Is surgical resection useful in elderly newly diagnosed glioblastoma patients? Outcome evaluation and prognostic factors assessment.

ASTRACT: BACKGROUND: The incidence of glioblastoma among elderly patients is constantly increasing. The value of radiation therapy and concurrent/adjuvant chemotherapy has been widely assessed. So far, the role of surgery has not been thoroughly investigated. The study aimed to evaluate safety and impact of several entities of surgical resection on outcome of elderly patients with newly diagnosed glioblastoma treated by a multimodal approach. METHODS: Patients ≥ 65 years, underwent surgery were included. The extent of surgical resection (EOR) was defined as complete resection (CR = 100%), gross total resection (GTR = 90-99%), sub-total resection (STR = 78-90%), partial resection (PR = 30-78%), and biopsy. After surgery, all patients received adjuvant radiotherapy (60/2 Gy fraction) with concomitant/adjuvant temozolomide chemotherapy. RESULTS: From March 2004 to December 2015, 178 elderly with a median age of 71 years (range 65-83 years) were treated. CR was obtained in 8 (4.5%), GTR in 63 (35.4%), STR in 46 (25.8%), PR in 16 (9.0%), and biopsy in 45 (25.3%). RT was started in all patients, concurrent/adjuvant CHT in 149 (83.7%) and 132 (74.2%). The median follow-up time was 12.2 months (range 0.4-50.4 months). The median, 1- and 2-year progression-free survival was 8.9 months (95%CI 7.8-100 months), 32.0 ± 3.5%, and 12.9 ± 2.6%. The median, 1- and 2-year overall survival were 12.2 (95%CI 11.3-13.1 months), 51.1 ± 3.7%, and 16.3 ± 2.9%. Tumor location, extent of resection, and neurological status after surgery statistically affected survival (p ≪ 0.01). CONCLUSION: Maximal surgical resection is safe and feasible in elderly patients with influence on survival. A preoperative evaluation has to be carried out.

Segmentation of glioblastomas in early post-operative multi-modal MRI with deep neural networks.

Extent of resection after surgery is one of the main prognostic factors for patients diagnosed with glioblastoma. To achieve this, accurate segmentation and classification of residual tumor from post-operative MR images is essential. The current standard method for estimating it is subject to high inter- and intra-rater variability, and an automated method for segmentation of residual tumor in early post-operative MRI could lead to a more accurate estimation of extent of resection. In this study, two state-of-the-art neural network architectures for pre-operative segmentation were trained for the task. The models were extensively validated on a multicenter dataset with nearly 1000 patients, from 12 hospitals in Europe and the United States. The best performance achieved was a 61% Dice score, and the best classification performance was about 80% balanced accuracy, with a demonstrated ability to generalize across hospitals. In addition, the segmentation performance of the best models was on par with human expert raters. The predicted segmentations can be used to accurately classify the patients into those with residual tumor, and those with gross total resection.

Multi-class glioma segmentation on real-world data with missing MRI sequences: comparison of three deep learning algorithms.

This study tests the generalisability of three Brain Tumor Segmentation (BraTS) challenge models using a multi-center dataset of varying image quality and incomplete MRI datasets. In this retrospective study, DeepMedic, no-new-Unet (nn-Unet), and NVIDIA-net (nv-Net) were trained and tested using manual segmentations from preoperative MRI of glioblastoma (GBM) and low-grade gliomas (LGG) from the BraTS 2021 dataset (1251 in total), in addition to 275 GBM and 205 LGG acquired clinically across 12 hospitals worldwide. Data was split into 80% training, 5% validation, and 15% internal test data. An additional external test-set of 158 GBM and 69 LGG was used to assess generalisability to other hospitals' data. All models' median Dice similarity coefficient (DSC) for both test sets were within, or higher than, previously reported human inter-rater agreement (range of 0.74-0.85). For both test sets, nn-Unet achieved the highest DSC (internal = 0.86, external = 0.93) and the lowest Hausdorff distances (10.07, 13.87 mm, respectively) for all tumor classes (p < 0.001). By applying Sparsified training, missing MRI sequences did not statistically affect the performance. nn-Unet achieves accurate segmentations in clinical settings even in the presence of incomplete MRI datasets. This facilitates future clinical adoption of automated glioma segmentation, which could help inform treatment planning and glioma monitoring.

Perioperative corticosteroid treatment impairs tumor-infiltrating dendritic cells in patients with newly diagnosed adult-type diffuse gliomas.

Introduction: Adult-type diffuse gliomas are malignant primary brain tumors characterized by very poor prognosis. Dendritic cells (DCs) are key in priming antitumor effector functions in cancer, but their role in gliomas remains poorly understood. Methods: In this study, we characterized tumor-infiltrating DCs (TIDCs) in adult patients with newly diagnosed diffuse gliomas by using multi-parametric flow cytometry and single-cell RNA sequencing. Results: We demonstrated that different subsets of DCs are present in the glioma microenvironment, whereas they are absent in cancer-free brain parenchyma. The largest cluster of TIDCs was characterized by a transcriptomic profile suggestive of severe functional impairment. Patients undergoing perioperative corticosteroid treatment showed a significant reduction of conventional DC1s, the DC subset with key functions in antitumor immunity. They also showed phenotypic and transcriptional evidence of a more severe functional impairment of TIDCs. Discussion: Overall, the results of this study indicate that functionally impaired DCs are recruited in the glioma microenvironment. They are severely affected by dexamethasone administration, suggesting that the detrimental effects of corticosteroids on DCs may represent one of the mechanisms contributing to the already reported negative prognostic impact of steroids on glioma patient survival.

Advancing Imaging to Enhance Surgery: From Image to Information Guidance.

Conventional magnetic resonance imaging (cMRI) has an established role as a crucial disease parameter in the multidisciplinary management of glioblastoma, guiding diagnosis, treatment planning, assessment, and follow-up. Yet, cMRI cannot provide adequate information regarding tissue heterogeneity and the infiltrative extent beyond the contrast enhancement. Advanced magnetic resonance imaging and PET and newer analytical methods are transforming images into data (radiomics) and providing noninvasive biomarkers of molecular features (radiogenomics), conveying enhanced information for improving decision making in surgery. This review analyzes the shift from image guidance to information guidance that is relevant for the surgical treatment of glioblastoma.

Glioblastoma Surgery Imaging-Reporting and Data System: Validation and Performance of the Automated Segmentation Task.

For patients with presumed glioblastoma, essential tumor characteristics are determined from preoperative MR images to optimize the treatment strategy. This procedure is time-consuming and subjective, if performed by crude eyeballing or manually. The standardized GSI-RADS aims to provide neurosurgeons with automatic tumor segmentations to extract tumor features rapidly and objectively. In this study, we improved automatic tumor segmentation and compared the agreement with manual raters, describe the technical details of the different components of GSI-RADS, and determined their speed. Two recent neural network architectures were considered for the segmentation task: nnU-Net and AGU-Net. Two preprocessing schemes were introduced to investigate the tradeoff between performance and processing speed. A summarized description of the tumor feature extraction and standardized reporting process is included. The trained architectures for automatic segmentation and the code for computing the standardized report are distributed as open-source and as open-access software. Validation studies were performed on a dataset of 1594 gadolinium-enhanced T1-weighted MRI volumes from 13 hospitals and 293 T1-weighted MRI volumes from the BraTS challenge. The glioblastoma tumor core segmentation reached a Dice score slightly below 90%, a patientwise F1-score close to 99%, and a 95th percentile Hausdorff distance slightly below 4.0 mm on average with either architecture and the heavy preprocessing scheme. A patient MRI volume can be segmented in less than one minute, and a standardized report can be generated in up to five minutes. The proposed GSI-RADS software showed robust performance on a large collection of MRI volumes from various hospitals and generated results within a reasonable runtime.

Intraoperative Computed Tomography and Finite Element Modelling for Multimodal Image Fusion in Brain Surgery.

BACKGROUND: intraoperative computer tomography (iCT) and advanced image fusion algorithms could improve the management of brainshift and the navigation accuracy. OBJECTIVE: To evaluate the performance of an iCT-based fusion algorithm using clinical data. METHODS: Ten patients with brain tumors were enrolled; preoperative MRI was acquired. The iCT was applied at the end of microsurgical resection. Elastic image fusion of the preoperative MRI to iCT data was performed by deformable fusion employing a biomechanical simulation based on a finite element model. Fusion accuracy was evaluated: the target registration error (TRE, mm) was measured for rigid and elastic fusion (Rf and Ef) and anatomical landmark pairs were divided into test and control structures according to distinct involvement by the brainshift. Intraoperative points describing the stereotactic position of the brain were also acquired and a qualitative evaluation of the adaptive morphing of the preoperative MRI was performed by 5 observers. RESULTS: The mean TRE for control and test structures with Rf was 1.81 ± 1.52 and 5.53 ± 2.46 mm, respectively. No significant change was observed applying Ef to control structures; the test structures showed reduced TRE values of 3.34 ± 2.10 mm after Ef (P < .001). A 32% average gain (range 9%-54%) in accuracy of image registration was recorded. The morphed MRI showed robust matching with iCT scans and intraoperative stereotactic points. CONCLUSIONS: The evaluated method increased the registration accuracy of preoperative MRI and iCT data. The iCT-based non-linear morphing of the preoperative MRI can potentially enhance the consistency of neuronavigation intraoperatively.

Cerebrospinal fluid tumor DNA for liquid biopsy in glioma patients' management: Close to the clinic?

Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.

Mapping in Low-Grade Glioma Surgery: Low- and High-Frequency Stimulation.

Surgery for lower grade glioma requires the use of brain mapping techniques to identify functional boundaries, which represent the limit of the resection. Two stimulation paradigms are currently available and their use should be tailored to the clinical context to extend tumor removal and decrease the odds of postoperative permanent deficits.

Innovation in Neurosurgery: The Concept of Cognitive Mapping.

In recent years, advances in cortical-subcortical mapping, intraoperative neurophysiology, and neuropsychology have increased the ability to remove intrinsic brain tumors, expanding indications and maximizing the extent of resection. This has provided a significant improvement in progression-free survival, time of malignant transformation (in low-grade gliomas), and overall survival. Although current techniques enable preservation of language and motor functions during surgery, the maintenance of a complex set of functions defined with the term cognition is not always achievable. Cognition is defined as every neural process underlying a high human function and includes motor haptic and visuospatial functions, memory, social interactions, empathy, and emotions. In this regard, an extensive preoperative and postoperative neuropsychological evaluation is strongly suggested to assess cognitive impairment due to tumor growth, to assess surgical result, and to plan cognitive rehabilitation. This article discusses the main recent innovations introduced for cognitive mapping with the aim to preserve cognitive functions, which are essential to maintain a high quality of life.

Intracranial Meningiomas: A Systematic Analysis of Prognostic Factors for Recurrence in a Large Single Institution Surgical Series.

BACKGROUND: Meningioma is the most common primary intracranial tumor. Surgical resection is the first choice of treatment, whereas the role of adjuvant radiotherapy (RT) is still unclear. Aim of the study was to evaluate prognostic factors influencing the local recurrence rate. METHODS: Patients who had grade I-II meningiomas and underwent surgery were included in the present study. The extent of surgical resection was defined according to Simpson criteria, and were dichotomized as gross total and subtotal resection (STR). Adjuvant RT was considered in case of STR. Clinical outcome was evaluated by neurological examination and brain magnetic resonance imaging, which was performed every 6 months for the first year and yearly thereafter. RESULTS: From January 2000 to December 2015, 296 patients were analyzed. Most were women (65.9%), with a Karnofsky performance status ≥80 (94.6%), grade I meningioma (79.4%), and symptoms at diagnosis (91.5%). STR was performed in 58%, followed by adjuvant RT in 10%. Improvement or stability of neurological status was obtained in 90.4% of patients. The median follow-up time was 79 months (range, 24-214 months). Local recurrence occurred in 87 (29.4%) patients, at a median time of 56 months (range, 6-214 months). No patients, who underwent surgery plus adjuvant RT, had local relapse. The median, 2-, 5-, 10-year progression-free survival were 172 months, 91.1%, 80.7%, and 67.2%, respectively. On univariate and multivariate analysis factors impacting on progression-free survival were grade, extent of surgical resection, and adjuvant RT in case of STR, regardless of meningioma grade. CONCLUSIONS: Overall, our findings suggest that recurrence rates are influenced by grade, extent of surgical resection, and use of adjuvant RT in not completely resected meningioma, regardless of tumor grade.

Surgery Followed by Hypofractionated Radiosurgery on the Tumor Bed in Oligometastatic Patients With Large Brain Metastases. Results of a Phase 2 Study.

PURPOSE: This prospective phase II study assessed safety and feasibility of surgery followed by hypofractionated radiosurgery (HSRS) on the tumor bed in oligometastatic patients with single large brain metastases (BMs). METHODS AND MATERIALS: Between June 2015 and May 2018, 101 patients were enrolled. Oligometastatic disease was defined by a maximum of 5 extracranial metastatic lesions. HSRS was performed within 1 month of surgery and consisted of 30 Gy in 3 fractions. Local control, occurrence of new BMs, overall survival, and treatment-related toxicities were assessed. RESULTS: At a median follow-up time of 26 months, local recurrence occurred in 6 patients (5.9%). Six-month, 1-year, and 2-year local control rates were 100%, 98.9% ± 1.1%, and 85.9% ± 0.6%, respectively. New BMs occurred in 39 patients (38.6%); median brain distant progression time and 6-month, 1-year, and 2-year brain distant progression rates were 39 months (95% CI, 19-39 months), 17% ± 3.7%, 31.4% ± 4.8%, and 42.5% ± 5.9%, respectively. At the last observation time, 50 patients (49.5%) were alive and 51 (50.5%) were dead; 10 patients died owing to neurologic causes and 40 as a result of systemic progression. Median overall survival time and 6-month, 1-year, and 2-year overall survival rates were 22 months (95% CI, 20-30 months), 95% ± 2.1%, 81.9% ± 3.8%, and 46.6% ± 6%, respectively. Infratentorial site, residual tumor volume, longer interval time between primary diagnosis and occurrence of BMs, and oligometastatic disease status significantly influenced outcome. Grade 2 to 3 radionecrosis occurred in 26 patients. Neurocognitive functions remained stable or, in some cases, improved. CONCLUSIONS: Surgery followed by HSRS on the tumor bed is a safe and effective approach, affording good brain control with acceptable toxicities. As for extracranial metastatic sites, patients with BMs can benefit from local ablative treatment in the context of an oligometastatic disease.

Predictors of Epileptic Seizures and Ability to Work in Supratentorial Cavernous Angioma Located Within Eloquent Brain Areas.

BACKGROUND: The postoperative outcomes and the predictors of seizure control are poorly studied for supratentorial cavernous angiomas (CA) within or close to the eloquent brain area. OBJECTIVE: To assess the predictors of preoperative seizure control, postoperative seizure control, and postoperative ability to work, and the safety of the surgery. METHODS: Multicenter international retrospective cohort analysis of adult patients benefitting from a functional-based surgical resection with intraoperative functional brain mapping for a supratentorial CA within or close to eloquent brain areas. RESULTS: A total of 109 patients (66.1% women; mean age 38.4 ± 12.5 yr), were studied. Age >38 yr (odds ratio [OR], 7.33; 95% confidence interval [CI], 1.53-35.19; P = .013) and time to surgery > 12 mo (OR, 18.21; 95% CI, 1.11-296.55; P = .042) are independent predictors of uncontrolled seizures at the time of surgery. Focal deficit (OR, 10.25; 95% CI, 3.16-33.28; P < .001) is an independent predictor of inability to work at the time of surgery. History of epileptic seizures at the time of surgery (OR, 7.61; 95% CI, 1.67-85.42; P = .003) and partial resection of the CA and/or of the hemosiderin rim (OR, 12.02; 95% CI, 3.01-48.13; P < .001) are independent predictors of uncontrolled seizures postoperatively. Inability to work at the time of surgery (OR, 19.54; 95% CI, 1.90-425.48; P = .050), Karnofsky Performance Status ≤ 70 (OR, 51.20; 95% CI, 1.20-2175.37; P = .039), uncontrolled seizures postoperatively (OR, 105.33; 95% CI, 4.32-2566.27; P = .004), and worsening of cognitive functions postoperatively (OR, 13.71; 95% CI, 1.06-176.66; P = .045) are independent predictors of inability to work postoperatively. CONCLUSION: The functional-based resection using intraoperative functional brain mapping allows safe resection of CA and the peripheral hemosiderin rim located within or close to eloquent brain areas.

Long-Term Follow-Up of Patients with Metastatic Epidural Spinal Cord Compression from Breast Cancer Treated with Surgery Followed by Radiotherapy.

OBJECTIVE: To evaluate role of surgery plus radiotherapy (RT) in patients with metastatic epidural spinal cord compression from breast cancer with a follow-up >10 years. METHODS: The study included 23 patients treated between 2004 and 2008. Surgical treatment was performed in patients with good performance status, limited metastatic disease, and progressive neurologic deficit and/or intractable pain. RT was performed delivering a median total dose of 30 Gy in 10 fractions. Clinical outcome was evaluated using the modified visual analog scale for pain, Frankel grade for neurologic deficit, and magnetic resonance imaging before and after treatments and every 3 months thereafter. RESULTS: Minimal resection was performed in 17.4% of patients, curettage in 47.8%, and total tumorectomy in 34.8%, followed by RT in 78.3%. Pain remission was obtained in 98% of patients, and recovery of neurologic function was obtained in 92.9%. Median follow-up time was 153 months (range, 128-209 months). No relapse at site of treatments occurred. Median overall survival time was 47 months (95% confidence interval 33-114 months), and 2-, 5-, and 10-year overall survival rates were 81% (±8.6%), 42.9% (±10.8%), and 28.6% (±9.9%). On univariate analysis, performance status, type of surgical resection, breast cancer phenotype, and presence of other bone metastases were recorded as influencing survival; the last-mentioned was also confirmed in multivariate analysis. CONCLUSIONS: Surgery plus RT is a safe and feasible treatment with limited morbidity. In selected patients with good performance status, positive hormonal receptors, and limited metastatic disease, surgical intervention should be strongly considered early on.

Long-Term Follow-Up of Patients with Metastatic Epidural Spinal Cord Compression from Solid Tumors Submitted for Surgery Followed by Radiation Therapy.

OBJECTIVE: To evaluate the outcome of patients with epidural spinal cord compression from different solid tumors treated with a combined approach, surgery plus radiotherapy (RT), with a follow-up longer than 10 years. METHODS: Ninety-seven patients treated between 2002 and 2009 were included. Surgical treatment was performed in patients with good performance status, limited metastatic disease, life expectancy longer than 3 months, and progressive neurologic deficit and/or intractable pain. RT was performed delivering a median total dose of 30 Gy in 10 fractions. Clinical outcome was evaluated using the modified visual analog scale for pain, the Frankel scale for neurologic deficit, and magnetic resonance imaging before treatment, after treatment, and every 3 months thereafter. RESULTS: Palliative decompression was performed in 27% of patients, tumor curettage (debulking) was performed in 51%, and total vertebrectomy was performed in 22%, followed by RT in 78% of cases. Pain remission was obtained in 98% of patients, and recovery of neurologic function was obtained in 51%. The median follow-up time was 135 months (range, 96-209 months). The 5- and 10-year local control rates were 82.8% and 82.8%, respectively. The median and 5- and 10-year progression-free survival rates were 12 months, 16.9%, and 11.3%, respectively; the median and 5- and 10-year overall survival rates were 18 months, 21.3%, and 12%, respectively. On univariate and multivariate analysis, factors recorded as conditioning survival were the performance status and the presence of other metastases at the time of vertebral treatment (P < 0.01). CONCLUSIONS: Our update confirmed that surgery plus RT is a safe and feasible treatment with limited morbidity. In selected patients with favorable prognostic factors, the combined treatment may significantly impact on survival.