Decoding the clinical effects of low-grade glioma–induced cortical excitability

J Neurosurg 140:18–26, 2024

Patients with low-grade glioma (LGG) in eloquent regions often present with seizures, and findings on detailed neuropsychological testing are often abnormal. This study evaluated the association between cortical excitability, seizures, and cognitive function in patients with LGG.

METHODS LGG patients who underwent transcranial magnetic stimulation (TMS) from January 2021 to December 2022 were studied. Cortical excitability was measured using the resting motor thresholds (RMTs) of the upper and lower extremities. Early postoperative seizures served as the seizure endpoint. Neuropsychological assessment was completed prior to surgery contemporaneous with the TMS studies.

RESULTS A total of 31 patients were analyzed for seizure outcome. Median (interquartile range [IQR]) upper-extremity RMT was 39% (34%–46%) of maximum stimulator output, and the median (IQR) lower-extremity RMT was 69% (51%79%). Lower-extremity RMT was higher in patients with early postoperative seizures, especially in those with motor region tumors (p = 0.02); however, RMT was not associated with seizures at presentation or long-term seizure control. A total of 26 patients completed neuropsychological assessment. There were significant negative correlations between upper-extremity RMT and psychomotor processing speed (Wechsler Adult Intelligence Scale–Fourth Edition [WAIS-IV] Processing Speed Index r = −0.42, p = 0.031; WAIS-IV Coding r = −0.41, p = 0.036; WAIS-IV Symbol Search r = −0.39, p = 0.048), executive function (Trail Making Test Part B r = −0.41, p = 0.036), and hand dexterity (Grooved Pegboard Test r = −0.50, p = 0.047).

CONCLUSIONS RMT was positively correlated with early postoperative seizure risk and negatively correlated with psychomotor processing speed, executive function, and hand dexterity. These findings support the theory of local and regional resting oscillatory network dysfunction from a glioma-brain network.

Analysis of Prognostic Factors and Surgical Management of Elderly Patients with Low-Grade Gliomas

World Neurosurg. (2023) 176:e20-e31

The number of elderly patients with low-grade glioma (LGG) is increasing, but their prognostic factors and surgical treatment are still controversial. This paper aims to investigate the prognostic factors of overall survival and cancer-specific survival in elderly patients with LGG and analyze the optimal surgical treatment strategy.

METHODS: Patients in the study were obtained from the Surveillance, Epidemiology, and End Results database and patients were randomized into a training and a test set (7:3). Clinical variables were analyzed by univariate and multivariate Cox regression analysis to screen for significant prognostic factors, and nomograms visualized the prognosis. In addition, survival analysis of elderly patients regarding different surgical management was also analyzed by Kaplan-Meier curves.

RESULTS: Six prognostic factors were screened by univariate and multivariate Cox regression analysis on the training set: tumor site, laterality, histological type, the extent of surgery, radiotherapy, and chemotherapy, and all factors were visualized by nomogram. And we evaluated the accuracy of the nomogram model using consistency index, calibration plots, receiver operator characteristic curves, and decision curve analysis, showing that the nomogram has strong accuracy and applicability. We also found that gross total resection improved overall survival and cancer-specific survival in patients with LGG aged ‡65 years relative to those who did not undergo surgery (P < 0.001).

CONCLUSIONS: Based on the Surveillance, Epidemiology, and End Results database, we created and validated prognostic nomograms for elderly patients with LGG, which can help clinicians to provide personalized treatment services and clinical decisions for their patients. More importantly, we found that older age alone should not preclude aggressive surgery for LGGs.

Precuneal gliomas promote behaviorally relevant remodeling of the functional connectome

J Neurosurg 138:1531–1541, 2023

The precuneus hosts one of the most complex patterns of functional connectivity in the human brain. However, due to the extreme rarity of neurological lesions specifically targeting this structure, it remains unknown how focal damage to the precuneus may impact resting-state functional connectivity (rsFC) at the brainwide level. The aim of this study was to investigate glioma-induced rsFC modulations and to identify patterns of rsFC remodeling that accounted for the maintenance of cognitive performance after awake-guided surgical excision.

METHODS In a unique series of patients with IDH1-mutated low-grade gliomas (LGGs) infiltrating the precuneus who were treated at a single neurosurgical center (Montpellier University Medical Center, 2014–2021), the authors gauged the dynamic modulations induced by tumors on rsFC in comparison with healthy participants. All patients received a preoperative resting-state functional MRI and underwent operation guided by awake cognitive mapping. Connectome multivariate pattern analysis (MVPA), seed-network analysis, and graph theoretical analysis were conducted and correlated to executive neurocognitive scores (i.e., phonological and semantic fluencies, Trail-Making Test [TMT] parts A and B) obtained 3 months after surgery.

RESULTS Seventeen patients with focal precuneal infiltration were selected (mean age 38.1 ± 11.2 years) and matched to 17 healthy participants (mean age 40.5 ± 10.4 years) for rsFC analyses. All patients underwent awake cognitive mapping, allowing total resection (n = 3) or subtotal resection (n = 14), with a mean extent of resection of 90.6% ± 7.3%. Using MVPA (cluster threshold: p–false discovery rate corrected < 0.05, voxel threshold: p-uncorrected < 0.001), remote hotspots with significant rsFC changes were identified, including both insulas, the anterior cingulate cortex, superior sensorimotor cortices, and both frontal eye fields. Further seed-network analyses captured 2 patterns of between-network redistribution especially involving hyperconnectivity between the salience, visual, and dorsal attentional networks. Finally, the global efficiency of the salience-visual-dorsal attentional networks was strongly and positively correlated to 3-month postsurgical scores (n = 15) for phonological fluency (r 15 = 0.74, p = 0.0027); TMT-A (r 15 = 0.65, p = 0.012); TMTB (r 15 = 0.70, p = 0.005); and TMT-B-A (r 15 = 0.62, p = 0.018).

CONCLUSIONS In patients with LGGs infiltrating the precuneus, remote and distributed functional connectivity modulations in the preoperative setting are associated with better maintenance of cognitive performance after surgery. These findings provide a new vision of the mechanistic principles underlying neural plasticity and cognitive compensation in patients with LGGs.

Recurrent insular low-grade gliomas: factors guiding the decision to reoperate

J Neurosurg 138:1216–1226, 2023

Reoperation has been established as an effective therapeutic strategy in recurrent diffuse low-grade gliomas (LGGs). Insular gliomas represent a specific surgical challenge because of the surrounding vascular and functional structures. The aim of this study was to investigate the main clinicoradiological factors guiding the decision to reoperate on recurrent insular LGGs (ILGGs).

METHODS In this retrospective consecutive series, the authors screened all patients operated on for an ILGG in their institution who further presented with a tumor regrowth without the development of contrast enhancement. They compared patients who were subsequently offered a reoperation under awake mapping at recurrence or who underwent reoperation after adjuvant treatment had reduced the volume of the initial tumor recurrence (with a proven pathological diagnosis of LGG after the second surgery) to patients who were not selected for a reoperation. The first group (reoperated group; n = 20) included all recurrent ILGG patients who underwent second resection, and the second group (nonreoperated group; n = 60) included patients who did not undergo reoperation but underwent adjuvant oncological treatment.

RESULTS Factors significantly associated with reoperation were extent of resection (EOR) at first surgery (91.9% vs 89.7%, p = 0.014), residual tumor volume (9.5 ± 7.1 mL [range 0–30 mL] vs 6.3 ± 7.3 mL [range 0–30 mL], p = 0.02) at first surgery and left temporopolar infiltration at the time of tumor recurrence (Liebermeister statistical analysis, 4293 voxels survived false discovery rate correction with p < 0.05; maximal z-statistic = 6.50). Infiltration of the anterior perforated substance at tumor recurrence was significantly anticorrelated to reoperation (179 voxels survived false discovery rate correction with p < 0.05; minimal z-statistic = −4.33). The mean EOR was 83.7% at reoperation with a 90% survival rate at last follow-up (9.3 ± 3.8 years), low postsurgical morbidity (Karnofsky Performance Status score ≥ 80 in 95% of patients), a high rate of postoperative professional resumption (95%), and seizure control in 57.1% of patients.

CONCLUSIONS In selected patients with recurrent ILGG without radiographic evidence of malignant transformation, reoperation with intraoperative awake mapping is associated with favorable oncological outcomes and a low postsurgical morbidity. A greater EOR and a lower residual tumor volume at first surgery were significantly associated with reoperation. Patients who benefited from a second surgery typically had a recurrent pattern within cortical areas (such as the temporopolar region), while other patients typically presented with a deeper infiltrative pattern within the anterior perforated substance and the surrounding white matter pathways. Such original findings may be helpful to select the optimal indications of reoperation in recurrent ILGG.

The need to consider return to work as a main outcome in patients undergoing surgery for diffuse low‐grade glioma: a systematic review

Acta Neurochirurgica (2022) 164:2789–2809

For a long time, return to work (RTW) has been neglected in patients harboring a diffuse low-grade glioma (LGG). However, a majority of LGG patients worked at time of diagnosis. Moreover, these patients now live longer given current treatment paradigms, especially thanks to early maximal surgery.

Methods We systematically searched available medical databases for studies that reported data on RTW in patients who underwent resection for LGG.

Results A total of 30 studies were selected: 19 considered RTW (especially rate and timing) as an outcome and 11 used scales of health-related quality of life (HRQoL) which included work-related aspects. Series that considered RTW as a main endpoint were composed of 1014 patients, with postoperative RTW rates ranging from 31 to 97.1% (mean 73.1%). Timing to RTW ranged from 15 days to 22 months (mean 6.3 months). Factors related to an increased proportion of RTW were: younger age, better neurologic status, having a white-collar occupation, working pre-operatively, being the sole breadwinner, the use of awake surgery, and greater extent of resection. Female sex, older age, poor neurologic status, pre-operative history of work absences, slow lexical access speed, and postoperative seizures were negatively related to RTW. No studies that used HRQoL scales directly investigated RTW rate or timing.

Conclusions RTW was scarcely analyzed in LGG patients who underwent resection. However, because they are usually young, with no or only mild functional deficits and have a longer life expectancy, postoperative RTW should be assessed more systematically and accurately as a main outcome. As majority (61.5–100%) of LGG patients were working at time of surgery, the responsibility of neurosurgeons is to bring these patients back to their previous activities according to his/her wishes. RTW might also be included as a critical endpoint for future prospective studies and randomized control trials on LGGs.

Double dose of 5-aminolevulinic acid and its effect on protoporphyrin IX accumulation in low-grade glioma

J Neurosurg 137:943–952, 2022

Administration of 5-aminolevulinic acid (5-ALA) does not regularly elicit fluorescence in low-grade glioma (LGG) at currently established doses and timing of administration. One explanation may be differences in blood-brain barrier (BBB) integrity compared to high-grade glioma. The authors hypothesized that for a BBB semipermeable to 5-ALA there might be a relationship between plasma 5-ALA concentration and its movement into the brain. A higher dose would elicit more 5-ALA conversion into protoporphyrin IX (PPIX). The authors present a case series of patients harboring LGG who received higher doses of 5-ALA.

METHODS Patients undergoing surgery for indeterminate glioma later diagnosed as LGG were included in this study. 5-ALA was administered at a standard dose of 20 mg/kg body weight (bw) 4 hours prior to induction of anesthesia. A subgroup of patients received a higher dose of 40 mg/kg bw. Fluorescence was evaluated visually and PPIX concentration (cPPIX) was determined ex vivo by hyperspectral measurements in freshly extracted tissue. All adverse events were recorded.

RESULTS A total of 23 patients harboring diffuse low-grade astrocytomas (n = 19) and oligodendrogliomas (n = 4) were analyzed. Thirteen patients received 20 mg/kg bw, and 10 patients received 40 mg/kg bw of 5-ALA. In the 20 mg/ kg group, 30.8% (4 of 13) of tumors harbored areas of visible fluorescence, compared to 60% of cases (n = 6 of 10) with 40 mg/kg bw. The threshold to visibility was 1 μg/ml in both groups. Measured over all biopsies, the mean cPPIX was significantly higher in the double-dose group (1.8 vs 0.45 μg/ml; p < 0.001). In non–visibly fluorescent tissue the mean cPPIX was 0.146 μg/ml in the 20 mg/kg and 0.347 μg/ml in the 40 mg/kg group, indicating an increase of 138% (p < 0.001).

CONCLUSIONS These observations demonstrate different regions with different levels of PPIX accumulation in LGG. With higher 5-ALA doses cPPIX increases, leading to more regions surpassing the visibility threshold of 1 μg/ml. These observations can be explained by the fact that the BBB in LGG is semipermeable to 5-ALA. Higher 5-ALA doses result in more PPIX conversion, an observation with implications for future dosing in LGG.

Awake Mapping With Transopercular Approach in Right Insular–Centered Low-Grade Gliomas Improves Neurological Outcomes and Return to Work

Neurosurgery 91:182–190, 2022

Asleep vs awake surgery for right insula–centered low-grade glioma (LGG) is still debated.

OBJECTIVE: To compare neurological outcomes and return to work after resection for right insular/paralimbic LGG performed without vs with awake mapping.

METHODS: A personal surgical experience of right insula–centered LGG was analyzed, by comparing 2 consecutive periods. In the first period (group 1), patients underwent asleep surgery with motor mapping. In the second period (group 2), patients underwent intraoperative awake mapping of movement and cognitive functions.

RESULTS: This consecutive series included 143 LGGs: 41 in group 1 (1999-2009) and 102 in group 2 (2009-2020). There were no significant difference concerning preoperative clinicoradiological characteristics and histopathology results between both groups. Intraoperative motor mapping was positive in all cases in group 1. In group 2, beyond motor mapping, somatosensory, visuospatial, language, and/or cognitive functions were identified during cortical–subcortical stimulation. Postoperatively, 3 patients experienced a long-lasting deterioration with 2 hemiparesis due to deep stroke (1.3%) and 1 severe depressive syndrome, all of them in group 1 vs none in group 2 (P = .022). The rate of RTW was 81.5% in group 1 vs 95.5% in group 2 (P = .016). The tumor volume and extent of resection did not significantly differ across both groups.

CONCLUSION: This is the first study comparing asleep vs awake surgery for right insula– centered LGG. Despite similar extent of resection, functional outcomes were significantly better in awake patients by avoiding permanent neurological impairment and by increasing RTW. These results support the mapping of higher-order functions during awake procedure.

The immunology of low-grade gliomas

Neurosurg Focus 52 (2):E2, 2022

Low-grade gliomas (LGGs), which harbor an isocitrate dehydrogenase (IDH) mutation, have a better prognosis than their high-grade counterparts; nonetheless, they remain incurable and impart significant negative impacts on patients’ quality of life.

Although immunotherapies represent a novel avenue of treatment for patients with LGGs, they have not yet been successful. Accurately selecting and evaluating immunotherapies requires a detailed understanding of LGG tumor immunology and the underlying tumor immune phenotype.

A growing body of literature suggests that LGGs significantly differ in their immunology from high-grade gliomas, highlighting the importance of investigation into LGG immunology specifically.

In this review, the authors aimed to discuss relevant research surrounding the LGG tumor immune microenvironment, including immune cell infiltration, tumor immunogenicity, checkpoint molecule expression, the impact of an IDH mutation, and implications for immunotherapies, while also briefly touching on current immunotherapy trials and future directions for LGG immunology research.

Recurrent Low-Grade Gliomas: Does Reoperation Affect Neurocognitive Functioning?

Neurosurgery 90:221–232, 2022

Reoperations in patients with recurrent low-grade gliomas (RLGG) were proposed to control tumor residual and delay the risk of malignant transformation over time.

OBJECTIVE: To investigate neurocognitive outcomes in patients with RLGG who underwent a second surgery with awake monitoring.

METHODS: In this retrospective study, patients who underwent a second awake surgery for RLGG were included. Patients had presurgical and 3-mo postsurgical neuropsychological assessments. Data were converted into Z-scores and combined by the cognitive domain. Number of patients with cognitive deficits (Z-score <À1.65), variations of Z-scores, and extent of resection (EOR) were analyzed.

RESULTS: Sixty-two patients were included (mean age: 41.2 ± 10.0 yr). None had permanent neurological deficits postoperatively. Eight patients (12.9%) had a cognitive deficit preoperatively. Four additional patients (6.5%) had a cognitive deficit 3 mo after reoperation. Among other patients, 13 (21.0%) had a mild decline without cognitive deficits while 29 (46.8%) had no change of their performances and 8 (12.9%) improved. Overall, 94.2% of the patients returned to work. There were no correlations between EOR and Z-scores. Total/ subtotal resections were achieved in 91.9% of the patients (mean residual: 3.1 cm3 ). Fiftyeight patients (93.5%) were still alive after an overall follow-up of 8.3 yr.

CONCLUSION: Reoperation with awake monitoring in patients with RLGG was compatible with an early recovery of neuropsychological abilities. Four patients (6.5%) presented a new cognitive deficit at 3 mo postoperatively. Total/subtotal resections were achieved in most patients. Based on these favorable outcomes, reoperation should be considered in a more systematic way.

Fluorescence real-time kinetics of protoporphyrin IX after 5-ALA administration in low-grade glioma

J Neurosurg 136:9–15, 2022

5-Aminolevulinic acid (5-ALA) induces fluorescence in high-grade glioma (HGG), which is used for resection. However, the value of 5-ALA–induced fluorescence in low-grade glioma (LGG) is unclear. Time dependency and time kinetics have not yet been investigated. The purpose of this study was to investigate real-time kinetics of protoporphyrin IX (PpIX) in LGG based on hyperspectral fluorescence-based measurements and identify factors that predict fluorescence.

METHODS Patients with grade II gliomas and imaging from which HGGs could not be completely ruled out received 5-ALA at 20 mg/kg body weight 4 hours prior to surgery. Fluorescence intensity (FI) and PpIX concentration (CPpIX) were measured in tumor tissue utilizing a hyperspectral camera. Apparent diffusion coefficient (ADC)–based tumor cell density, Ki-67/MIB-1 index, chromosomal 1p/19q codeletion, and 18 F-fluoroethyl-l-tyrosine ( 18 F-FET) PET values and their role for predicting fluorescence were evaluated.

RESULTS Eighty-one biopsies from 25 patients were included. Tissues with fluorescence demonstrated FI and CPpIX maxima between 7 and 8 hours after administration. When visible fluorescence was observed, peaks of FI and CPpIX were observed within this 7- to 8-hour time frame, regardless of any MRI gadolinium contrast enhancement. Gadolinium enhancement (p = 0.008), Ki-67/MIB-1 index (p < 0.001), 18 F-FET PET uptake ratio (p = 0.004), and ADC-based tumor cellularity (p = 0.017) significantly differed between fluorescing and nonfluorescing tissue, but not 1p/19q codeletions. Logistic regression demonstrated that 18 F-FET PET uptake and Ki-67/MIB-1 index were independently related to fluorescence.

CONCLUSIONS This study reports a fluorescence-based assessment of CPpIX in human LGG tissues related to 18 F-FET PET uptake and Ki-67/MIB-1. As in HGGs, fluorescence in LGGs peaked between 7 and 8 hours after 5-ALA application, which has consequences for the timing of administration.

Predicting the Extent of Resection in Low-Grade Glioma by Using Intratumoral Tractography to Detect Eloquent FasciclesWithin the Tumor

Neurosurgery 88(2) 2021: E190–E202

An early maximal safe surgical resection is the current treatment paradigm for low-grade glioma (LGG). Nevertheless, there are no reliable methods to accurately predict the axonal intratumoral eloquent areas and, consequently, to predict the extent of resection.

OBJECTIVE: To describe the functional predictive value of eloquent white matter tracts within the tumor by using a pre- and postoperative intratumoral diffusion tensor imaging (DTI) tractography protocol in patients with LGG.

METHODS: A preoperative intratumoral DTI-based tractography protocol, using the tumor segmented volume as the only seed region, was used to assess the tracts within the tumor boundaries in 22 consecutive patients with LGG. The reconstructed tracts were correlated with intraoperative electrical stimulation (IES)-based language and motor subcortical mapping findings and the extent of resection was assessed by tumor volumetrics.

RESULTS: Identification of intratumoral language and motor tracts significantly predicted eloquent areas within the tumor during the IES mapping: the positive predictive value for the pyramidal tract, the inferior fronto-occipital fasciculus, the arcuate fasciculus and the inferior longitudinal fasciculus positive was 100%, 100%, 33%, and 80%, respectively, whereas negative predictive value was 100% for all of them. The reconstruction of at least one of these tracts within the tumor was significantly associated with a lower extent of resection (67%) as opposed to the extent of resection in the cases with a negative intratumoral tractography (100%) (P< .0001).

CONCLUSION: Intratumoral DTI-based tractography is a simple and reliable method, useful in assessing glioma resectability based on the analysis of intratumoral eloquent areas associated with motor and language tracts within the tumor.

Impact of Intraoperative Magnetic Resonance Imaging and Other Factors on Surgical Outcomes for Newly Diagnosed Grade II Astrocytomas and Oligodendrogliomas: A Multicenter Study

Neurosurgery 88 (1) 2021: 63–73,

Few studies use large, multi-institutional patient cohorts to examine the role of intraoperative magnetic resonance imaging (iMRI) in the resection of grade II gliomas.

OBJECTIVE: To assess the impact of iMRI and other factors on overall survival (OS) and progression-free survival (PFS) for newly diagnosed grade II astrocytomas and oligodendrogliomas.

METHODS: Retrospective analyses of a multicenter database assessed the impact of patient-, treatment-, and tumor-related factors on OS and PFS.

RESULTS: A total of 232 resections (112 astrocytomas and 120 oligodendrogliomas) were analyzed. Oligodendrogliomas had longer OS (P < .001) and PFS (P = .01) than astrocytomas. Multivariate analyses demonstrated improved OS for gross total resection (GTR) vs subtotal resection (STR; P = .006, hazard ratio [HR]: .23) and near total resection (NTR; P = .02, HR: .64). GTR vs STR (P = .02, HR: .54), GTR vs NTR (P = .04, HR: .49), and iMRI use (P = .02, HR: .54) were associated with longer PFS. Frontal (P = .048, HR: 2.11) and occipital/parietal (P = .003, HR: 3.59) locations were associated with shorter PFS (vs temporal). Kaplan-Meier analyses showed longer OS with increasing extent of surgical resection (EOR) (P=.03) and 1p/19q gene deletions (P=.02). PFS improved with increasing EOR (P = .01), GTR vs NTR (P = .02), and resections above STR (P = .04). Factors influencing adjuvant treatment (35.3% of patients) included age (P=.002, odds ratio [OR]: 1.04) and EOR (P=.003,OR: .39) but not glioma subtype or location. Additional tumor resection after iMRI was performed in 105/159 (66%) iMRI cases, yielding GTR in 54.5% of these instances.

CONCLUSION: EOR is a major determinant of OS and PFS for patients with grade II astrocytomas and oligodendrogliomas. Intraoperative MRI may improve EOR and was associated with increased PFS.

The Glioma-Network Interface: A Review of the Relationship Between Glioma Molecular Subtype and Intratumoral Function

 

Neurosurgery 87:1078–1084, 2020

Gliomas are a major cause of morbidity. Direct cortical stimulation mapping offers the ability to identify functional areas within the broader neural network both cortically and subcortically. Since the World Health Organization (WHO) 2016 classification categorized gliomas into molecular subgroups with varied molecular signatures and clinical behavior, it is possible that gliomas may demonstrate rates of functional network integration.

We therefore retrospectively reviewed a data registry of 181 patients with dominant hemisphere frontal, parietal, insular, or temporal gliomas. Our goal was to test the hypothesis that WHO glioma histopathology and molecular subtype influences functional language or motor sites identified within the tumor.

Intratumoral function as determined by direct cortical and subcortical stimulation mapping was identified at the highest rate in isocitrate dehydrogenase mutant astrocytomas and oligodendrogliomas. Finally, we reviewed the emerging literature exploring the interface between functional neural networks and gliomas. These data shed light on glioma molecular and histological characteristics most commonly associated within intratumoral function.

Impact of facility type and volume in low-grade glioma outcomes

J Neurosurg 133:1313–1323, 2020

The object of this study was to investigate the impact of facility type (academic center [AC] vs non-AC) and facility volume (high-volume facility [HVF] vs low-volume facility [LVF]) on low-grade glioma (LGG) outcomes.

METHODS This retrospective cohort study included 5539 LGG patients (2004–2014) from the National Cancer Database. Patients were categorized by facility type and volume (non-AC vs AC, HVF vs LVF). An HVF was defined as the top 1% of facilities according to the number of annual cases. Outcomes included overall survival, treatment receipt, and postoperative outcomes. Kaplan-Meier and Cox proportional-hazards models were applied. The Heller explained relative risk was computed to assess the relative importance of each survival predictor.

RESULTS Significant survival advantages were observed at HVFs (HR 0.67, 95% CI 0.55–0.82, p < 0.001) and ACs (HR 0.84, 95% CI 0.73–0.97, p = 0.015), both prior to and after adjusting for all covariates. Tumor resection was 41% and 26% more likely to be performed at HVFs vs LVFs and ACs vs non-ACs, respectively. Chemotherapy was 40% and 88% more frequently to be utilized at HVFs vs LVFs and ACs vs non-ACs, respectively. Prolonged length of stay (LOS) was decreased by 42% and 24% at HVFs and ACs, respectively. After tumor histology, tumor pattern, and codeletion of 1p19q, facility type and surgical procedure were the most important contributors to survival variance. The main findings remained consistent using propensity score matching and multiple imputation.

CONCLUSIONS This study provides evidence of survival benefits among LGG patients treated at HVFs and ACs. An increased likelihood of undergoing resections, receiving adjuvant therapies, having shorter LOSs, and the multidisciplinary environment typically found at ACs and HVFs are important contributors to the authors’ finding.

Contemporary assessment of extent of resection in molecularly defined categories of diffuse low-grade glioma: a volumetric analysis

J Neurosurg 133:1291–1301, 2020

While the effect of increased extent of resection (EOR) on survival in diffuse infiltrating low-grade glioma (LGG) patients is well established, there is still uncertainty about the influence of the new WHO molecular subtypes. The authors designed a retrospective analysis to assess the interplay between EOR and molecular classes.

METHODS The authors retrospectively reviewed the records of 326 patients treated surgically for hemispheric WHO grade II LGG at Brigham and Women’s Hospital and Massachusetts General Hospital (2000–2017). EOR was calculated volumetrically and Cox proportional hazards models were built to assess for predictive factors of overall survival (OS), progression-free survival (PFS), and malignant progression–free survival (MPFS).

RESULTS There were 43 deaths (13.2%; median follow-up 5.4 years) among 326 LGG patients. Median preoperative tumor volume was 31.2 cm3 (IQR 12.9–66.0), and median postoperative residual tumor volume was 5.8 cm3 (IQR 1.1–20.5). On multivariable Cox regression, increasing postoperative volume was associated with worse OS (HR 1.02 per cm3; 95% CI 1.00–1.03; p = 0.016), PFS (HR 1.01 per cm3; 95% CI 1.00–1.02; p = 0.001), and MPFS (HR 1.01 per cm3; 95% CI 1.00–1.02; p = 0.035). This result was more pronounced in the worse prognosis subtypes of IDH-mutant and IDH-wildtype astrocytoma, for which differences in survival manifested in cases with residual tumor volume of only 1 cm3. In oligodendroglioma patients, postoperative residuals impacted survival when exceeding 8 cm3. Other significant predictors of OS were age at diagnosis, IDH-mutant and IDH-wildtype astrocytoma classes, adjuvant radiotherapy, and increasing preoperative volume.

CONCLUSIONS The results corroborate the role of EOR in survival and malignant transformation across all molecular subtypes of diffuse LGG. IDH-mutant and IDH-wildtype astrocytomas are affected even by minimal postoperative residuals and patients could potentially benefit from a more aggressive surgical approach.

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

J Neurosurg 133:273–280, 2020

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.

 

Is supratotal resection achievable in low-grade gliomas? Feasibility, putative factors, safety, and functional outcome

J Neurosurg 132:1692–1705, 2020

Surgery for low-grade gliomas (LGGs) aims to achieve maximal tumor removal and maintenance of patients’ functional integrity. Because extent of resection is one of the factors affecting the natural history of LGGs, surgery could be extended further than total resection toward a supratotal resection, beyond tumor borders detectable on FLAIR imaging. Supratotal resection is highly debated, mainly due to a lack of evidence of its feasibility and safety. The authors explored the intraoperative feasibility of supratotal resection and its short- and long-term impact on functional integrity in a large cohort of patients. The role of some putative factors in the achievement of supratotal resection was also studied.

METHODS Four hundred forty-nine patients with a presumptive radiological diagnosis of LGG consecutively admitted to the neurosurgical oncology service at the University of Milan over a 5-year period were enrolled. In all patients, a policy was adopted to perform surgery according to functional boundaries, aimed at achieving a supratotal resection whenever possible, without any patient or tumor a priori selection. Feasibility, general safety, and tumor or patient putative factors possibly affecting the achievement of a supratotal resection were analyzed. Postsurgical patient functional performance was evaluated in five cognitive domains (memory, language, praxis, executive functions, and fluid intelligence) using a detailed neuropsychological evaluation and quality of life (QOL) examination.

RESULTS Total resection was feasible in 40.8% of patients, and supratotal resection in 32.3%. The achievement of a supratotal versus total resection was independent of age, sex, education, tumor volume, deep extension, location, handedness, appearance of tumor border, vicinity to eloquent sites, surgical mapping time, or surgical tools applied. Supratotal resection was associated with a long clinical history and histological grade II, suggesting that reshaping of brain networks occurred. Although a consistent amount of apparently MRI-normal brain was removed with this approach, the procedure was safe and did not carry additional risk to the patient, as demonstrated by detailed neuropsychological evaluation and QOL examination. This approach also improved seizure control.

CONCLUSIONS Supratotal resection is feasible and safe in routine clinical practice. These results show that a long clinical history may be the main factor associated with its achievement.

Intraoperative 3D ultrasound–guided resection of diffuse low-grade gliomas

J Neurosurg 132:518–529, 2020

Extent of resection (EOR) and residual tumor volume are linked to prognosis in low-grade glioma (LGG) and there are various methods for facilitating safe maximal resection in such patients. In this prospective study the authors assess radiological and clinical results in consecutive patients with LGG treated with 3D ultrasound (US)–guided resection under general anesthesia.

METHODS Consecutive LGGs undergoing primary surgery guided with 3D US between 2008 and 2015 were included. All LGGs were classified according to the WHO 2016 classification system. Pre- and postoperative volumetric assessments were performed, and volumetric results were linked to overall and malignant-free survival. Pre- and postoperative health-related quality of life (HRQoL) was evaluated.

RESULTS Forty-seven consecutive patients were included. Twenty LGGs (43%) were isocitrate dehydrogenase (IDH)– mutated, 7 (14%) were IDH wild-type, 19 (40%) had both IDH mutation and 1p/19q codeletion, and 1 had IDH mutation and inconclusive 1p/19q status. Median resection grade was 93.4%, with gross-total resection achieved in 14 patients (30%). An additional 24 patients (51%) had small tumor remnants < 10 ml. A more conspicuous tumor border (p = 0.02) and lower University of California San Francisco prognostic score (p = 0.01) were associated with less remnant tumor tissue, and overall survival was significantly better with remnants < 10 ml (p = 0.03). HRQoL was maintained or improved in 86% of patients at 1 month. In both cases with severe permanent deficits, relevant ischemia was present on diffusionweighted postoperative MRI.

CONCLUSIONS Three-dimensional US–guided LGG resections under general anesthesia are safe and HRQoL is preserved in most patients. Effectiveness in terms of EOR appears to be consistent with published studies using other advanced neurosurgical tools. Avoiding intraoperative vascular injury is a key factor for achieving good functional outcome.

Early postoperative delineation of residual tumor after low-grade glioma resection by probabilistic quantification of diffusion-weighted imaging

J Neurosurg 130:2016–2024, 2019

In WHO grade II low-grade gliomas (LGGs), early postoperative MRI (epMRI) may overestimate residual tumor on FLAIR sequences. Consequently, MRI at 3–6 months follow-up (fuMRI) is used for delineation of residual tumor. This study sought to evaluate if integration of apparent diffusion coefficient (ADC) maps permits an accurate estimation of residual tumor early on epMRI.

METHODS From a consecutive cohort, 43 cases with an initial surgery for an LGG, and complete epMRI (< 72 hours after resection) and fuMRI including ADC maps, were retrospectively identified. Residual FLAIR hyperintense tumor was manually segmented on epMRI and corresponding ADC maps were coregistered. Using an expectation maximization algorithm, residual tumor segments were probabilistically clustered into areas of residual tumor, ischemia, or normal white matter (NWM) by fitting a mixture model of superimposed Gaussian curves to the ADC histogram. Tumor volumes from epMRI, clustering, and fuMRI were statistically compared and agreement analysis was performed.

RESULTS Mean FLAIR hyperintensity suggesting residual tumor was significantly larger on epMRI compared to fuMRI (19.4 ± 16.5 ml vs 8.4 ± 10.2 ml, p < 0.0001). Probabilistic clustering of corresponding ADC histograms on epMRI identified subsegments that were interpreted as mean residual tumor (7.6 ± 10.2 ml), ischemia (8.1 ± 5.9 ml), and NWM (3.7 ± 4.9 ml). Therefore, mean tumor quantification error between epMRI and fuMRI was significantly reduced (11.0 ± 10.6 ml vs -0.8 ± 3.7 ml, p < 0.0001). Mean clustered tumor volumes on epMRI were no longer significantly different from the fuMRI reference (7.6 ± 10.2 ml vs 8.4 ± 10.2 ml, p = 0.16). Correlation (Pearson r = 0.96, p < 0.0001), concordance correlation coefficient (0.89, 95% confidence interval 0.83), and Bland-Altman analysis suggested strong agreement between both measures after clustering.

CONCLUSIONS Probabilistic segmentation of ADC maps facilitates accurate assessment of residual tumor within 72 hours after LGG resection. Multiparametric image analysis detected FLAIR signal alterations attributable to surgical trauma, which led to overestimation of residual LGG on epMRI compared to fuMRI. The prognostic value and clinical impact of this method has to be evaluated in larger case series in the future.

 

Is Visible Aminolevulinic Acid-Induced Fluorescence an Independent Biomarker for Prognosis in Histologically Confirmed (World Health Organization 2016) Low-Grade Gliomas?

Neurosurgery, Volume 84, Issue 6, June 2019, Pages 1214–1224

Approximately 20% of low-grade gliomas (LGG) display visible protoporphyrin fluorescence during surgery after 5-aminolevulinic acid (5-ALA) administration.

OBJECTIVE: To determine if fluorescence represents a prognostic marker in LGG.

METHODS: Seventy-four consecutive patients with LGG (World Health Organization 2016) were operated on with 5-ALA. Fluorescent tissue was specifically biopsied. Tumor size, age, Karnofsky index, contrast-enhancement, fluorescence, and molecular factors (IDH1/IDH2-mutations, Ki67/MIB1 Index, 1p19q codeletions, ATRX, EGFR, p53 expression, and O6-methylguanine DNA methyltransferase promotor methylation), were related to progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS).

RESULTS: Sixteen of seventy-four LGGs (21.6%) fluoresced. Fluorescence was partially related to weak enhancement on magnetic resonance imaging and increased (positron emission tomography)PET-FET uptake, but not to Karnofsky Performance Score, tumor size, or age. Regarding molecular markers, only EGFR expression differed marginally (fluorescing vs nonfluorescing: 19% vs 5%; P = .057). Median follow-up was 46.4 mo (95% confidence interval [CI]: 41.8-51.1). PFS, MTFS, and OS were shorter in fluorescing tumors (PFS: median 9.8 mo, 95% CI: 1.00-27.7 vs 45.8, 31.9-59.7, MTFS: 43.0 [27.5-58.5] vs 64.6 [57.7- 71.5], median not reached, P = .015; OS: 51.6, [34.8-68.3] vs [68.2, 62.7-73.8], P = .002). IDH mutations significantly predicted PFS, MTFS, and OS. In multivariate analysis IDH status and fluorescence both independently predictedMTFS and OS. PFSwas not independently predicted by fluorescence.

CONCLUSION: This is the first report investigating the role of ALA-induced fluorescence in histologically confirmed LGG. Fluorescence appeared to be a marker for inherent malignant transformation and OS, independently of known prognostic markers. Fluorescence in LGG might be taken into account when deciding on adjuvant therapies.