Step-by-Step Dissection of the Extreme Lateral Transodontoid Approach to the Anterior Craniovertebral Junction: Surgical Anatomy and Technical Nuances.

BACKGROUND: Multicompartmental lesions of the anterior craniovertebral junction require aggressive management. However, the lesions can be difficult to reach, and the surgical procedure is difficult to understand. The aim of this study was to create a procedural, stepwise microsurgical educational resource for junior trainees to learn the surgical anatomy of the extreme lateral transodontoid approach (ELTOA). METHODS: Ten formalin-fixed, latex-injected cadaveric heads were dissected under an operative microscope. Dissections were performed under the supervision of a skull base fellowship-trained neurosurgeon who has advanced skull base experience. Key steps of the procedure were documented with a professional camera and a high-definition video system. A relevant clinical case example was reviewed to highlight the principles of the selected approach and its application. The clinical case example also describes a rare complication: a pseudoaneurysm of the vertebral artery. RESULTS: Key steps of the ELTOA include patient positioning, skin incision, superficial and deep muscle dissection, vertebral artery dissection and transposition, craniotomy, clivus drilling, odontoidectomy, and final extradural and intradural exposure. CONCLUSIONS: The ELTOA is a challenging approach, but it allows for significant access to the anterior craniovertebral junction, which increases the likelihood of gross total lesion resection. Given the complexity of the approach, substantial training in the dissection laboratory is required to develop the necessary anatomic knowledge and to minimize approach-related morbidity.

Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial.

BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.

The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.

BACKGROUND: Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking. METHODS: We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed. RESULTS: In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation. CONCLUSIONS: Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).

Anterior petrosal (Kawase) approach to petroclival meningioma: 2-dimensional operative video.

Petroclival meningiomas are challenging lesions that can be treated with several surgical approaches. The authors present a 66-year-old woman with a 1.6-cm left petroclival meningioma that was initially observed and then radiated after it grew 8 years later. Despite radiation, the tumor continued to grow to 4 cm; therefore, the patient was referred to the authors' institution. A left anterior petrosal (Kawase) approach was performed. Postoperatively, the patient had transient cranial nerve IV and VI palsy that improved. The case presentation, surgical anatomy, operative technique, postoperative course, and different surgical approaches are reviewed. The patient gave verbal consent for participating in the surgical video. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21259.

Exercise improves health-related quality of life sleep and fatigue domains in adult high- and low-grade glioma patients.

PURPOSE: The impact of exercise on health-related quality of life (HRQOL) in patients with glioma remains unknown. We hypothesized that glioma patients with low exercise tolerance experience more distress in HRQOL sleep and fatigue domains than patients with high tolerance to exercise. METHODS: Thirty-eight male and female patients with low- or high-grade glioma treated at a single tertiary care institution participated. Patients completed a validated telephone survey to determine their exercise habits before and following diagnosis. An unpaired t-test was run to measure the interaction between exercise tolerances on HRQOL functional and impairment domains. RESULTS: Those with low pre-morbid physical activity levels had more distress in HRQOL sleep and fatigue domains. The effects were independent of plasma brain-derived neurotrophic factor (BDNF) levels and the degree of exercise did not appear to impact plasma BDNF in adult glioma patients. CONCLUSIONS: The aim of this study was to examine the significance of exercise habits on perioperative functional outcomes in patients with low-grade or high-grade glioma. We found that glioma patients with low tolerance to exercise had more sleep disturbances and greater fatigue than glioma patients with high tolerance to exercise. Furthermore, exercise tolerance in the adult glioma population does not appear to impact plasma BDNF secretion.

Ventricular Volume Change as a Predictor of Shunt-Dependent Hydrocephalus in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) that often requires acute placement of an external ventricular drain (EVD). The current systems available for determining which patients will require long-term cerebrospinal fluid diversion remain subjective. We investigated the ventricular volume change (ΔVV) after EVD clamping as an objective predictor of shunt dependence in patients with aSAH. METHODS: We performed a retrospective medical record review and image analysis of patients treated for aSAH at a single academic institution who had required EVD placement for acute hydrocephalus and had undergone 1 EVD weaning trial. Head computed tomography (CT) scans obtained before and after EVD clamping were analyzed using a custom semiautomated MATLAB program (MathWorks, Natick, Massachusetts, USA), which segments each CT scan into 5 tissue types using k-means clustering. Differences in the pre- and postclamp ventricular volumes were calculated. RESULTS: A total of 34 patients with an indwelling shunt met the inclusion criteria and were sex- and age-matched to 34 controls without a shunt. The mean ΔVV was 19.8 mL in the shunt patients and 3.8 mL in the nonshunt patients (P < 0.0001). The area under the receiver operating characteristic curve was 0.84. The optimal ΔVV threshold was 11.4 mL, with a sensitivity of 76.5% and specificity of 88.2% for predicting shunt dependence. The mean ΔVV was significantly greater for the patients readmitted for shunt placement compared with the patients not requiring cerebrospinal fluid diversion (18.69 mL vs. 3.84 mL; P = 0.005). Finally, 70% of the patients with delayed shunt dependence had ΔVV greater than the identified threshold. CONCLUSIONS: The ΔVV volume between head CT scans taken before and after EVD clamping was predictive of early and delayed shunt dependence.

Imaging Errors in Distinguishing Pituitary Adenomas From Other Sellar Lesions.

BACKGROUND: Pituitary adenomas and nonadenomatous lesions in the sellar region may be difficult to distinguish by imaging yet that distinction is critical in guiding management. The nature of the diagnostic errors in this setting has not been well documented. METHODS: Two neurosurgeons and 2 neuroradiologists of differing experience levels viewed deidentified MRIs of 18 nonadenomatous sellar lesions and 21 adenomas. They recorded their diagnoses, the imaging features they used to make those diagnoses, and their confidence in making those diagnoses. RESULTS: Among the 18 nonadenoma cases, 11 (61%) were incorrectly diagnosed as adenoma by at least 1 reader, including Rathke cleft cyst, plasmacytoma, aneurysm, craniopharyngioma, chordoma, Langerhans cell histiocytosis, metastasis, and undifferentiated sinonasal carcinoma. Among the 21 adenoma cases, 8 (38%) were incorrectly diagnosed by at least 1 reader as craniopharyngioma, Rathke cleft cyst, sinonasal carcinoma, hemangioblastoma, and pituitary hyperplasia. Incorrect imaging diagnoses were made with high confidence in 13% of readings. Avoidable errors among the nonadenomatous cases occurred when readers failed to appreciate that the lesion was separate from the pituitary gland. Unavoidable errors in those cases occurred when the lesions were so large that the pituitary gland had been obliterated or the imaging features of a nonadenomatous lesion resembled those of a cystic pituitary adenoma. Avoidable errors in misdiagnosis of adenomas as nonadenomas occurred when readers failed to appreciate features highly characteristic of adenomas. An unavoidable error occurred because a cystic adenoma had features correctly associated with craniopharyngioma. CONCLUSIONS: Errors in imaging differentiation of pituitary adenoma from nonadenomatous lesions occurred often and sometimes with high confidence among a small sample of neurosurgeons and neuroradiologists. In the misdiagnosis of nonadenomatous lesions as adenomas, errors occurred largely from failure to appreciate a separate pituitary gland, but unavoidable errors occurred when large lesions had obliterated this distinguishing feature. In the misdiagnosis of adenomas as nonadenomatous lesions, avoidable errors occurred because readers failed to recognize imaging features more characteristic of adenomas and because cystic adenomas share features with craniopharyngiomas and Rathke cleft cysts. Awareness of these errors should lead to improved management of sellar lesions.

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and ß-Thalassemia.

Transfusion-dependent ß-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).

Vascular compromise in a torsed transposed ulnar nerve case in support of intravenous contrast administration.

Nerve torsion is a recognized etiology in brachial and peripheral neuropathy. Vascular compromise of peripheral nerves is uncommon given their unique vascular supply. Preoperative imaging diagnosis of nerve torsion and vascular compromise can be made in some cases, which impacts treatment. We present a previously unreported case of long segment torsion and vascular compromise of the ulnar nerve following anterior subcutaneous transposition with a description of the imaging findings based on the unique structure of the nerve and the presence of a blood nerve barrier (BNB) and a discussion of the potential vulnerability of a transposed and torsed nerve.

Normal cerebral ventricular volume growth in childhood.

OBJECTIVE: Normal percentile growth charts for head circumference, length, and weight are well-established tools for clinicians to detect abnormal growth patterns. Currently, no standard exists for evaluating normal size or growth of cerebral ventricular volume. The current standard practice relies on clinical experience for a subjective assessment of cerebral ventricular size to determine whether a patient is outside the normal volume range. An improved definition of normal ventricular volumes would facilitate a more data-driven diagnostic process. The authors sought to develop a growth curve of cerebral ventricular volumes using a large number of normal pediatric brain MR images. METHODS: The authors performed a retrospective analysis of patients aged 0 to 18 years, who were evaluated at their institution between 2009 and 2016 with brain MRI performed for headaches, convulsions, or head injury. Patients were excluded for diagnoses of hydrocephalus, congenital brain malformations, intracranial hemorrhage, meningitis, or intracranial mass lesions established at any time during a 3- to 10-year follow-up. The volume of the cerebral ventricles for each T2-weighted MRI sequence was calculated with a custom semiautomated segmentation program written in MATLAB. Normal percentile curves were calculated using the lambda-mu-sigma smoothing method. RESULTS: Ventricular volume was calculated for 687 normal brain MR images obtained in 617 different patients. A chart with standardized growth curves was developed from this set of normal ventricular volumes representing the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles. The charted data were binned by age at scan date by 3-month intervals for ages 0-1 year, 6-month intervals for ages 1-3 years, and 12-month intervals for ages 3-18 years. Additional percentile values were calculated for boys only and girls only. CONCLUSIONS: The authors developed centile estimation growth charts of normal 3D ventricular volumes measured on brain MRI for pediatric patients. These charts may serve as a quantitative clinical reference to help discern normal variance from pathologic ventriculomegaly.

Using a Mobile Application for Evaluation of Procedural Learning in Neurosurgery.

BACKGROUND: Feedback is a major component of any educational process. Competency assessment and feedback are essential tools for teaching surgical skills. Most current systems of assessment within neurosurgical residency programs use evaluations aggregated over a period of time, which lead to significant bias, rather than case-specific feedback. We describe the use of a mobile device application called SIMPL (System for Improving and Measuring Procedural Learning) to allow for immediate surgical competency assessment and improve the quality of feedback after every operative experience. METHODS: We retrospectively assessed our use of this program and neurosurgery residents' response to the program. Institutional review board approval was not required, and no patients were involved in the study. This application has already been implemented within general surgery programs with promising results. We document its implementation in a neurosurgery program and the output of the program for residents and program directors. RESULTS: This is the first documentation of such an application within a neurosurgical residency program. In a 6-month period at a single institution, around 300 evaluations were completed by residents and faculty, with a >80% response rate within both groups. Furthermore, these evaluations were companied by a 60% dictation rate from faculty, which contains verbal feedback that is available to residents for playback at any time. CONCLUSIONS: The telephone-based SIMPL application allows for assessment of surgical competency and remains quick and easy to use, giving it the potential to improve individual neurosurgical training experiences across the United States.

Isolation and characterization of immune cells from the tumor microenvironment of genetically engineered pediatric high-grade glioma models using the sleeping beauty transposon system.

Gliomas are the most common malignant brain tumors in the pediatric population. Even though great efforts have been made to understand their distinctive molecular characteristics, there has not been any improvements in the median survival in decades. In children, high-grade glial tumors have a median survival of 9-15 months. It has recently been demonstrated that pediatric high-grade gliomas (pHGG) are biologically and molecularly different from the adult counterparts, which could explain why conventional treatments universally fail. The development of an in vivo pHGG model harboring the specific genetic alterations encountered in pediatric gliomas is imperative in order to study the molecular basis that drives the progression and aggressiveness of these tumors. It would also enable harnessing these results for the development of novel therapeutic approaches. Our lab has implemented a method to induce brain tumors using transposon-mediated integration of plasmid DNA into cells of the subventricular zone of neonatal mouse brain. One of the main advantages of this method is that tumors are induced by altering the genome of the host cells, allowing us to recapitulate the salient features of the human disease. In this chapter we describe a method to isolate two cell populations from tumors generated in situ in mice, i.e., one population enriched in tumor cells and another population enriched in CD45+ cells. We also present methodologies as to how tumor infiltrating immune cells can be phenotypically characterized using flow cytometry.

Prospects of biological and synthetic pharmacotherapies for glioblastoma.

Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas.Areas covered: Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches.Expert opinion: Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials.

Functional characterization of tumor antigen-specific T-cells isolated from the tumor microenvironment of sleeping beauty induced murine glioma models.

Diffuse Gliomas represent 80% of brain tumors with an average survival of the most aggressive form glioblastoma (GBM) 15-22 months from the time of diagnosis. The current standard of care includes tumor resection, chemotherapy and radiation, nevertheless, the incidence of recurrence remains high and there is a critical need for developing new therapeutic strategies. T-cell mediated immunotherapy that triggers an anti-tumor T cell-mediated memory response is a promising approach since it will not only attack the primary tumor but also prevent recurrence. Multiple immunotherapeutic strategies against glioma are currently being tested in clinical trials. We have developed an immune-mediated gene therapy (Thymidine kinase plus Fms-like tyrosine kinase 3 ligand: TK/Flt3L) which induces a robust anti-tumor T cell response leading to tumor regression, long-term survival and immunological memory in GBM models. Efficacy of the anti-glioma T cell therapy is determined by anti-tumor specific effector T cells. Therefore, assessing effector T cell activation status and function are critical readouts for determining the effectiveness of the therapy. Here, we detail methodologies to evaluate tumor specific T-cell responses using a genetically engineered Sleeping Beauty transposase-mediated glioma model. We first describe the glioma model and the generation of neurospheres (NS) that express the surrogate antigen cOVA. Then, we describe functional assays to determine anti-tumor T-cell response.

BDNF, COMT, and DRD2 polymorphisms and ability to return to work in adult patients with low- and high-grade glioma.

BACKGROUND: Cognitive and language dysfunction is common among patients with glioma and has a significant impact on survival and health-related quality of life (HRQOL). Little is known about the factors that make individual patients more or less susceptible to the cognitive sequelae of the disease. A better understanding of the individual and population characteristics related to cognitive function in glioma patients is required to appropriately stratify patients, prognosticate, and develop more efficacious treatment regimens. There is evidence that allelic variation among genes involved in neurotransmission and synaptic plasticity are related to neurocognitive performance in states of health and neurologic disease. METHODS: We studied the association of single-nucleotide polymorphism variations in brain-derived neurotrophic factor (BDNF, rs6265), dopamine receptor 2 (DRD2, rs1076560), and catechol-O-methyltransferase (COMT, rs4680) with neurocognitive function and ability to return to work in glioma patients at diagnosis and at 3 months. We developed a functional score based on the number of high-performance alleles that correlates with the capacity for patients to return to work. RESULTS: Patients with higher-performing alleles have better scores on neurocognitive testing with the Repeatable Battery for the Assessment of Neuropsychological Status and Stroop test, but not the Trail Making Test. CONCLUSIONS: A better understanding of the genetic contributors to neurocognitive performance in glioma patients and capacity for functional recovery is necessary to develop improved treatment strategies based on patient-specific factors.

Health Related Quality of Life in Adult Low and High-Grade Glioma Patients Using the National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL Assessments.

Health related quality of life (HRQOL) measures have become increasingly important in the management of glioma patients in both research and clinical practice settings. Functional impairment is common in low-grade and high-grade glioma patients as the disease has both oncological and neurological manifestations. Natural disease history as well as medical or surgical treatment can negatively influence HRQOL. There are no universal standards for HRQOL assessment in glioma patients. In this study, we examine patient perspectives on functional outcome domains and report the prevalence of impairments rates using the National Institutes of Health (NIH) Patient Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL item banks as measures of HRQOL. Retrospective analysis of a prospectively collected dataset involving 79 glioma patients reveals that quality of life concerns are the most important consideration behind making decisions about treatment in 80.7% of patients. The prevalence of functional impairment by PROMIS and NEURO-QOL assessment is high, ranging from 28.6% in the physical function domain to 43.9% in the cognitive function domain. Pain and anxiety related to physical decline is higher in LGG patients compared to HGG patients. Aphasia severity also impacts HRQOL. The results of this study suggest that the PROMIS and NEURO-QOL assessments may be important HRQOL metrics for future use in larger clinical research and clinical trial settings.

Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes.

Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI < 0.1), while ultra-rare missense variants were significantly overrepresented in cases only in constrained genes (pLI > 0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.