Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary ...risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging.
Liquid biopsy, as a non-invasive technique for cancer diagnosis, has emerged as a major step forward in conquering tumors. Current practice in diagnosis of central nervous system (CNS) tumors ...involves invasive acquisition of tumor biopsy upon detection of tumor on neuroimaging. Liquid biopsy enables non-invasive, rapid, precise and, in particular, real-time cancer detection, prognosis and treatment monitoring, especially for CNS tumors. This approach can also uncover the heterogeneity of these tumors and will likely replace tissue biopsy in the future. Key components of liquid biopsy mainly include circulating tumor cells (CTC), circulating tumor nucleic acids (ctDNA, miRNA) and exosomes and samples can be obtained from the cerebrospinal fluid, plasma and serum of patients with CNS malignancies. This review covers current progress in application of liquid biopsies for diagnosis and monitoring of CNS malignancies.
Medical student interest in neurosurgery is decreasing and resident attrition is trending upwards in favor of more lifestyle-friendly specialties that receive greater exposure during medical school. ...The University of Toronto began offering an annual two week comprehensive, focused surgical experience (Surgical Exploration and Discovery (SEAD) program) to 20 first year medical students increasing exposure to surgical careers. This study determines how SEAD affects students' views of a career in neurosurgery.
Surveys were administered to 38 SEAD participants over two program cycles. Information was obtained regarding demographics, impacts of SEAD, and factors affecting career decision making. Subgroup analyses assessed for factors predicting pre- and post-intervention interest in neurosurgery.
Ninety-seven percent (n=37) of students completed the survey. Before SEAD, 25% were interested in neurosurgery but this decreased to 10% post-SEAD (p=0.001). However, post-SEAD interest increased from 10% to 38% if lifestyle factors were theoretically controlled across surgical specialties (p<0.005). A majority (81%) felt SEAD improved their understanding of neurosurgery, 62.2% felt that exposure to other surgical specialties reduced their interest in neurosurgery, and 21% felt SEAD increased their interest in neurosurgery. Nineteen percent intended to explore neurosurgery further with observerships and one student planned to organize neurosurgical research.
This surgical exposure intervention increased understanding about neurosurgery and reduced overall interest in neurosurgery as a career. However, those remaining interested were motivated to plan further neurosurgical clinical experiences. The SEAD program may, therefore, aid in early selection of students motivated to satisfy the demands of a neurosurgical career.
The role of surgery in recurrent glioblastoma multiforme (GBM) remains a controversial topic. The goal of this study was to perform a case control analysis including time to tumor recurrence as an ...additional prognostic factor in order to determine which patients benefit most from repeat surgery.
Our brain tumor database was reviewed over a 10-year period for all adult (≥18 years old) patients with primary isocitrate dehydrogenase wildtype GBM who received surgery for recurrent disease. These patients were then age, sex, and treatment matched to case controls from our institution who received medical therapy for recurrent disease.
A total of 174 adult patients with GBM were included in the study, 87 patients who received surgery for recurrent GBM (surgery cohort) and 87 patients who did not receive surgery for recurrent GBM (nonsurgery cohort). The surgery cohort had longer overall survival (P = 0.0003) and postrecurrence survival (P = 0.001) than the nonsurgery cohort. When the surgery cohort was split into 2 groups on the basis of time to tumor recurrence, the long time to recurrence group (>6 months) demonstrated significantly increased survival compared with the short time to recurrence group (P < 0.0001). Multivariate analysis of both cohorts demonstrated surgery for recurrent GBM was independently significant after adjusting for age, Karnofsky Performance Scale, and time to tumor recurrence (P < 0.0001).
Surgery for recurrent GBM leads to improved survival independent of age, Karnofsky Performance Scale, and time to tumor recurrence. Patients with time to tumor recurrence >6 months benefit most from additional surgery.
Abstract
Background
Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This ...study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes.
Methods
Methylation profiles of 68 chordoma surgical samples were obtained between 1996 and 2018 across three international centers along with matched plasma methylomes where available.
Results
Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR = 14.2, 95%CI: 2.1–94.8, P = 0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poor-performing “Immune-infiltrated” subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity were observed in the better-performing “Cellular” subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versus-other binomial generalized linear models in random 20% testing sets (mean AUROC = 0.84, 95%CI: 0.52–1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data.
Conclusions
Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome-based biomarkers to noninvasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.
Abstract
Background
Resolving the differential diagnosis between brain metastases (BM), glioblastomas (GBM), and central nervous system lymphomas (CNSL) is an important dilemma for the clinical ...management of the main three intra-axial brain tumor types. Currently, treatment decisions require invasive diagnostic surgical biopsies that carry risks and morbidity. This study aimed to utilize methylomes from cerebrospinal fluid (CSF), a biofluid proximal to brain tumors, for reliable non-invasive classification that addresses limitations associated with low target abundance in existing approaches.
Methods
Binomial GLMnet classifiers of tumor type were built, in fifty iterations of 80% discovery sets, using CSF methylomes obtained from 57 BM, GBM, CNSL, and non-neoplastic control patients. Publicly-available tissue methylation profiles (N = 197) on these entities and normal brain parenchyma were used for validation and model optimization.
Results
Models reliably distinguished between BM (area under receiver operating characteristic curve AUROC = 0.93, 95% confidence interval CI: 0.71–1.0), GBM (AUROC = 0.83, 95% CI: 0.63–1.0), and CNSL (AUROC = 0.91, 95% CI: 0.66–1.0) in independent 20% validation sets. For validation, CSF-based methylome signatures reliably distinguished between tumor types within external tissue samples and tumors from non-neoplastic controls in CSF and tissue. CSF methylome signals were observed to align closely with tissue signatures for each entity. An additional set of optimized CSF-based models, built using tumor-specific features present in tissue data, showed enhanced classification accuracy.
Conclusions
CSF methylomes are reliable for liquid biopsy-based classification of the major three malignant brain tumor types. We discuss how liquid biopsies may impact brain cancer management in the future by avoiding surgical risks, classifying unbiopsiable tumors, and guiding surgical planning when resection is indicated.
Chordomas are clinically aggressive tumors with a high rate of disease progression despite maximal therapy. Given the limited therapeutic options available, there remains an urgent need for the ...development of novel therapies to improve clinical outcomes. Cell surface proteins are attractive therapeutic targets yet are challenging to profile with common methods. Four chordoma cell lines were analyzed by quantitative proteomics using a differential ultracentrifugation organellar fractionation approach. A subtractive proteomics strategy was applied to select proteins that are plasma membrane enriched. Systematic data integration prioritized PLA2R1 (secretory phospholipase A2 receptor-PLA2R1) as a chordoma-enriched surface protein. The expression profile of PLA2R1 was validated across chordoma cell lines, patient surgical tissue samples, and normal tissue lysates via immunoblotting. PLA2R1 expression was further validated by immunohistochemical analysis in a richly annotated cohort of 25-patient tissues. Immunohistochemistry analysis revealed that elevated expression of PLA2R1 is correlated with poor prognosis. Using siRNA- and CRISPR/Cas9-mediated knockdown of PLA2R1, we demonstrated significant inhibition of 2D, 3D and in vivo chordoma growth. PLA2R1 depletion resulted in cell cycle defects and metabolic rewiring via the MAPK signaling pathway, suggesting that PLA2R1 plays an essential role in chordoma biology. We have characterized the proteome of four chordoma cell lines and uncovered PLA2R1 as a novel cell-surface protein required for chordoma cell survival and association with patient outcome.
•Patients with recurrences after reirradiation had a shorter PFS compared to patients with recurrences after their first RT.•Higher MIB1-index is predictive of poorer outcome post-fRT (fractionated ...radiotherapy) in WHO grade 2 meningiomas.•Adjuvant fRT shortly after surgery may lead to improved outcomes compared to salvage fRT after recurrence/progression has been observed.•For WHO grade 2 meningiomas, adjuvant fRT following gross total resection leads to improved PFS outcomes compared to delaying fRT until recurrence, or following STR regardless of fRT timing.•High grade adverse events are rare following adjuvant and salvage fRT and usually patients with prior seizures or seizure predisposition.
Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3–10 years post-fRT and to determine the optimal timing of fRT.
Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT.
404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT.
There is a paucity of clinical factors that can predict a meningioma’s response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.
Maximal safe resection is the standard-of-care treatment for adults with intracranial ependymoma. The value of adjuvant radiotherapy remains unclear as these tumors are rare and current data are ...limited to a few retrospective cohort studies. In this study, the authors assembled a cohort of patients across multiple international institutions to assess the utility of adjuvant radiotherapy in this patient population.
Adults with intracranial ependymoma managed surgically at the University Health Network in Toronto, Canada, the University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma, and The Ottawa Hospital in Ottawa, Canada, were included in this study. The primary end points were progression-free survival (PFS) and overall survival (OS). Clinicopathological variables were assessed in univariate and multivariate Cox proportional hazard models for prognostic significance of PFS and OS.
A total of 122 patients diagnosed between 1968 and 2019 were identified for inclusion. The majority of patients had grade II ependymomas on histopathology (78%) that were infratentorially located (71%), underwent gross-total (GTR) or near-total resection (NTR; 55%), and were treated with adjuvant radiotherapy (67%). A volumetric analysis of the extent of resection in 49 patients with available tumor volume data supported the accuracy of the categorical GTR, NTR, and subtotal resection (STR) groups utilized. Independent statistically significant predictors of poorer PFS in the multivariate analysis included STR or biopsy (vs GTR/NTR; HR 5.4, 95% confidence interval CI 2.4-11.0, p < 0.0001) and not receiving adjuvant radiotherapy; cranial (HR 0.5, 95% CI 0.2-1.1) and craniospinal (HR 0.2, 95% CI 0.04-0.5) adjuvant radiotherapy regimens improved PFS (p = 0.0147). Predictors of poorer OS in the multivariate analysis were grade III histopathology (vs grade II: HR 5.7, 95% CI 1.6-20.2, p = 0.0064) and undergoing a biopsy/STR (vs GTR/NTR: HR 9.8, 95% CI 3.2-30.1, p = 0.0001).
The results of this 50-year experience in treating adult intracranial ependymomas confirm an important role for maximal safe resection (ideally GTR or NTR) and demonstrate that adjuvant radiotherapy improves PFS. This work will guide future studies as testing for molecular ependymoma alterations become incorporated into routine clinical practice.
Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the ...potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment.
Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions.
Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment.
The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.
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