a laser range scanner, the proposed method for reconstructing 3D surfaces intraoperatively achieves root mean square errors (surface-to-surface distance) in the 0.28-0.81 mm range on the phantom object and in the 0.54-1.35 mm range on 4 clinical cases. The digitization accuracy of the presented stereovision methods indicate that the operating microscope can be used to deliver the persistent intraoperative input required by computational biomechanical models to update the patients preoperative images and facilitate active surgical guidance.