Explainable hybrid vision transformers and convolutional network for multimodal glioma segmentation in brain MRI.

Accurate localization of gliomas, the most common malignant primary brain cancer, and its different sub-region from multimodal magnetic resonance imaging (MRI) volumes are highly important for interventional procedures. Recently, deep learning models have been applied widely to assist automatic lesion segmentation tasks for neurosurgical interventions. However, these models are often complex and represented as "black box" models which limit their applicability in clinical practice. This article introduces new hybrid vision Transformers and convolutional neural networks for accurate and robust glioma segmentation in Brain MRI scans. Our proposed method, TransXAI, provides surgeon-understandable heatmaps to make the neural networks transparent. TransXAI employs a post-hoc explanation technique that provides visual interpretation after the brain tumor localization is made without any network architecture modifications or accuracy tradeoffs. Our experimental findings showed that TransXAI achieves competitive performance in extracting both local and global contexts in addition to generating explainable saliency maps to help understand the prediction of the deep network. Further, visualization maps are obtained to realize the flow of information in the internal layers of the encoder-decoder network and understand the contribution of MRI modalities in the final prediction. The explainability process could provide medical professionals with additional information about the tumor segmentation results and therefore aid in understanding how the deep learning model is capable of processing MRI data successfully. Thus, it enables the physicians' trust in such deep learning systems towards applying them clinically. To facilitate TransXAI model development and results reproducibility, we will share the source code and the pre-trained models after acceptance at https://github.com/razeineldin/TransXAI .

Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.

PURPOSE: Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma. METHODS: This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters. RESULTS: We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (P = .79). Incision-suture times (P < .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS (P < .001) and OS (P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors (P = .006). CONCLUSION: We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.

Role of interhemispheric connectivity in recovery from postoperative supplementary motor area syndrome in glioma patients.

OBJECTIVE: Surgical resection of gliomas involving the supplementary motor area (SMA) frequently results in SMA syndrome, a symptom complex characterized by transient akinesia and mutism. Because the factors influencing patient functional outcomes after surgery remain elusive, the authors investigated network-based predictors in a multicentric cohort of glioma patients. METHODS: The participants were 50 patients treated for glioma located in the SMA at one of the three centers participating in the study. Postoperative functional outcomes (motor deficits, mutism) and duration of symptoms were assessed during hospitalization. Long-term outcome was assessed 3 months after surgery. MRI-based lesion-symptom mapping was performed to estimate the severity of gray matter damage and white matter disconnection. RESULTS: The median duration of acute symptoms was 3 days (range 1-42 days). Long-term deficits involving fine motor movements and speech were found at follow-up in 27 patients (54%). Disconnection of the central callosal fibers was associated with prolonged acute symptoms (p < 0.05). Postoperative mutism was significantly related to disconnection severity of the left frontopontine tract, frontal aslant tract, cingulum, and corticostriatal tract (p < 0.05). Disconnection of midposterior callosal fibers and lesion loads within the left medial Brodmann area 4 were associated with long-term motor deficits (p < 0.05). CONCLUSIONS: This study provides evidence for the pathophysiology and predictive factors of postoperative SMA syndrome by demonstrating the relation of the disconnection of callosal fibers with prolonged symptom duration (central segment) and long-term motor deficits (midposterior segment). These data may be useful for presurgical risk assessment and adequate consultation for patients prior to undergoing resection of glioma located within the SMA region.

Resilience in Lower Grade Glioma Patients.

Current data show that resilience is an important factor in cancer patients' well-being. We aim to explore the resilience of patients with lower grade glioma (LGG) and the potentially influencing factors. We performed a cross-sectional assessment of adult patients with LGG who were enrolled in the LoG-Glio registry. By phone interview, we administered the following measures: Resilience Scale (RS-13), distress thermometer, Montreal Cognitive Assessment Test for visually impaired patients (MoCA-Blind), internalized stigmatization by brain tumor (ISBI), Eastern Cooperative Oncological Group performance status (ECOG), patients' perspective questionnaire (PPQ) and typical clinical parameters. We calculated correlations and multivariate regression models. Of 74 patients who were assessed, 38% of those showed a low level of resilience. Our results revealed significant correlations of resilience with distress (p < 0.001, −0.49), MOCA (p = 0.003, 0.342), ECOG (p < 0.001, −0.602), stigmatization (p < 0.001, −0.558), pain (p < 0.001, −0.524), and occupation (p = 0.007, 0.329). In multivariate analyses, resilience was negatively associated with elevated ECOG (p = 0.020, ß = −0.383) and stigmatization levels (p = 0.008, ß = −0.350). Occupation showed a tendency towards a significant association with resilience (p = 0.088, ß = −0.254). Overall, low resilience affected more than one third of our cohort. Low functional status is a specific risk factor for low resilience. The relevant influence of stigmatization on resilience is a novel finding for patients suffering from a glioma and should be routinely identified and targeted in clinical routine.

Evaluation of a Navigated 3D Ultrasound Integration for Brain Tumor Surgery: First Results of an Ongoing Prospective Study.

The aim of the study was to assess the quality, accuracy and benefit of navigated 2D and 3D ultrasound for intra-axial tumor surgery in a prospective study. Patients intended for gross total resection were consecutively enrolled. Intraoperatively, a 2D and 3D iUS-based resection was performed. During surgery, the image quality, clinical benefit and navigation accuracy were recorded based on a standardized protocol using Likert's scales. A total of 16 consecutive patients were included. Mean ratings of image quality in 2D iUS were significantly higher than in 3D iUS (p < 0.001). There was no relevant decrease in rating during the surgery in 2D and 3D iUS (p > 0.46). The benefit was rated 2.2 in 2D iUS and 2.6 in 3D iUS (p = 0.08). The benefit remained stable in 2D, while there was a slight decrease in the benefit in 3D after complete tumor resection (p = 0.09). The accuracy was similar in both (mean 2.2 p = 0.88). Seven patients had a small tumor remnant in intraoperative MRT (mean 0.98 cm3) that was not appreciated with iUS. Crucially, 3D iUS allows for an accurate intraoperative update of imaging with slightly lower image quality than 2D iUS. Our preliminary data suggest that the benefit and accuracy of 2D and 3D iUS navigation do not undergo significant variations during tumor resection.

Explainability of deep neural networks for MRI analysis of brain tumors.

PURPOSE: Artificial intelligence (AI), in particular deep neural networks, has achieved remarkable results for medical image analysis in several applications. Yet the lack of explainability of deep neural models is considered the principal restriction before applying these methods in clinical practice. METHODS: In this study, we propose a NeuroXAI framework for explainable AI of deep learning networks to increase the trust of medical experts. NeuroXAI implements seven state-of-the-art explanation methods providing visualization maps to help make deep learning models transparent. RESULTS: NeuroXAI has been applied to two applications of the most widely investigated problems in brain imaging analysis, i.e., image classification and segmentation using magnetic resonance (MR) modality. Visual attention maps of multiple XAI methods have been generated and compared for both applications. Another experiment demonstrated that NeuroXAI can provide information flow visualization on internal layers of a segmentation CNN. CONCLUSION: Due to its open architecture, ease of implementation, and scalability to new XAI methods, NeuroXAI could be utilized to assist radiologists and medical professionals in the detection and diagnosis of brain tumors in the clinical routine of cancer patients. The code of NeuroXAI is publicly accessible at https://github.com/razeineldin/NeuroXAI .

Eloquent Lower Grade Gliomas, a Highly Vulnerable Cohort: Assessment of Patients' Functional Outcome After Surgery Based on the LoG-Glio Registry.

Majority of lower grade glioma (LGG) are located eloquently rendering surgical resection challenging. Aim of our study was to assess rate of permanent deficits and its predisposing risk factors. We retrieved 83 patients harboring an eloquently located LGGs from the prospective LoG-Glio Database. Patients without surgery or incomplete postoperative data were excluded. Sign rank test, explorative correlations by Spearman ρ and multivariable regression for new postoperative deficits were calculated. Eloquent region involved predominantly motor (45%) and language (40%). At first follow up after 3 months permanent neuro-logical deficits (NDs) were noted in 39%. Mild deficits remained in 29% and severe deficits in 10%. Complete tumor removal (CTR) was successfully in 62% of intended cases. Postoperative and 3-month follow up National Institute of Health Stroke Score (NIHSS) showed significantly lower values than preoperatively (p<0.001). 38% cases showed a decreased NIHSS at 3-month, while occurrence was only 14% at 9-12-month follow up. 6/7 patients with mild aphasia recovered after 9-12 months, while motor deficits present at 3-month follow up were persistent in majority of patients. Eastern oncology group functional status (ECOG) significantly decreased by surgery (p < 0.001) in 31% of cases. Between 3-month and 9-12-months follow up no significant improvement was seen. In the multivariable model CTR (p=0.019, OR 31.9), and ECOG>0 (p=0.021, OR 8.5) were independent predictors for permanent postoperative deficit according to NIHSS at 3-month according to multivariable regression model. Patients harboring eloquently located LGG are highly vulnerable for permanent deficits. Almost one third of patients have a permanent reduction of their functional status based on ECOG. Risk of an extended resection has to be balanced with the respective oncological benefit. Especially, patients with impaired pre-operative status are at risk for new permanent deficits. There is a relevant improvement of neurological symptoms in the first year after surgery, especially for patients with slight aphasia.

Characterization of tumor remnants in intraoperative MRI-assisted microscopic and endoscopic transsphenoidal resection of less invasive pituitary adenomas.

INTRODUCTION: Intraoperative magnetic resonance imaging (iMRI) improves the intraoperative detection of adenoma remnants in transsphenoidal surgery. iMRI might be redundant in endoscopic pituitary surgery in non-invasive tumors (Knosp 0-2) due to a superior visualization of anatomical structures in the periphery of the sella turcica compared to the microscopic technique. We identified the anatomical location of tumor remnants in iMRI and evaluated risk factors for secondary resection after iMRI and hereby selected patients with pituitary adenomas who may benefit from iMRI-assisted resection. METHODS: We conducted a retrospective monocenter study of patients who underwent iMRI-assisted transsphenoidal surgical resection of pituitary adenomas at our department between 2012 and 2020. A total number of 190 consecutive iMRI-assisted transsphenoidal surgeries of pituitary adenomas graded as Knosp 0-2 were selected for analysis. Exclusion criteria were missing iMRI availability or pathologies other than adenomas. Of these 190 cases, 46.3% (N = 88) were treated with microscopic, 48.4% (N = 92) with endoscopic, and 5.3% (N = 10) with endoscopic-assisted technique. Volumetric measurement of preoperative, intraoperative, and postoperative tumor extension was performed. Demographic data, tumor characteristics, and MRI features were evaluated. Additionally, analysis of adenoma remnants identified by iMRI was performed. RESULTS: An additional resection after iMRI was performed in 16.3% (N = 31). iMRI helped to reach gross total resection (GTR) in 83.9% (26/31) of these cases. False-positive resection was found in 1 patient (0.5%). Multivariable logistic analysis identified tumor volume (OR = 1.2, p = 0.007) recurrence (OR = 11.3, p = 0.002) and microscopic technique (OR = 2.8, p = 0.029) as independent risk factors for additional resection. Simultaneously, the endoscopic technique was significantly associated with GTR as evaluated by iMRI (OR = 2.8, p = 0.011) and postoperative MRI (OR = 5.8, p = 0.027). The detailed analysis of adenoma remnants on iMRI revealed the suprasellar location in a diaphragm fold, penetrating tumor above the diaphragm, or undetected invasion of cavernous sinus as well as in case of microscopic resection tumor location outside the line of sight as the main reasons for incomplete resections. CONCLUSION: Tumor volume, recurrence, and microscopic technique were identified as independent predictors for additional resection in patients with Knosp 0-2 adenomas. iMRI might increase the extent of resection (EOR) safely even after the endoscopic visualization of the sella with very low risk for false-positive findings. Remnants of tumors hidden within the diaphragmic folds, intrathecally, or behind the infiltrated wall of cavernous sinus not recognized on preoperative MRI were the most common findings in iMRI.

The Impact of an Ultra-Early Postoperative MRI on Treatment of Lower Grade Glioma.

The timing of MRI imaging after surgical resection may have an important role in assessing the extent of resection (EoR) and in determining further treatment. The aim of our study was to evaluate the time dependency of T2 and FLAIR changes after surgery for LGG. The Log-Glio database of patients treated at our hospital from 2016 to 2021 was searched for patients >18a and non-enhancing intra-axial lesion with complete MR-imaging protocol. A total of 16 patients matched the inclusion criteria and were thus selected for volumetric analysis. All patients received an intraoperative scan (iMRI) after complete tumor removal, an ultra-early postoperative scan after skin closure, an early MRI within 48 h and a late follow up MRI after 3-4 mo. Detailed volumetric analysis of FLAIR and T2 abnormalities was conducted. Demographic data and basic characteristics were also analyzed. An ultra-early postoperative MRI was performed within a median time of 30 min after skin closure and showed significantly lower FLAIR (p = 0.003) and T2 (p = 0.003) abnormalities when compared to early postoperative MRI (median 23.5 h), though no significant difference was found between ultra-early and late postoperative FLAIR (p = 0.422) and T2 (p = 0.575) images. A significant difference was calculated between early and late postoperative FLAIR (p = 0.005) and T2 (p = 0.019) MRI scans. Additionally, we found no significant difference between intraoperative and ultra-early FLAIR/T2 (p = 0.919 and 0.499), but we found a significant difference between iMRI and early MRI FLAIR/T2 (p = 0.027 and p = 0.035). Therefore, a postoperative MRI performed 24 h or 48 h might lead to false positive findings. An MRI scan in the first hour after surgery (ultra-early) correlated best with residual tumor at 3 months follow up. An iMRI with open skull, at the end of resection, was similar to an ultra-early MRI with regard to residual tumor.

Adding Flexible Instrumentation to a Curved Videolaryngoscope: A Novel Tool for Laryngeal Surgery.

OBJECTIVES: Transoral surgery of the larynx with rigid instruments is not always possible. This may result in insufficient therapy or in an increased need for open surgery. For these patients, alternative surgical systems are needed. Here, we demonstrate a curved prototype for laryngeal surgery equipped with flexible instruments. STUDY DESIGN: Pre-clinical user study in an ex vivo porcine laryngeal model. METHODS: The prototype was built from established medical devices, namely a hyperangulated videolaryngoscope and modified flexible instruments as well as three-dimensional printed parts. Feasibility of laryngeal manipulation was evaluated in a user study (n = 19) with a porcine ex vivo laryngeal model. Using three different visualization technologies, the participants performed various fine motor skills tasks and rated the usability of the system on a 5-point Likert scale. RESULTS: Exposure, accessibility, and manipulation of important laryngeal structures were always possible using the new prototype. The participants needed considerably less time (mean, 96.4 seconds ± 6.4 seconds vs. 111.5 seconds ± 4.5 seconds, P = .18), reported significantly better general impression (mean score 3.0 vs. 3.8, P = .041) and significantly lower user head and neck strain (2.6 vs. 1.7, P = .022) using a 40-inch television screen as compared to a standard videolaryngoscope monitor. CONCLUSION: The results indicate that our curved prototype and large monitor visualization may provide a cost-effective minimally invasive alternative for difficult laryngeal exposure. Its special advantages include avoiding the need for a straight line of sight and a simple and cost-effective construction. The system could be further improved through advances in camera chip technology and smaller instruments. Laryngoscope, 131:E561-E568, 2021.

Towards the targeted assessment of relevant problems: Optimization of the distress Thermometer for adult neuro-oncological patients.

OBJECTIVE: Generic psychosocial screening tools may not reflect the unique symptom profile of brain tumour patients (BTPs). The aim was to adapt the problem list of the distress thermometer (DT) for BTPs. METHODS: First, items of low relevance for BTPs were identified on basis of retrospective analyses. Second, relevant yet missing problems were identified via an extensive literature search, qualitative interviews with BTPs and experts, as well as an online expert survey. The resulting raw version of the adapted problem list in BTPs was subsequently pretested. RESULTS: In the first part, data of n = 657 BTPs were analysed. Twelve items (20%) were excluded in this step as they proved to be less relevant for BTPs (i.e., items were endorsed by less than 10% and without significant correlations to patients' DT score). In the second part, qualitative interviews and the online survey with 102 professionals led to the addition of 21 new and the modification and condensation of 17 relevant problems specific for BTPs. This adapted list was than successfully pretested in n = 19 patients, leading to the 'distress thermometer brain tumour problem list' (DT-BT), consisting of 42 relevant problems. CONCLUSION: The adapted problem list for the DT particularly reflects the neurological and psychosocial burden of an intracranial tumour and allows for the targeted assessment of the specific burdens and needs of BTPs. Our revised version of the DTs problem list (DT-BT) should in the next step be widely validated in multinational samples.

Ten years' experience with intraoperative MRI-assisted transsphenoidal pituitary surgery.

OBJECTIVE: Many innovations have been introduced into pituitary surgery in the quest to maximize the extent of tumor resection. Because of the deep and narrow surgical corridor as well as the heterogeneity of confronted pathologies, anatomical orientation and identification of the target tissue can become difficult. Intraoperative MRI (iMRI) may have the potential to increase extent of resection (EOR) in transsphenoidal pituitary surgery. Furthermore, it may simplify anatomical orientation and risk assessment in difficult cases. Here, the authors evaluated the additional value of iMRI for the resection of pituitary adenomas performed in the past 10 years in their department. METHODS: They performed a retrospective single-center analysis of patients treated for pituitary adenoma in their department after the introduction of iMRI between 2008 and 2018. Of 495 transsphenoidal approaches, 300 consecutive MRI-assisted surgeries for pituitary adenomas encompassing 294 patients were selected for further analysis. Microscopic, endoscopic, or endoscope-assisted microscopic transsphenoidal approaches were distinguished. EOR as well as additional resection following iMRI was evaluated via detailed volumetric analysis. Patients were stratified according to the Knosp adenoma classification. Furthermore, demographic data, clinical symptoms, endocrine outcome, and complications were evaluated. Univariable and multivariable Cox regression analyses of progression-free survival (PFS) were performed. RESULTS: Pituitary adenomas classified as Knosp grades 0-2 were found in 60.3% of cases (n = 181). The most common tumors were nonfunctioning adenomas (75%). Continued resection following iMRI significantly increased EOR (7.5%, p < 0.001) and the proportion of gross-total resections (GTRs) in transsphenoidal pituitary surgery (54% vs 68.3%, p < 0.001). Additional resection after iMRI was performed in 37% of cases. Only in the subgroup of patients with Knosp grades 0-2 adenomas treated with the microsurgical technique was additional resection significantly more common than in the endoscopic group (p = 0.039). Residual tumor volume, Knosp grade, and age were confirmed as independent predictors of PFS (p < 0.001, p = 0.021, and p = 0.029, respectively) in a multivariable Cox regression analysis. Improvement of visual field deficits was documented in 78.6% of patients whose optic apparatus had been affected preoperatively. Revision surgery was done in 7.3% of cases; in 5.6% of cases, it was performed for cerebrospinal fluid fistula. CONCLUSIONS: In this series, iMRI led to the detection of a resectable tumor remnant in a high proportion of patients, resulting in a greater EOR and higher proportion of GTRs after continued resection in microsurgical and endoscopic transsphenoidal resection of pituitary adenomas. The volume of residual tumor was the most important predictor of PFS. Given the study data, the authors postulated that every bit of removed tumor serves the patient and increases their chances of a favorable outcome.

DeepSeg: deep neural network framework for automatic brain tumor segmentation using magnetic resonance FLAIR images.

PURPOSE: Gliomas are the most common and aggressive type of brain tumors due to their infiltrative nature and rapid progression. The process of distinguishing tumor boundaries from healthy cells is still a challenging task in the clinical routine. Fluid-attenuated inversion recovery (FLAIR) MRI modality can provide the physician with information about tumor infiltration. Therefore, this paper proposes a new generic deep learning architecture, namely DeepSeg, for fully automated detection and segmentation of the brain lesion using FLAIR MRI data. METHODS: The developed DeepSeg is a modular decoupling framework. It consists of two connected core parts based on an encoding and decoding relationship. The encoder part is a convolutional neural network (CNN) responsible for spatial information extraction. The resulting semantic map is inserted into the decoder part to get the full-resolution probability map. Based on modified U-Net architecture, different CNN models such as residual neural network (ResNet), dense convolutional network (DenseNet), and NASNet have been utilized in this study. RESULTS: The proposed deep learning architectures have been successfully tested and evaluated on-line based on MRI datasets of brain tumor segmentation (BraTS 2019) challenge, including s336 cases as training data and 125 cases for validation data. The dice and Hausdorff distance scores of obtained segmentation results are about 0.81 to 0.84 and 9.8 to 19.7 correspondingly. CONCLUSION: This study showed successful feasibility and comparative performance of applying different deep learning models in a new DeepSeg framework for automated brain tumor segmentation in FLAIR MR images. The proposed DeepSeg is open source and freely available at https://github.com/razeineldin/DeepSeg/.

Glioma patients in outpatient care-optimization of psychosocial care in neuro-oncological patients (GLIOPT): Protocol for a cluster randomized controlled trial.

BACKGROUND: Patients with high-grade gliomas (HGG) often suffer from high distress and require psychosocial support. However, due to neurological and neurocognitive deficits, adequate assessment of distress and support needs remains challenging in clinical practice. The objective of the present study is to investigate whether a systematic implementation of signaling questions into the routine outpatient consultation will be helpful to bridge this gap. METHODS/DESIGN: This is a multicenter cluster randomized study with two arms. Randomization is done on a cluster level with 13 hospitals providing regular neuro-oncological outpatient services conducted by neurologists and/or neurosurgeons. The intervention will include an assessment of psychosocial distress of patients in doctor-patient conversation compared to assessment of psychosocial distress via questionnaire (control, standard of care). In total, 616 HGG patients will be enrolled. The outcome will be the number of HGG patients with increased psychosocial distress who receive professional support from psychosocial services. Secondary endpoints are inter alia number of patients reporting psychosocial distress and unmet needs detected correctly by the respective method; quality of life; psychological well-being and burden of the patients before and after doctor-patient consultation; as well as the length of the doctor-patient consultation. DISCUSSION: Patients with HGG are confronted with an oncological diagnosis and at the same time with high symptom burden. This often leads to distress, which is not always adequately recognized and treated. So far, only a limited number of adequate instruments are available to assess HGG patient's distress. Yet, an adequate care and support network might facilitate the course of the disease and tumor therapies for patients. Our hypothesis is that an assessment conducted directly by attending doctors and in which the doctors talk to patients with HGG will be more effective than an assessment via a questionnaire, leading to better identifying patients in need of support. This may lead to an improvement of health care in these patients. Further, this method might be implemented also in other brain tumor patients (e.g., patients with brain metastases). TRIAL REGISTRATION: German Clinical Trials Register, DRKS00018079. Registered on 3rd September 2019.

Health-related quality of life and distress in elderly vs. younger patients with high-grade glioma-results of a multicenter study.

OBJECTIVE: Half of all newly diagnosed patients with glioblastoma are > 65 years still with a poor prognosis. Preserving quality of life is of high importance. However, patient reported outcome (PRO) data in this patient group is rare. The aim was to compare health-related quality of life (HRQoL) and distress between elderly and younger patients with high-grade glioma (HGG). METHODS: We used baseline data of a prospective study where HGG patients were enrolled from 4 hospitals. Distress was measured using the distress thermometer (DT), HRQoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) plus brain module (BN20). We compared distress and HRQoL by age (≥ 65 vs. < 65 years), gender, performance score, and time since diagnosis using multivariate linear and logistic regressions. RESULTS: A total of n = 93 (30%) out of n = 309 patients were ≥ 65 years (mean 70 years, range 65-86 years). Mean DT score of elderly patients (5.2, SD 2.6) was comparable with younger patients (4.9, SD 2.6). Elderly patients reported significantly lower global health (GHS, mean elderly vs. younger; 50.8 vs. 60.5, p = 0.003), worse physical (56.8 vs. 73.3, p < 0.001) and lower cognitive functioning (51.1 vs. 63.2, p = 0.002), worse fatigue (52.5 vs. 43.5, p = 0.042), and worse motor dysfunction (34.9 vs. 23.6, p = 0.030). KPS and not age was consistently associated with HRQoL. CONCLUSION: Physical functioning was significantly reduced in the elderly compared with younger HGG patients, and at the same time, emotional functioning and DT scores were comparable. KPS shows a greater association with HRQoL than with calendric age in HGG patients reflecting the particular importance for adequate assessment of HRQoL and general condition in elderly patients.

Multicentric Registry Study on Epidemiological and Biological Disease Profile as Well as Clinical Outcome in Patients with Low-Grade Gliomas: The LoG-Glio Project.

BACKGROUND: World Health Organization (WHO) grade II low-grade gliomas (LGGs) in adults are rare, and patients' mean overall survival (OS) is relatively long. Epidemiological data on factors influencing tumor genesis and progression are scarce, and prospective data on surgical management are still lacking. Because of the molecular heterogeneity of LGG, a comprehensive molecular characterization is required for any clinical and epidemiological research. Further, a detailed radiologic assessment is needed as the only established objective criterion for progressive disease. Both radiologic and molecular assessments have to be standardized to produce comparable data. The aim of the registry is to improve the evidence for surgical management of LGG patients by establishing a multicenter registry with a strong surgical and clinical focus including mandatory biobanking. METHODS: The LoG-Glio project is a prospective national observational multicenter registry that began on November 1, 2015. Inclusion criteria encompass all patients > 18 years of age with a radiologic suspicion of LGG. Patients with severe neurologic or psychiatric disorders that may interfere with their informed consent or if there is no possibility for further follow-up are excluded. Diagnosis of glioblastoma WHO grade IV isocitrate dehydrogenase (IDH) wild type leads to a secondary exclusion of patients. In addition to demographic data, results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, add-on for patients with brain tumors, and National Health Institute Stroke Scale before and after surgery and during regular follow-ups are collected. At each time point a detailed recording of surgical and adjuvant treatment is performed. Radiologic assessment involves three-dimensional (3D) acquisition of T1, fluid-attenuated inversion recovery, and T2 sequences. For the final evaluation, a central detailed neuropathologic and molecular assessment of tumor samples and a radiologic evaluation of imaging sets are part of the study protocol. RESULTS: We report the first 100 consecutively registered patients for LoG-Glio. Three patients dropped out due to loss of follow-up. Of the remaining recruited patients, 8 were classified as wait and scan; 89 had surgery. Using the inclusion criteria described previously, 70 patients had an IDH-mutated glioma, 10 had miscellaneous rare LGGs, and 8 patients had an IDH wild-type WHO grade II or III glioma. CONCLUSION: The LoG-Glio registry has been successfully implemented. Applied selection criteria result in an appropriately balanced patient cohort. Short-term outcome data on epidemiology as well as the influence of current surgical techniques and adjuvant treatment on patient outcomes are expected. In the long run, the aim of the registry is to validate the new molecular-based WHO classification and the influence of the extent of resection on progression-free survival and OS. The registry provides an open platform for future research projects benefiting patients with LGG. TRIAL REGISTRATION: NCT02686229 Clinical trials.

Surgery for Diffuse WHO Grade II Gliomas: Volumetric Analysis of a Multicenter Retrospective Cohort From the German Study Group for Intraoperative Magnetic Resonance Imaging.

BACKGROUND: In diffuse WHO grade II gliomas (LGG), the extent of resection (EOR) required to achieve significant survival benefits remains elusive. OBJECTIVE: To evaluate the association of residual volume (RV) and EOR with progression-free survival (PFS) or overall survival (OS) in LGG in a retrospective, multicenter series by the German study group of intraoperative MRI (GeSGIM). METHODS: Consecutive cases were retrospectively assessed from 5 centers. Tumors were volumetrically quantified before and after surgery, and clinical data were analyzed, including IDH mutations and neurologic deficits. Kaplan-Meier estimates, accelerated failure time models (AFT), and multivariate Cox regression models were calculated to identify determinants of survival. RESULTS: A total of 140 cases were analyzed. Gross total resection (GTR) was associated with significantly longer PFS compared to any incomplete resection (P = .009). A significant survival disadvantage was evident even for small (>0-5 ml) residuals and increased for moderate (>5-20 ml) and large remnants (>20 ml) P = .001). Accordingly, PFS increased continuously for 20% incremental steps of EOR (P < .001). AFT models supported the notion of a continuous association of RV and EOR with PFS. Multivariate Cox regression models confirmed RV (P = .01) and EOR (P = .005) as continuous prognosticators of PFS. Univariate analysis showed significant associations of RV and EOR with OS. CONCLUSION: Our data support the hypothesis of a continuous relationship of RV and EOR with survival for LGG with superiority seen for GTR. Hence, GTR should be achieved whenever safely feasible, and resections should be maximized whenever tumor has to be left behind to spare function.

To treat or not to treat? A retrospective multicenter assessment of survival in patients with IDH-mutant low-grade glioma based on adjuvant treatment.

OBJECTIVE: The level of evidence for adjuvant treatment of diffuse WHO grade II glioma (low-grade glioma, LGG) is low. In so-called "high-risk" patients most centers currently apply an early aggressive adjuvant treatment after surgery. The aim of this assessment was to compare progression-free survival (PFS) and overall survival (OS) in patients receiving radiation therapy (RT) alone, chemotherapy (CT) alone, or a combined/consecutive RT+CT, with patients receiving no primary adjuvant treatment after surgery. METHODS: Based on a retrospective multicenter cohort of 288 patients (≥ 18 years old) with diffuse WHO grade II gliomas, a subgroup analysis of patients with a confirmed isocitrate dehydrogenase (IDH) mutation was performed. The influence of primary adjuvant treatment after surgery on PFS and OS was assessed using Kaplan-Meier estimates and multivariate Cox regression models, including age (≥ 40 years), complete tumor resection (CTR), recurrent surgery, and astrocytoma versus oligodendroglioma. RESULTS: One hundred forty-four patients matched the inclusion criteria. Forty patients (27.8%) received adjuvant treatment. The median follow-up duration was 6 years (95% confidence interval 4.8-6.3 years). The median overall PFS was 3.9 years and OS 16.1 years. PFS and OS were significantly longer without adjuvant treatment (p = 0.003). A significant difference in favor of no adjuvant therapy was observed even in high-risk patients (age ≥ 40 years or residual tumor, 3.9 vs 3.1 years, p = 0.025). In the multivariate model (controlled for age, CTR, oligodendroglial diagnosis, and recurrent surgery), patients who received no adjuvant therapy showed a significantly positive influence on PFS (p = 0.030) and OS (p = 0.009) compared to any other adjuvant treatment regimen. This effect was most pronounced if RT+CT was applied (p = 0.004, hazard ratio [HR] 2.7 for PFS, and p = 0.001, HR 20.2 for OS). CTR was independently associated with longer PFS (p = 0.019). Age ≥ 40 years, histopathological diagnosis, and recurrence did not achieve statistical significance. CONCLUSIONS: In this series of IDH-mutated LGGs, adjuvant treatment with RT, CT with temozolomide (TMZ), or the combination of both showed no significant advantage in terms of PFS and OS. Even in high-risk patients, the authors observed a similar significantly negative impact of adjuvant treatment on PFS and OS. These results underscore the importance of a CTR in LGG. Whether patients ≥ 40 years old should receive adjuvant treatment despite a CTR should be a matter of debate. A potential tumor dedifferentiation by administration of early TMZ, RT, or RT+CT in IDH-mutated LGG should be considered. However, these data are limited by the retrospective study design and the potentially heterogeneous indication for adjuvant treatment.