Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.

Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Multivariate mapping of low-resilient neurocognitive systems within and around low-grade gliomas.

Accumulating evidence suggests that the brain exhibits a remarkable capacity for functional compensation in response to neurological damage, a resilience potential that is deeply rooted in the malleable features of its underlying anatomo-functional architecture. This propensity is particularly exemplified by diffuse low-grade gliomas (DLGGs), a subtype of primary brain tumour. However, functional plasticity is not boundless, and surgical resections directed at structures with limited neuroplasticity may lead to incapacitating impairments. Yet, maximizing DLGG resections offers substantial oncological benefits, especially when the resection extends beyond the tumour margins (i.e., supra-tumour or supra-total resection). In this context, the primary objective of this study was to identify which cerebral structures were associated with less favourable cognitive outcomes after surgery, while accounting for intra-tumour and supra-tumour features of the surgical resections. To reach this objective, we leveraged a unique cohort of 400 DLGG patients who underwent surgery with awake cognitive mapping. Patients benefited from a neuropsychological assessment consisting of 18 subtests administered before and 3 months post-surgery. We analysed changes in performance and applied topography-focused and disconnection-focused multivariate lesion-symptom mapping (LSM) using support vector regressions with an attempt to capture resected cortico-subcortical structures less amenable to full cognitive compensations. The observed changes in performance were of a limited magnitude suggesting an overall recovery (13/18 tasks fully recovered despite a mean resection extent of 92.4%). Nevertheless, LSM analyses revealed that a lack of recovery in picture naming was linked to damage in the left inferior temporal gyrus and inferior longitudinal fasciculus. Similarly, for semantic fluency abilities, an association was established with damage to the left precuneus/posterior cingulate. For phonologic fluency abilities, the left dorso-medial frontal cortex and the frontal aslant tract were implicated. Moreover, difficulties in spatial exploration were associated with injury to the right dorsomedial prefrontal cortex and its underlying connectivity. An exploratory analysis suggested that supra-tumoral resections were associated with a less pronounced recovery following specific resection patterns, such as supra-tumour resections of the left uncinate fasciculus (picture naming), the left corticostriatal tract and the anterior corpus callosum (phonologic fluency), the hippocampus and para-hippocampus (episodic memory), and the right frontal-mesial areas (visuospatial exploration). Collectively, these patterns of results shed new light on both low-resilient neural systems and the prediction of cognitive recovery following glioma surgery. Furthermore, they indicate that supra-tumour resections were only occasionally less well-tolerated from a cognitive viewpoint. In doing so, they have deep implications for surgical planning and rehabilitation strategies.

Integrating direct electrical brain stimulation with the human connectome.

Neurological and neurodevelopmental conditions are a major public health concern for which new therapies are urgently needed. The development of effective therapies relies on the precise mapping of the neural substrates causally involved in behaviour generation. Direct electrical stimulation (DES) performed during cognitive and neurological monitoring in awake surgery is currently considered the gold standard for the causal mapping of brain functions. However, DES is limited by the focal nature of the stimulation sites, hampering a real holistic exploration of human brain functions at the network level. We used 4137 DES points derived from 612 glioma patients in combination with human connectome data-resting-state functional MRI, n = 1000 and diffusion weighted imaging, n = 284-to provide a multimodal description of the causal macroscale functional networks subtending 12 distinct behavioural domains. To probe the validity of our procedure, we (i) compared the network topographies of healthy and clinical populations; (ii) tested the predictive capacity of DES-derived networks; (iii) quantified the coupling between structural and functional connectivity; and (iv) built a multivariate model able to quantify single subject deviations from a normative population. Lastly, we probed the translational potential of DES-derived functional networks by testing their specificity and sensitivity in identifying critical neuromodulation targets and neural substrates associated with postoperative language deficits. The combination of DES and human connectome data resulted in an average 29.4-fold increase in whole brain coverage compared to DES alone. DES-derived functional networks are predictive of future stimulation points (97.8% accuracy) and strongly supported by the anatomical connectivity of subcortical stimulations. We did not observe any significant topographical differences between the patients and the healthy population at both group and single subject level. Showcasing concrete clinical applications, we found that DES-derived functional networks overlap with effective neuromodulation targets across several functional domains, show a high degree of specificity when tested with the intracranial stimulation points of a different stimulation technique and can be used effectively to characterize postoperative behavioural deficits. The integration of DES with the human connectome fundamentally advances the quality of the functional mapping provided by DES or functional imaging alone. DES-derived functional networks can reliably predict future stimulation points, have a strong correspondence with the underlying white matter and can be used for patient specific functional mapping. Possible applications range from psychiatry and neurology to neuropsychology, neurosurgery and neurorehabilitation.

Intraoperative functional remapping unveils evolving patterns of cortical plasticity.

The efficiency with which the brain reorganizes following injury not only depends on the extent and the severity of the lesion, but also on its temporal features. It is established that diffuse low-grade gliomas (DLGG), brain tumours with a slow-growth rate, induce a compensatory modulation of the anatomo-functional architecture, making this kind of tumours an ideal lesion model to study the dynamics of neuroplasticity. Direct electrostimulation (DES) mapping is a well-tried procedure used during awake resection surgeries to identify and spare cortical epicentres which are critical for a range of functions. Because DLGG is a chronic disease, it inevitably relapses years after the initial surgery, and thus requires a second surgery to reduce tumour volume again. In this context, contrasting the cortical mappings obtained during two sequential neurosurgeries offers a unique opportunity to both identify and characterize the dynamic (i.e. re-evolving) patterns of cortical re-arrangements. Here, we capitalized on an unprecedented series of 101 DLGG patients who benefited from two DES-guided neurosurgeries usually spaced several years apart, resulting in a large DES dataset of 2082 cortical sites. All sites (either non-functional or associated with language, speech, motor, somatosensory and semantic processing) were recorded in Montreal Neurological Institute (MNI) space. Next, we used a multi-step approach to generate probabilistic neuroplasticity maps that reflected the dynamic rearrangements of cortical mappings from one surgery to another, both at the population and individual level. Voxel-wise neuroplasticity maps revealed regions with a relatively high potential of evolving reorganizations at the population level, including the supplementary motor area (SMA, Pmax = 0.63), the dorsolateral prefrontal cortex (dlPFC, Pmax = 0.61), the anterior ventral premotor cortex (vPMC, Pmax = 0.43) and the middle superior temporal gyrus (STG Pmax = 0.36). Parcel-wise neuroplasticity maps confirmed this potential for the dlPFC (Fisher's exact test, PFDR-corrected = 6.6 × 10-5), the anterior (PFDR-corrected = 0.0039) and the ventral precentral gyrus (PFDR-corrected = 0.0058). A series of clustering analyses revealed a topological migration of clusters, especially within the left dlPFC and STG (language sites); the left vPMC (speech arrest/dysarthria sites) and the right SMA (negative motor response sites). At the individual level, these dynamic changes were confirmed for the dlPFC (bilateral), the left vPMC and the anterior left STG (threshold free cluster enhancement, 5000 permutations, family-wise error-corrected). Taken as a whole, our results provide a critical insight into the dynamic potential of DLGG-induced continuing rearrangements of the cerebral cortex, with considerable implications for re-operations.

Development of an educational method to rethink and learn oncological brain surgery in an "a la carte" connectome-based perspective.

BACKGROUND: Understanding the structural connectivity of white matter tracts (WMT) and their related functions is a prerequisite to implementing an "a la carte" "connectomic approach" to glioma surgery. However, accessible resources facilitating such an approach are lacking. Here we present an educational method that is readily accessible, simple, and reproducible that enables the visualization of WMTs on individual patient images via an atlas-based approach. METHODS: Our method uses the patient's own magnetic resonance imaging (MRI) images and consists of three main steps: data conversion, normalization, and visualization; these are accomplished using accessible software packages and WMT atlases. We implement our method on three common cases encountered in glioma surgery: a right supplementary motor area tumor, a left insular tumor, and a left temporal tumor. RESULTS: Using patient-specific perioperative MRIs with open-sourced and co-registered atlas-derived WMTs, we highlight the critical subnetworks requiring specific surgical monitoring identified intraoperatively using direct electrostimulation mapping with cognitive monitoring. The aim of this didactic method is to provide the neurosurgical oncology community with an accessible and ready-to-use educational tool, enabling neurosurgeons to improve their knowledge of WMTs and to better learn their oncologic cases, especially in glioma surgery using awake mapping. CONCLUSIONS: Taking no more than 3-5 min per patient and irrespective of their resource settings, we believe that this method will enable junior surgeons to develop an intuition, and a robust 3-dimensional imagery of WMT by regularly applying it to their cases both before and after surgery to develop an "a la carte" connectome-based perspective to glioma surgery.

Aggressive pituitary neuroendocrine tumors: current practices, controversies, and perspectives, on behalf of the EANS skull base section.

Aggressive pituitary neuroendocrine tumors (APT) account for 10% of pituitary tumors. Their management is a rapidly evolving field of clinical research and has led pituitary teams to shift toward a neuro-oncological-like approach. The new terminology "Pituitary neuroendocrine tumors" (PitNet) that was recently proposed to replace "pituitary adenomas" reflects this change of paradigm. In this narrative review, we aim to provide a state of the art of actual knowledge, controversies, and recommendations in the management of APT. We propose an overview of current prognostic markers, including the recent five-tiered clinicopathological classification. We further establish and discuss the following recommendations from a neurosurgical perspective: (i) surgery and multi-staged surgeries (without or with parasellar resection in symptomatic patients) should be discussed at each stage of the disease, because it may potentialize adjuvant medical therapies; (ii) temozolomide is effective in most patients, although 30% of patients are non-responders and the optimal timeline to initiate and interrupt this treatment remains questionable; (iii) some patients with selected clinicopathological profiles may benefit from an earlier local radiotherapy and/or chemotherapy; (iv) novel therapies such as VEGF-targeted therapies and anti-CTLA-4/anti-PD1 immunotherapies are promising and should be discussed as 2nd or 3rd line of treatment. Finally, whether neurosurgeons have to operate on "pituitary adenomas" or "PitNets," their role and expertise remain crucial at each stage of the disease, prompting our community to deal with evolving concepts and therapeutic resources.

Current status and treatment modalities in metastases to the pituitary: a systematic review.

BACKGROUND: Metastases to the pituitary (MP) are uncommon, accounting for 0.4% of intracranial metastases. Through advances in neuroimaging and oncological therapies, patients with metastatic cancers are living longer and MP may be more frequent. This review aimed to investigate clinical and oncological features, treatment modalities and their effect on survival. METHODS: A systematic review was performed according to PRISMA recommendations. All cases of MP were included, excepted primary pituitary neoplasms and autopsy reports. Descriptive and survival analyses were then conducted. RESULTS: The search identified 2143 records, of which 157 were included. A total of 657 cases of MP were reported, including 334 females (50.8%). The mean ± standard deviation age was 59.1 ± 11.9 years. Lung cancer was the most frequent primary site (31.0%), followed by breast (26.2%) and kidney cancers (8.1%). Median survival from MP diagnosis was 14 months. Overall survival was significantly different between lung, breast and kidney cancers (P < .0001). Survival was impacted by radiotherapy (hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.35-0.67; P < .0001) and chemotherapy (HR 0.58; 95% CI 0.36-0.92; P = .013) but not by surgery. Stereotactic radiotherapy tended to improve survival over conventional radiotherapy (HR 0.66; 95% CI 0.39-1.12; P = .065). Patients from recent studies (≥ 2010) had longer survival than others (HR 1.36; 95% CI 1.05-1.76; P = .0019). CONCLUSION: This systematic review based on 657 cases helped to better identify clinical features, oncological characteristics and the effect of current therapies in patients with MP. Survival patterns were conditioned upon primary cancer histologies, the use of local radiotherapy and systemic chemotherapy, but not by surgery.

Whole-genome analysis informs breast cancer response to aromatase inhibition.

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

The UCSC Interaction Browser: multidimensional data views in pathway context.

High-throughput data sets such as genome-wide protein-protein interactions, protein-DNA interactions and gene expression data have been published for several model systems, especially for human cancer samples. The University of California, Santa Cruz (UCSC) Interaction Browser (http://sysbio.soe.ucsc.edu/nets) is an online tool for biologists to view high-throughput data sets simultaneously for the analysis of functional relationships between biological entities. Users can access several public interaction networks and functional genomics data sets through the portal as well as upload their own networks and data sets for analysis. Users can navigate through correlative relationships for focused sets of genes belonging to biological pathways using a standard web browser. Using a new visual modality called the CircleMap, multiple 'omics' data sets can be viewed simultaneously within the context of curated, predicted, directed and undirected regulatory interactions. The Interaction Browser provides an integrative viewing of biological networks based on the consensus of many observations about genes and their products, which may provide new insights about normal and disease processes not obvious from any isolated data set.

Subtype and pathway specific responses to anticancer compounds in breast cancer.

Breast cancers are comprised of molecularly distinct subtypes that may respond differently to pathway-targeted therapies now under development. Collections of breast cancer cell lines mirror many of the molecular subtypes and pathways found in tumors, suggesting that treatment of cell lines with candidate therapeutic compounds can guide identification of associations between molecular subtypes, pathways, and drug response. In a test of 77 therapeutic compounds, nearly all drugs showed differential responses across these cell lines, and approximately one third showed subtype-, pathway-, and/or genomic aberration-specific responses. These observations suggest mechanisms of response and resistance and may inform efforts to develop molecular assays that predict clinical response.

Disruption of the left anterior ventrolateral temporal cortex along with the inferior longitudinal fasciculus impairs the ability to retrieve famous face names: Evidence from three longitudinal case studies.

The cortical distribution of the proper name (PN) retrieval network has been widely studied contrary to its connectional anatomy. Here, we report the case of three patients with a low-grade glioma damaging the mid-to-anterior part of the left temporal lobe. A longitudinal behavioural assessment showed that the surgery caused a long-lasting decline in PN retrieval performances in all patients. Furthermore, a detailed analysis of surgery-related structural disconnections revealed that interruption of the inferior longitudinal fasciculus was the unique common denominator.

PARADIGM-SHIFT predicts the function of mutations in multiple cancers using pathway impact analysis.

MOTIVATION: A current challenge in understanding cancer processes is to pinpoint which mutations influence the onset and progression of disease. Toward this goal, we describe a method called PARADIGM-SHIFT that can predict whether a mutational event is neutral, gain-or loss-of-function in a tumor sample. The method uses a belief-propagation algorithm to infer gene activity from gene expression and copy number data in the context of a set of pathway interactions. RESULTS: The method was found to be both sensitive and specific on a set of positive and negative controls for multiple cancers for which pathway information was available. Application to the Cancer Genome Atlas glioblastoma, ovarian and lung squamous cancer datasets revealed several novel mutations with predicted high impact including several genes mutated at low frequency suggesting the approach will be complementary to current approaches that rely on the prevalence of events to reach statistical significance. AVAILABILITY: All source code is available at the github repository http:github.org/paradigmshift. CONTACT: jstuart@soe.ucsc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Brain Plasticity Profiling as a Key Support to Therapeutic Decision-Making in Low-Grade Glioma Oncological Strategies.

The ability of neural circuits to compensate for damage to the central nervous system is called postlesional plasticity. In diffuse low-grade gliomas (LGGs), a crosstalk between the brain and the tumor activates modulations of plasticity, as well as tumor proliferation and migration, by means of paracrine and electrical intercommunications. Such adaptative mechanisms have a major impact on the benefits and risks of oncological treatments but are still disregarded by current neuro-oncological guidelines. In this review, the authors first aimed to highlight clinical, radiological, and oncological markers that robustly reflect the plasticity potentials and limitations in LGG patients, including the location of the tumor and the degree of critical white matter tract infiltration, the velocity of tumor expansion, and the reactional changes of neuropsychological performances over time. Second, the interactions between the potential/limitations of cerebral plasticity and the efficacy/tolerance of treatment options (i.e., surgery, chemotherapy, and radiotherapy) are reviewed. Finally, a longitudinal and multimodal treatment approach accounting for the evolutive profiles of brain plasticity is proposed. Such an approach integrates personalized predictive models of plasticity potentials with a step-by-step therapeutic decision making and supports onco-functional balanced strategies in patients with LGG, with the ultimate aim of optimizing overall survival and quality of life.

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

OBJECTIVE: 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.

Evidence for a critical role of the left inferior parietal lobule and underlying white matter connectivity in proficient text reading.

OBJECTIVE: Reading proficiency is an important skill for personal and socio-professional daily life. Neurocognitive models underlie a dual-route organization for word reading, in which information is processed by both a dorsal phonological "assembled phonology route" and a ventral lexical-semantic "addressed phonology route." Because proficient reading should not be reduced to the ability to read words one after another, the current study was designed to shed light on the neural bases specifically underpinning text reading and the relative contributions of each route to this skill. METHODS: Twenty-two patients with left-sided, diffuse, low-grade glioma who underwent operations while awake were included. They were divided into 3 groups on the basis of tumor location: the inferior parietal lobule (IPL) group (n = 6), inferior temporal gyrus (Tinf) group (n = 6), and fronto-insular (control) group (n = 10). Spoken language and reading abilities were tested in all patients the day before surgery, during surgery, and 3 months after surgery, and cognitive functioning was evaluated before and 3 months after surgery. Text-reading scores obtained before and 3 months after surgery were compared within each group and between groups, correlations between reading scores and both spoken language and cognitive scores were calculated, postoperative cortical-subcortical resection location was estimated, and multiple regression analysis was conducted to examine the relationship between reading proficiency and lesion location. RESULTS: The results indicated that only the patients in the IPL group showed a significant decrease in text-reading scores between periods, which was not associated with lower scores in naming or verbal fluency; patients in the Tinf group showed a slight nonsignificant decrease in text reading between periods, which was associated with a clear decrease in naming and semantic verbal fluency; and patients in the control group showed no differences between preoperative and postoperative reading and spoken language scores. The results of the analysis of these behavioral results and anatomical data (resection cavities and white matter damage) suggest critical roles for the left inferior parietal lobule and underlying white matter connectivity, especially the posterior segment of the arcuate fasciculus, in proficient text reading. CONCLUSIONS: Text-reading proficiency may depend on not only the integrity of both processing routes but also their capacity for interaction, with critical roles for the left inferior parietal lobule and posterior arcuate fasciculus. These findings have fundamental as well as clinical implications.

Non-surgical periodontal therapy improves oral health-related quality of life.

AIM: The influence of non-surgical periodontal therapy on oral health-related quality of life (OHQoL) was investigated. MATERIALS AND METHODS: Sixty-five Chinese adults (25 men, mean 47.4 years) with moderate-to-advanced chronic periodontitis were recruited. All received oral hygiene instructions (OHI) and non-surgical periodontal treatment in a quadrant-wise approach, followed by recalls at 1, 3, 6, 9 and 12 months post treatment, when OHI and prophylaxis were repeated. Clinical parameters were recorded, and oral health impact profile short-form (OHIP-14S) was administered at all time points. RESULTS: Moderate-to-deep sites (≥4 mm) decreased from 31.0% to 3.0% at 12 months post treatment (p < 0.005) which corresponded well with reductions in plaque, 72.8% to 25.4% (p < 0.005) and bleeding on probing, 86.3% to 32.0% (p < 0.005). Median OHIP-14S scores gradually reduced from 17 at baseline to 14 over the first 6 months and remained plateaued at 12-month post treatment (p < 0.005). Improvements in subdomains of physical pain, psychological discomfort and psychological disability accounted for the changes. CONCLUSION: This study demonstrates that OHQoL, in particular, pain and psychological subdomains, improvement was associated with non-surgical periodontal therapy responses. Clinicians could capitalize upon the positive psychological OHQoL impacts of mechanical periodontal treatment for subsequent patient-centred motivation during maintenance therapy.

Factors Associated With Long-term Survival in Women Who Get Pregnant After Surgery for WHO Grade II Glioma.

BACKGROUND AND OBJECTIVES: Women with a World Health Organization grade II glioma (GIIG) often question clinicians about the effects of pregnancy on their disease. Previous reports have indicated a higher risk of glioma progression during and after pregnancy. Here, the aim was to investigate postpregnancy outcomes and predictive factors affecting overall survival in female patients who underwent GIIG surgery. METHODS: Inclusion criteria were adult women who have been pregnant after a GIIG resection and with a stable oncologic status at the time of pregnancy (no ongoing oncologic treatment, no contrast enhancement, no debilitating clinical condition). Relevant cases were identified from a databank (1998-2021) of patients who underwent surgical resection for a histologically confirmed GIIG in our department. RESULTS: Among 345 women with GIIG in their reproductive years (age <45 years), 16 patients (4.6%, mean age at delivery 30.9 ± 5.1 years) were pregnant (twice in 5 cases). The mean interval between the last oncologic treatment (surgery alone in 11 patients, surgery followed by chemotherapy and/or radiotherapy in 5 patients) and pregnancy was 3.5 years (range 0.75-10 years). Two patients experienced seizures during pregnancy. The delivery was vaginal and uneventful in all cases but 1 (1 caesarean). All children had normal mental and physical development. The glioma behavior changed in 7 patients (43.7%), with an acceleration of the velocity of diameter expansion and/or the occurrence of a contrast enhancement during or within 3 months after pregnancy, resulting in medical treatment and/or reoperation in the early postpartum period in 7 cases. The median clinical follow-up from delivery was 5.3 years (range 1.25-11.6 years). Four other patients received delayed adjuvant therapy for glioma progression. Seven patients (43.7%) died at a median time from delivery of 3.9 years (range 1.25-5.9 years). Overall, the median survival from delivery was 5.75 years. A crucial finding is that patients who underwent a complete surgical resection and patients with stable lesions before pregnancy lived longer (log rank, p = 0.046 and p = 0.0026, respectively). DISCUSSION: Tumor residual volume and tumor speed growth are strong predictive factors conditioning postpregnancy long-term survival in patients with GIIG. Identifying patients at risk is critical to provide relevant counsel to women with GIIG with a desire for motherhood.

Constant Multi-Tasking With Time Constraint to Preserve Across-Network Dynamics Throughout Awake Surgery for Low-Grade Glioma: A Necessary Step to Enable Patients Resuming an Active Life.

Awake surgery for brain gliomas improves resection while minimizing morbidity. Although intraoperative mapping was originally used to preserve motor and language functions, the considerable increase of life expectancy, especially in low-grade glioma, resulted in the need to enhance patients' long-term quality of life. If the main goal of awake surgery is to resume normal familial and socio-professional activities, preventing hemiparesis and aphasia is not sufficient: cognitive and emotional functions must be considered. To monitor higher-order functions, e.g., executive control, semantics or mentalizing, further tasks were implemented into the operating theater. Beyond this more accurate investigation of function-specific neural networks, a better exploration of the inter-system communication is required. Advances in brain connectomics led to a meta-network perspective of neural processing, which emphasizes the pivotal role of the dynamic interplay between functional circuits to allow complex and flexible, goal-directed behaviors. Constant multi-tasking with time constraint in awake patients may be proposed during intraoperative mapping, since it provides a mirror of the (dys)synchronization within and across neural networks and it improves the sensitivity of behavioral monitoring by increasing cognitive demand throughout the resection. Electrical mapping may hamper the patient to perform several tasks simultaneously whereas he/she is still capable to achieve each task in isolation. Unveiling the meta-network organization during awake mapping by using a more ecological multi-demand testing, more representative of the real-life conditions, constitutes a reliable way to tailor the surgical onco-functional balance based upon the expectations of each patient, enabling him/her to resume an active life with long-lasting projects.

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

BACKGROUND: 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 <-1.65), 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). Fifty-eight 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.

Cognitive preservation following awake mapping-based neurosurgery for low-grade gliomas: A longitudinal, within-patient design study.

BACKGROUND: Awake surgery with intraoperative electrical mapping emerged as a gold-standard approach in newly diagnosed diffuse low-grade glioma (DLGG) to optimize the extent of resection (EOR) while sparing critical brain structures. However, no study has assessed to what extent cognitive recovery occurs following awake mapping-guided neurosurgery in a large, longitudinal, and homogeneous series of DLGG. METHODS: A longitudinal study on the cognitive status of 157 DLGG patients was performed. Neuropsychological assessments were done before and three months after awake mapping-based surgery. Z-scores and variations of Z-scores were computed to determine the number of patients with cognitive deficit(s) or decline. Clinical, surgical, and histopathological variables were studied to investigate factors contributing to neurocognitive outcomes. RESULTS: Eighty-seven patients (55.4%) had preoperative cognitive impairments. Statistical analysis between the preoperative (baseline) and postoperative assessments demonstrated a significant difference in three domains (Executive, Psychomotor Speed and Attention, Verbal Episodic Memory). Eighty-six percent of patients exhibited no postoperative cognitive decline, and among them, 10% exhibited cognitive improvement. The mean EOR was 92.3%±7.8%. The EOR, postoperative volume, and tumor lateralization had a significant association with cognitive decline. No patients demonstrated permanent postoperative neurologic deficits, but 5.8% did not resume their preoperative professional activities. The 5-year survival rate was 82.2%. CONCLUSIONS: This is the largest series ever reported with systematic longitudinal neuropsychological assessment. 86% of patients demonstrated no cognitive decline despite large resections and only 5.8% did not return to work. This work supports the practice of awake surgery with cognitive mapping as safe and effective in DLGG patients.