Tag: low-grade glioma

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Guidelines for the Treatment of Adults With WHO Grade II Diffuse Glioma: Update

Neurosurgery 98:984–991, 2026

These updated CNS evidence-based guidelines consolidate current literature on the management of WHO grade II diffuse gliomas, covering imaging, surgical strategies, neuropathology, radiotherapy, chemotherapy, and recurrence. They summarize evidence levels, provide topic-specific recommendations, and identify areas needing higher-quality research to inform clinical decisions.

The document details unchanged, updated, and new recommendations—ranging from MRI protocols and intraoperative mapping to molecular testing and adjuvant therapy—while describing methodology, conflict-of-interest procedures, and plans for periodic revision to ensure clinical relevance.

Scope: Updated evidence-based recommendations for adult WHO grade II diffuse glioma across imaging, surgery, neuropathology/molecular markers, radiotherapy, chemotherapy, and recurrence management.

Methods: Systematic search of MEDLINE/Embase/Cochrane covering Jan 1, 2013–Jan 31, 2020, with recommendations based on evidence rather than consensus.

Imaging (minimum MRI): Minimum evaluation includes T2-weighted and pre- and post-gadolinium T1-weighted MRI; serial imaging is used to detect new enhancement or significant growth suggesting higher-grade transformation.

Imaging (advanced/PET): Diffusion plus perfusion techniques (e.g., DSC/DCE/ASL) are suggested when standard MRI cannot distinguish grade II from higher-grade gliomas; amino-acid PET (FET or FDOPA) may be added when not evident on MRI to help with grading, prognosis (FET), or progression detection (FDOPA).

Surgery: When safe/feasible, resection (gross total or subtotal) is recommended over biopsy alone to reduce progression; extent of resection should be maximized when safely possible (including for IDH-mutant and IDH–wild-type tumors).

Pathology/molecular testing: Diagnosis relies on histopathology from representative tissue; IDH mutation testing is recommended for classification/prognosis, and 1p/19q loss-of-heterozygosity testing is recommended in oligodendroglial cases for prognosis/treatment planning.

Adjuvant therapy (high-risk): For high-risk grade II diffuse glioma (age >40 or <40 without gross total resection), adding chemotherapy to radiotherapy is recommended to improve overall survival (including procarbazine/PCV-based approaches) and is also recommended without decline in neurocognitive function.

Recurrence: At suspected recurrence, advanced imaging (MRS/perfusion/diffusion/PET) is suggested; temozolomide is suggested (often initial choice) and procarbazine may help (strongest evidence in oligodendroglioma); radiation is suggested if not previously given and reirradiation may be considered.

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Functional status in long-term survivors after mapping-guided surgery for diffuse low-grade glioma

J Neurosurg 144:139–150, 2026

This clinical study reports long-term functional outcomes in 103 consecutive patients with diffuse low-grade glioma who underwent mapping-guided resections and were followed for at least 15 years. Key findings include high overall survival (83.5%), mean postoperative KPS of 94.8, and 90% return-to-work rate, with low permanent neurological morbidity across 205 resections.

Comparative analysis shows patients who sustained employment had smaller pre/postoperative tumor volumes, greater extent of resection (including more supratotal resections), and less exposure to radiotherapy. The data support early maximal safe resection and postponement of radiotherapy to preserve long-term functional status and professional activity.

Functional Preservation: Long-term survivors of diffuse low-grade glioma (LGG) surgery had high rates of preserved functional status, with 90.7% of surviving patients maintaining a Karnofsky Performance Scale (KPS) score ≥ 80 after an average of 18.2 years follow-up.

Return to Work: 90% of patients were able to return to work after mapping-guided resection, and maintaining professional activity was strongly associated with higher preoperative KPS and greater extent of resection (EOR).

Extent of Resection (EOR): Greater EOR, particularly supratotal or total resections, correlated with better long-term functional outcomes and higher rates of continued employment.

Radiation Therapy Impact: Early or any radiotherapy (RT) was linked to lower rates of return to work and a reduced proportion of patients with KPS ≥ 80 at last follow-up, while chemotherapy did not show this negative association.

Timing of Surgery: Early surgery at diagnosis, especially in patients with higher KPS and smaller tumor volume, increased the chance for maximal resection and long-term preservation of functional status.

Low Neurological Morbidity: Permanent postoperative neurological deficits were rare (1.5% after 205 resections), supporting the safety of maximal resection with intraoperative mapping.

Malignant Transformation: The risk of malignant transformation was lower in patients with greater EOR and those who continued to work, suggesting oncological benefit from radical resection.

Adjuvant Therapy Strategy: A wait-and-watch strategy after maximal safe resection, postponing adjuvant treatments unless necessary, helped preserve long-term quality of life and autonomy.

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Awake surgery for IDH-mutant grade 2 glioma involving the corpus callosum: long-term onco-functional results after callosectomy in 157 consecutive patients

J Neurosurg 143:1280–1289, 2025

This clinical study reports outcomes from 157 consecutive patients with IDH‑mutant grade 2 gliomas infiltrating the corpus callosum who underwent connectome-guided awake surgery with callosectomy. It summarizes surgical technique, extent of resection, complication rates, return-to-work statistics, histology, adjuvant treatments, reoperations, and long-term overall survival.

Comparative analysis contrasts complete (total/supratotal) versus incomplete resections, showing higher extent of resection, greater reoperation potential, and longer median overall survival when callosal tumor was fully removed, while preserved function and a 96.8% return-to-work rate underline favorable onco-functional balance.

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Electrocorticography and navigated transcranial magnetic stimulation–tailored supratotal resection for epileptogenic low-grade gliomas

J Neurosurg 142:918–926, 2025

The study evaluates ECoG-nTMS–tailored supratotal resection (ETT-SpTR) for low-grade gliomas with epilepsy, demonstrating improved seizure control and preserved neurological function compared to gross-total resection. ETT-SpTR effectively identifies high-risk epilepsy areas, enhancing epileptic and functional outcomes without permanent deficits.

• Objective: Evaluate the effectiveness of ECoG-nTMS–tailored supratotal resection (ETT-SpTR) for low-grade gliomas (LGGs) in controlling seizures and preserving neurological function.

• Methods: Retrospective analysis of patients with LGG and epileptic seizures undergoing resective surgery, comparing gross-total resection (GTR) with ETT-SpTR.

• Results: ETT-SpTR significantly improved seizure control (85.7% Engel class IA) compared to GTR (25% Engel class IA) with no permanent neurological deficits.

• Conclusion: ETT-SpTR is effective in improving epileptic outcomes and preserving functions without causing permanent neurological worsening.

• Preoperative Techniques: Functional cortical areas were identified using TMS, and ECoG guided the removal of high-risk epilepsy areas (HREAs).

• Statistical Analysis: Significant differences in seizure control between groups, with ETT-SpTR showing better outcomes.

• Limitations: Small patient cohort and limited follow-up period; future studies required for confirmation.

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Longitudinal brain volumetrics in glioma survivors

J Neurosurg 141:634–641, 2024

Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT.

METHODS This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models.

RESULTS The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36–18.9 years), and the median number of time points analyzed per patient was 12 (range 2–40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (β = −0.06, p < 0.001) and use of RT (β = −1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (β = −0.08, p < 0.001), midline involvement (β = 1.31, p = 0.006), and use of RT (β = −1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (β = −0.0027, p = 0.001), tumor resection (β = −0.069, p < 0.001), use of chemotherapy (β = −0.0597, p = 0.003), and use of RT (β = −0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model.

CONCLUSIONS This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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