Journal of Neuro-Oncology

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Online ISSN: 1573-7373
Print ISSN: 0167-594X
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Kaplan–Meier curves of local control (a), PFS (b), and OS (c) according to radiation dose (after adjusted by mitotic count). EQD2 equivalent dose in 2-Gy fractions (α/β ratio = 4 Gy)
Dose–response relationship of ART with respect to local control and survival outcomes. Estimated logarithm HRs (solid lines) with 95% confidence intervals (shading) for the association between ART dose and LC, PFS, and OS in 135 patients based on the degrees of freedom in multivariate additive Cox model function in a smoothHR optimal extended Cox-type additive hazards regression model. A dose of EQD2 69.12 Gy (vertical lines) was used as the reference value for calculating the HRs. EQD2 equivalent dose in 2-Gy fractions (α/β ratio = 4 Gy), HR hazard ratio, OS overall survival, PFS progression-free survival
Purpose This study aimed to identify the radiation dose–response relationship in patients with newly diagnosed atypical meningioma (AM) treated with adjuvant radiotherapy (ART) using conventional fractionation. Methods In total, 158 patients who underwent surgery and ART between 1998 and 2018 were reviewed. Among these patients, 135 with complete information on radiotherapy (RT) dose/fractionation and pathological reports were analyzed. We entered RT dose as a continuous variable into the Cox regression model using penalized spline to allow for a nonlinear relationship between RT dose and events. Local control (LC), progression-free survival (PFS), and overall survival (OS) were evaluated. The corresponding biological equivalent dose in 2 Gy fractions (EQD2) was calculated using an α/β ratio of 4 Gy. Results The median follow-up duration was 56.0 months. The median ART dose delivered was 61.2 Gy in 24–34 daily fractions, corresponding to a median EQD2 of 59.16 Gy. In multivariate analysis, larger size and higher mitotic count were associated with significantly reduced LC (P < 0.001 and P = 0.002, respectively), PFS (P < 0.001 and P = 0.006, respectively), and OS (P = 0.006 and P = 0.001, respectively). Meanwhile, a higher RT dose was significantly associated with improved LC, PFS, and OS. Moreover, RT showed a dose-dependent effect on LC, PFS, and OS; local failure, tumor progression, and death were reduced by 12%, 12%, and 16%, respectively, per 1 Gy increase in the dose (EQD2). Conclusion The dose of ART in AM has a dose–response relationship with LC and survival outcomes.
 
Kaplan-Meier analysis of overall survival rates among LUSC-BM patients who underwent stereotactic radiosurgery (SRS or GKRS): (a) overall survival; (b) effects KPS score; (c) effects of TKI use; (d) effects of immunotherapy. P-values are annotated in the graph and failure rates of both groups at 6-, 12-, 18- and 24-month intervals are shown in the side table
Kaplan-Meier analysis of local tumor control rates among LUSC-BM patients who underwent SRS: (a) local control rate; (b) effects of SRS margin dose; (c) effects of TKI use; (d) effects of maximal SRS dose; (e) effects of tumor histology; (f) effects of immunotherapy. P-values are annotated in the graph and failure rates of both groups at 6-, 12-, 18- and 24-month intervals are shown in the side table
Kaplan-Meier analysis of distant tumor failure rates among LUSC-BM patients who underwent SRS: (a) distant failure rate; (b) effects of gender; (c) effects of extracranial metastases; (d) effects of immunotherapy; (e) effects of total BM number; (f) effects of smoking. P-values are annotated in the graph and failure rates of both groups at 6-, 12-, 18- and 24-month intervals are shown in the side table
PurposeIn this study we report our 30-year experience in stereotactic radiosurgery (SRS) treatment of lung squamous cell carcinoma (LUSC) brain metastases (BMs). It will serve to provide detailed longitudinal outcomes and predictors of efficacy in treating LUSC-BMs with SRS.Method We retrospectively reviewed 51 patients and 109 tumors treated with SRS at our center between 1993 and 2022. Patient demographics, PDL1 genotype, immunotherapy use and mortality cause were recorded. Radiological and clinical outcomes were followed at 1-3-month intervals post-SRS. Cox-regression analysis and Kaplan-Meier survival curves were performed in statistical analysis.ResultsWe included 37 male and 14 female patients (median age 62.7 years at BM diagnosis). Median overall survival (OS) time was 6.9 months, 6-month OS rate was 62.1%, and Karnofsky performance scale (KPS) was the only independent predictor. Median time for local control maintenance was 7.6 months, 6-month local control rate was 69.1%, with TKI as the only independent predictor. Median time to distant failure was 5.13 months, 6-month distant failure rate was 51.1%, and factors with significant impact included gender (p = 0.002), presence of extracranial metastases (p < 0.001), use of immunotherapy(p < 0.001), PDL1 genotype (p = 0.034), and total intracranial metastases number (p = 0.008). However, no definitive benefits of immunotherapy were identified in patients with higher PDL1 mutational tumors.Conclusion In this study we defined the natural history of disease progression and outcomes in SRS-treated LUSC-BM patients. We also identified predictors of OS and tumor control among these patients. The findings of this study will serve as a guide when counseling these patients for SRS.
 
Flow-chart of excluded participants. Pre-SRS before treatment with Gamma Knife or Linear accelerator Stereotactic Radiosurgery; FU follow-up. Note A pause of neuropsychological assessment due to SARS-CoV-2 took place between March 2020 and June 2021. Consequently, patients were not able to do a follow-up neuropsychological assessment in this period
Individual neurocognitive changes at test level over 6 months after SRS for patients treated with 2.1 Gamma-Knife (pre-SRS—T6: n = 39–40) and 2.2 LINAC (pre-SRS—T6: n = 27–29). Numbers are expressed in percentages. T3 3 months; T6 6 months; TMT-A Trail Making Test A; DS digit span; TMT-B Trail Making Test B; LF letter fluency; HVLT-IR Hopkins Verbal Learning Test-Immediate Recall; HVLT-DR Hopkins Verbal Learning Test-Delayed Recall; HVLT-Recog Hopkins Verbal Learning Test-Recognition; GP-D Grooved Pegboard-Dominant; GP-ND Grooved Pegboard Non-dominant; BNT Boston Naming Test
Individual cumulative neurocognitive decline at patient level over 6 months after SRS, for 40 patients treated with Gamma Knife (3.1) and 29 patients treated with the LINAC (3.2)
Purpose Brain metastases (BM) themselves and treatment with stereotactic radiosurgery (SRS) can influence neurocognitive functioning. This prospective study aimed to assess neurocognitive decline in patients with BM after SRS. Methods A neuropsychological test battery was assessed yielding ten test outcomes. Neurocognitive decline at 3 and 6 months post SRS was compared to measurement prior to Gamma Knife (GK) or linear accelerator (LINAC) SRS. Reliable change indices with correction for practice effects were calculated to determine the percentage of neurocognitive decline (defined as decline on ≥ 2 test outcomes). Risk factors of neurocognitive decline were analyzed with binary logistic regression. Results Of 194 patients pre-SRS, 40 GK and 29 LINAC patients had data accessible at 6 months. Compared to baseline, 38% of GK patients declined at 3 months, and 23% declined at 6 months. GK patients declined on attention, executive functioning, verbal memory, and fine motor skill. Of LINAC patients, 10% declined at 3 months, and 24% at 6 months. LINAC patients declined on executive functioning, verbal memory, and fine motor skills. Risk factors of neurocognitive decline at 3 months were high age, low education level and type of SRS (GK or LINAC). At 6 months, high age was a risk factor. Karnofsky Performance Scale, BM volume, number of BM, tumor progression and neurocognitive impairment pre-SRS were no risk factors. Conclusion Neurocognitive decline occurs in a considerable proportion of patients with BM treated with GK or LINAC SRS. Overall, high age appears to be a risk factor for neurocognitive decline after SRS.
 
Flow chart showing search strategy. From Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/
Forest plot showing the overall survival of patients who underwent surgical resection versus biopsy of PCNSL
Forest plot showing the progression-free survival of patients who underwent surgical resection versus biopsy of PCNSL
Purpose Despite the improvement in treatment and prognosis of primary central nervous system lymphoma (PCNSL) over the last decades, the 5-year survival rate is approximately 30%; thus, new therapeutic approaches are needed to improve patient survival. The study’s aim was to evaluate the role of surgical resection of PCNSL. Methods Primary outcomes were the overall survival (OS) and progression-free survival (PFS) of patients with PCNSL who underwent surgical resection versus biopsy alone. The meta-analysis was conducted to calculate pooled hazard ratios (HRs) under a random-effects model for the time-to-event variables. The odds ratios (ORs) were calculated for binary, secondary outcome parameters. Results Seven studies (n = 1046) were included. We found that surgical resection was associated with significantly better OS (HR 0.63 [95% CI 0.51–0.77]) when compared with biopsy. PFS was also significantly improved (HR 0.64 [95% CI 0.49–0.85]) in patients who underwent resection compared with those who underwent biopsy. The heterogeneity for OS and PFS was low (I2 = 7% and 24%, respectively). We also found that patients who underwent biopsy more often had multiple (OR 0.38 [95% CI 0.19–0.79]) or deep-seated (OR 0.20 [95% CI 0.12–0.34]) lesions compared with those who underwent surgical resection. There were no significant differences in chemotherapy or radiotherapy use or the occurrence of postoperative complications between the two groups. Conclusion In selected patients, surgical resection of PCNSL is associated with significantly better overall survival and progression-free survival compared with biopsy alone.
 
PRISMA flow diagram of the systematic review of the literature on spheno-orbital meningiomas resected via an endoscopic endonasal approach. (From: Moher D, Liberti A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preffered Reporting Items for Systematic Analysis: The PRISMA Statement. PLos Med 6(6): e1000097. doi: 10.1371/journal.pmed1000097. For more information, visit www.prisma-statement.org.)
Brain magnetic resonance imaging of the patient. (A) Pre-operative axial image demonstrates significant orbital invasion via the superior orbital fissure (B) Pre-operative coronal image demonstrating the significant lateral cavernous sinus component of the tumor (solid red arrow), tumor bulk within the pterygopalatine fossa/infraorbital space (solid blue arrow), as well as optic nerve compression (dashed red arrow) (C) Post-operative axial image demonstrating no significant debulking of the intraorbital tumor (D) Post-operative coronal image 180 degree decompression of the left optic nerve, medial to the tumor bulk (solid red arrow)
Intraoperative images of the transpterygoid decompression of the optic nerve and orbit. (A) Pre-decompression surgery demonstrating hyperostotic bone over the medial opticocarotid recess and optic canal (encircled). (B) Post-decompression surgery demonstrating the dura of the optic canal (grey lines), freed of the bony and tumoral compression
Purpose Spheno-orbital meningiomas are rare tumors, accounting for up to 9% of all intracranial meningiomas. Patients commonly present with proptosis, and visual deficits. These slow growing tumors are hard to resect due to extension into several anatomical compartments, resulting in recurrence rates as high as 35–50%. Although open surgical approaches have been historically used for resection, a handful of endoscopic approaches have been reported in recent years. We aimed to review the literature and describe a case of spheno-orbital meningioma with severe vision loss which was resected with an endoscopic endonasal approach achieving complete resolution of visual symptoms. Methods A systematic review of literature was conducted in accordance with the PRISMA guidelines. PubMed, Cochrane, and Web of Science databases were queried for spheno-orbital meningiomas resected via an endoscopic endonasal approach. Furthermore, the presentation, surgical management, and post-operative outcomes of a 53-year-old female with a recurrent spheno-orbital meningioma are described. Results The search yielded 26 articles, of which 8 were included, yielding 19 cases. Average age at presentation was 60.5 years (range: 44–82), and 68.4% of patients were female. More than half of the cases achieved subtotal resection. Common complications associated with endoscopic endonasal surgery included CN V2 or CN V2/V3 hypoesthesia. Following surgical intervention, visual acuity and visual field remained stable or improved in the majority of the patients. Conclusion Endoscopic approaches are slowly gaining momentum for treatment of spheno-orbital meningiomas. Further studies on the clinical benefits of this approach on patient outcomes and post-operative complications is warranted.
 
Predicted hazard ratios across NF2 wild-type/mutant tumors and postoperative radiation status for a grade 2 meningioma in a female patient
Purpose High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT). Methods From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status. Results Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068–0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88–6.73, p = 0.087). Conclusion This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship.
 
PurposeGlioblastoma (GBM) is the most common and deadliest brain tumor with unrelenting and rapid disease progression. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Treatment failure and resistance is the rule and despite advances in imaging technology, early detection of treatment failure or impending resistance remains a challenge. There is a dire, unmet, need in clinical practice for minimally-invasive diagnostic tools to enable timely understanding of disease progression and treatment response. Here, we aim to address this clinical need by leveraging a unique characteristic of GBM: the overexpression of the α2 variant of the IL-13 receptor in over 75% of GBM tumors.Methods In this study we examined patients with primary GBM from Penn State and Cleveland Clinic compared to healthy controls.ResultsIL13Rα2 was detectable in plasma of GBM patients using ELISA but detection could be optimized by PEG precipitation to enrich for extracellular vesicles (EVs). Patients with GBM had elevated levels of plasma IL13Rα2, which correlated to levels of this receptor in the tumor tissue. Elevated plasma levels of IL13Rα2 predicted longer overall survival (OS) (19.8 vs. 13.2 months). Similarly, detection of IL13Rα2 + cells in tumor tissue also predicted longer OS (22.1 vs. 12.2 months).Conclusion These findings strongly suggest that expression of the IL13Rα2 receptor confer survival advantage in GBM patients, which can be determined through a minimally-invasive liquid biopsy. Detection of plasma IL13Rα2 can also be used to select GBM patients for targeted tumor therapy.
 
Adjuvant treatment following surgery. The bars represent percentage (%) of the total number of patients in each group. Chemo; chemotherapy alone. Radio; radiotherapy alone. Chemoradio con; concomitant chemoradiotherapy (e.g., radiotherapy concomitant with temozolomide +/- adjuvant). Chemoradio seq; sequential chemoradiotherapy (i.e. combined treatment but without concomitant chemotherapy). None; no adjuvant treatment.
The bars represent percentage (%) of all patients treated with radiotherapy (radiotherapy alone or concomitant with chemotherapy) within 6 months after surgery, divided with respect to photon (100% 2007–2011, 90.5% 2012–2016, 25% 2017–2021) or proton (0%, 9.5%, 75%) radiotherapy
Background Isocitrate dehydrogenase ( IDH ) mutated diffuse lower-grade gliomas (dLGG) are infiltrating brain tumors and increasing evidence is in favor of early multimodal treatment. In a Scandinavian population-based setting, we wanted to study treatment patterns over the last 15 years, focusing on the short-term postoperative course to better understand the potential negative consequences of treatment. Methods Patients ≥ 18 years with primary IDH -mutated dLGG grade 2 and 3, operated between January 2007–June 2021 were identified. Patients were divided into subgroups (2007–2011, 2012–2016, and 2017–2021) and comparisons regarding tumor- and disease characteristics, treatment, and postoperative outcome were performed. Results We identified 202 patients (n = 61, 2007–2011; n = 72, 2012–2016; n = 69, 2017–2021), where of 193 underwent resection without change in proportion of resections over time. More patients underwent complete resections in recent times (6.1%; 15.7%; 26.1%, respectively; p = 0.016). Forty-two patients had any neurological deficit postoperatively (14.8%; 23.6%; 23.2%; p = 0.379), mostly minor and transient. Differences in oncological therapy were seen between the investigated subgroups. Early radiotherapy alone (32.8%; 7%; 2.9%; p < 0.001), concomitant chemoradiotherapy (23%; 37.5%; 17.4%; p = 0.022), sequential chemoradiotherapy (0%; 18%; 49.3%; p < 0.001), and no adjuvant treatment (42.6%; 23.6%; 18.8%; p = 0.009) shifted during the studied period. Increasingly more patients received proton radiotherapy compared to photon radiotherapy during the later time periods (p < 0.001). Conclusion Complete resections were performed more often in later time periods without an apparent increase in surgical morbidity. Early adjuvant oncological treatment shifted towards providing chemotherapy and combined chemoradiotherapy more often in later time periods. Protons replaced photons as the radiation modality of choice.
 
NICE guidelines for management of glioma following biopsy or surgical resection
a Chemical structure of [¹⁸F]fluorodopa (–NH2 = amine group, –COOH = carboxyl group). b Amino acids reach tumour cells via amino acid transporters. Amino acid transporters can be uniporter, symporter or antiporter and each have carrier numbers as demonstrated
Structure and function of the LAT1 amino acid transporter
Metabolism of FDOPA (AAAD = aromatic amino acid decarboxylase, FDA = 18F6-dlurodopamine, COMT = catechol O-methyl transferase, OMFD = 3-O-methyl-6-fluoro-L-DOPA, FDOPAC = [¹⁸F]6-fluoro-L-3,4-dihydrophenylacetic acid, MAO = monoamine oxidase (MAO), FHVA = [¹⁸F]6-fluorohomovanillic acid)
Purpose Gliomas are the most commonly occurring brain tumour in adults and there remains no cure for these tumours with treatment strategies being based on tumour grade. All treatment options aim to prolong survival, maintain quality of life and slow the inevitable progression from low-grade to high-grade. Despite imaging advancements, the only reliable method to grade a glioma is to perform a biopsy, and even this is fraught with errors associated with under grading. Positron emission tomography (PET) imaging with amino acid tracers such as [ ¹⁸ F]fluorodopa ( ¹⁸ F-FDOPA), [ ¹¹ C]methionine ( ¹¹ C-MET), [ ¹⁸ F]fluoroethyltyrosine ( ¹⁸ F-FET), and ¹⁸ F-FDOPA are being increasingly used in the diagnosis and management of gliomas. Methods In this review we discuss the literature available on the ability of ¹⁸ F-FDOPA-PET to distinguish low- from high-grade in newly diagnosed gliomas. Results In 2016 the Response Assessment in Neuro-Oncology (RANO) and European Association for Neuro-Oncology (EANO) published recommendations on the clinical use of PET imaging in gliomas. However, since these recommendations there have been a number of studies performed looking at whether ¹⁸ F-FDOPA-PET can identify areas of high-grade transformation before the typical radiological features of transformation such as contrast enhancement are visible on standard magnetic resonance imaging (MRI). Conclusion Larger studies are needed to validate ¹⁸ F-FDOPA-PET as a non-invasive marker of glioma grade and prediction of tumour molecular characteristics which could guide decisions surrounding surgical resection.
 
Female predominance in meningiomas. A Figure from Wiemels et al. [11] age and sex incidence of meningioma per 100,000 people in United States from 2002 to 2006
Introduction Meningiomas are associated with several gonadal steroid hormone-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive. Methods We performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, we reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMed, Scopus, and the NIH clinical trials database. Results We identify that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria. Conclusions Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, we clarify the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies.
 
Flow chart of database searching strategy detailing the report selection procedure as outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guideline
Meta-analyses of proportions of patients who returned to work within 12 months following partial resection, subtotal resection, gross total resection and supratotal resection of diffuse low-grade glioma
Background Surgical resection offers survival benefits in patients with diffuse low-grade glioma (DLGG) but its association with functional outcomes is uncertain. This systematic review assessed functional outcomes associated with extent of resection (EoR) in adults with DLGG. Methods We searched Medline, Embase and CENTRAL on the 19th of February 2021 for observational studies reporting functional outcomes after surgical resection for patients aged ≥ 18 years with a new diagnosis of supratentorial DLGG according to any World Health Organization classification of primary brain tumors. The Newcastle–Ottawa Scale (NOS) informed our risk of bias assessments. The proportion of patients returning to work within 12 months entered a random-effects meta-analysis. PROSPERO registration number CRD42021238387. Results There were seven eligible moderate to high-quality (NOS > 6) observational studies identified from 1,183 records involving 234 patients with DLGG. Functional outcomes reported included neurocognition (n = 2 studies), performance status (n = 3), quality of life (QoL) (n = 1) and return to work (n = 6). The proportion of patients who returned to work within 12 months of surgery was 84% (95% confidence interval [CI] 50–96%, I-squared = 38%, 5 studies) for gross total resection, 66% (95% CI 14–96%, I² = 57%, 5 studies) for subtotal resection, and 31% (95% CI 4–82%, I² = 0%, 4 studies) for partial resection. There was insufficient data on other functional outcomes for quantitative synthesis. Conclusion A higher proportion of DLGG patients returned to work following gross total resection compared with those who had a subtotal or partial resection. Further studies with standardized assessments can clarify the association between EoR and different functional outcomes.
 
Decision Tree Analysis for Prediction of New Postoperative Neurological Deficit in Immediate Postoperative Period Patients Treated for Spinal Ependymoma
Decision Tree Analysis for Prediction of New Postoperative Neurological Deficit at Last Follow-Up in Patients Treated for Spinal Ependymoma
Purpose To interrogate the association of tumor-associated syrinxes with postoperative neurological and oncological outcomes in patients surgically treated for WHO grade 2 spinal ependymomas. Methods Adults treated for primary spinal intramedullary ependymomas between 2000 and 2020 were identified and data were gathered on preoperative neurological exam, radiographic characteristics, operative details, and postoperative neurological outcome. Neurological status was graded on the modified McCormick Scale (MMS). Neurological worsening immediately postoperatively and at last follow-up were defined by ≥ 1 MMS grade deterioration. Decision-tree analyses were also performed to identify independent predictors of new neurological deficits. Results Seventy patients were identified; mean age 45.4 ± 12.7; 60% male. Forty-eight patients (68.6%) had tumor-associated syrinxes, were more common among males (68.8%) and cervical lesions (68.8 vs. 31.8%; P = 0.005). Postoperatively patients with syrinxes had better MMS (P = 0.035) and were less likely to require a gait aid (39.6 vs. 81.8; P = 0.002). This latter difference persisted to last follow-up (22.9 vs. 59.1%; P = 0.006). On decision-tree analysis the strongest predictors of long-term neurological worsening were advanced age (≥ 63 years) and worse baseline neurological function. Worsened neurological status in the immediate postoperative period was best predicted by thoracic localization, the presence of a hemosiderin cap, and longer craniocaudal extension. Conclusion For spinal ependymomas, tumor-associated syrinxes may portend decreased risk for immediate postoperative neurologic deficits but do not predict long-term neurological outcomes (MMS) or odds of successful gross total resection. Thoracic localization appears to best predict new immediate postoperative deficits, and worse baseline neurological function and advanced age best predict long-term deficits.
 
(a) Scatter plot showing median values and interquartile range for PFS and OS in the 101-patient cohort with new or recurrent IDH wild-type HGGs. Median values are represented by a dashed line. Error bars represent the interquartile range. Temporal trends of median T1W-CE (b), T2W (c), and FLAIR (d) imaging volumes (cm³). T1W-CE, T2W, and FLAIR tumor volumes from preoperative (red), intraoperative (green), immediate postoperative (blue), and three-month postoperative (purple) MRI scans. The median value is represented by a colored circle. Error bars represent the interquartile range for each of the volumes
Relationship of T1W-CE (a, b), T2W (c, d), and FLAIR (e, f), imaging volumes on PFS and OS. Log-rank analyses of preoperative, intraoperative, immediate postoperative, and three-month postoperative imaging volumes—separated above and below the median—and their relationship with PFS and OS
Relationship of EOR (a, b) and additional resection (c, d) on PFS and OS. Log-rank analysis of EOR separated above and below the median value and its relationship with PFS (a) and OS (b). Log-rank analysis of no additional resection versus additional resection and its relationship with PFS (c) and OS (d)
Purpose Intraoperative magnetic resonance imaging (iMRI) has been efficacious in maximizing resection of high-grade gliomas (HGGs). In this single-institution study of patients with HGGs who underwent resection using iMRI, the authors present a volumetric-based survival analysis to evaluate progression-free survival (PFS) and overall survival (OS), as well as the impact of additional resection on survival. Methods This retrospective analysis included patients with HGGs who underwent resection using iMRI from 2011 to 2021. Volumetric analyses of T1-weighted contrast-enhancing (T1W-CE), T2-weighted (T2W), and T2W fluid-attenuated inversion recovery (FLAIR) MRI sequences were assessed at preoperative, intraoperative, immediate postoperative, and three-month postoperative timepoints. Statistical analyses were carried out using log-rank and multivariable Cox proportional hazard regression analyses. Results A total of 101 patients (median age 57.0 years) were treated. In keeping with prior studies, statistically significant associations between greater EOR and longer PFS and OS were seen (p = 0.012 and p = 0.006, respectively). The results demonstrated significant associations of lower preoperative T2W, 3-month postoperative T2W, and 3-month postoperative FLAIR volumes with longer PFS and OS (p = 0.045 and p = 0.026, p = 0.031 and p = 0.006, p = 0.018 and p = 0.004, respectively), as well as associations between lower immediate postoperative T2W and immediate postoperative FLAIR volumes with longer OS (p = 0.002 and p = 0.02). There was no observed association in either PFS or OS for patients undergoing additional resection after initial iMRI scan (p = 0.387 and p = 0.592). Conclusion This study of 101 patients with new or recurrent HGGs shows three-month postoperative T2W and FLAIR imaging volumes were significant prognosticators with respect to PFS and OS.
 
Expression of CPT1A and G6PD genes in GBM and effects of their double knockdown in GBM TSs. Expression levels of wild-type IDH in GBM tumor and tumor-free cortex tissue samples (Tumor, n = 55; Cortex, n = 15) determined via RNA-seq. aCPT1A and G6PD are overexpressed in GBM tumors compared with normal cortex tissue. b Cell viability and ATP levels in GBM TSs measured 48 h after transfection with siCPT1A, siG6PD, or siCPT1A + siG6PD. c Immunoblot analysis of proteins related to stemness and EMT. d Biological effects of combined etomoxir and DHEA therapy on GBM TSs. Cell viability and ATP levels in GBM TSs were evaluated after 72 h treatment with etomoxir, DHEA, or co-treatment with etomoxir (100 μM) and DHEA (20 μg/mL). e Fa-CI plots: Combination index (CI) trends using various ratio metric mixtures of Etomoxir and DHEA for TS13-64 and TS14-15. f OCR, measured 48 h after treatment with etomoxir, DHEA, or the etomoxir/DHEA combination
Stemness and invasiveness changes in response to etomoxir and DHEA. Stemness and invasiveness were evaluated after treatment with etomoxir (100 μM) and DHEA (20 μg/mL). a Using the neurosphere formation assay, the proportion of sphere-positive wells and size (radius) of spheres were used to quantify stemness. b Immunoblot analysis of stemness-related proteins. c 3D collagen matrix invasion assay showing that implanted GBM TSs are less invasive. The invaded area was measured to determine the inhibitory effects of etomoxir and DHEA therapy. d Immunoblot examination of EMT-related proteins
Gene expression profiles of GBM TSs after etomoxir and DHEA treatment. RNA-seq was employed to establish the gene expression profile of TS13-64. a Average gene expression in the top 30%. Average linkage hierarchical clustering was conducted with Euclidean distance as a distance metric. Expression levels were visualized as heatmaps. b Heatmaps depicting expression of genes associated with stemness and invasiveness. c Heatmaps depicting expression of FAO- and OxPhos-associated genes. d Upregulated enriched gene set following combination treatment with etomoxir and DHEA. e Downregulated enriched gene set following combination treatment with etomoxir and DHEA
Metabolite profiling in GBM TSs after treatment with etomoxir and DHEA. Metabolite analysis confirmed changes in the TCA cycle and PPP intermediates in GBM TSs (TS13-64) in response to the etomoxir/DHEA combination. GBM TSs were treated for 48 h with etomoxir (100 μM) and DHEA (20 μg/mL) and metabolites evaluated via LC–MS. The combination therapy of etomoxir and DHEA, which target CPT1A and G6PD, suppresses TCA cycle and PPP in GBM TSs
Therapeutic responses in a mouse orthotopic xenograft model. a, b Bioluminescence imaging was used to determine tumor volumes after xenograft of TS13-64-luc TSs. Total photon flux was applied to calculate signal intensity (*P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s post hoc test). c Kaplan–Meier survival curves were estimated for each group (***P < 0.001; log-rank test). d Schematic summary of the study results. Combined treatment with etomoxir and DHEA targeting CPT1A and G6PD, respectively, suppressed fatty acid production and ATP synthesis in GBM TSs. This double suppressive effect on tumor bioenergetics reduced stemness, EMT, and invasiveness, eventually leading to cell death. Therapeutic results were further verified in a preclinical mouse model
PurposeLimited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs).Methods Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC–MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model.ResultsCPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC–MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice.Conclusion Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.
 
Examples of SMA assessment on transverse abdominal CT slices (A, B) and TMT assessment on axial T1-weighted contrast enhanced cranial MR images (C, D). A and C A 53 year old female at risk of sarcopenia according to TMT assessment (SMA = 76 cm²; TMT = 3.4 mm). B and D A 63 year old female with normal muscle status according to TMT assessment (SMA = 140 cm²; TMT = 8.3 mm). Red: skeletal muscle; Yellow: visceral fat; Blue: subcutaneous fat
Flowchart of the patient selection process
Bar chart of the SMA distribution in percentiles of the study population according to the sex specific percentiles for SMA drawn up by van der Werf et al. [25] based on a healthy population
Purpose Reduced temporal muscle thickness (TMT) has recently been postulated as a prognostic imaging marker and an objective tool to assess patients frailty in glioblastoma. Our aim is to investigate the correlation of TMT and systemic muscle loss to confirm that TMT is an adequate surrogate marker of sarcopenia in newly diagnosed glioblastoma patients. Methods TMT was assessed on preoperative MR-images and skeletal muscle area (SMA) was assessed at the third lumbar vertebra on preoperative abdominal CT-scans. Previous published TMT sex-specific cut-off values were used to classify patients as ‘patient at risk of sarcopenia’ or ‘patient with normal muscle status’. Correlation between TMT and SMA was assessed using Spearman’s rank correlation coefficient. Results Sixteen percent of the 245 included patients were identified as at risk of sarcopenia. The mean SMA of glioblastoma patients at risk of sarcopenia (124.3 cm ² , SD 30.8 cm ² ) was significantly lower than the mean SMA of patients with normal muscle status (146.3 cm ² , SD 31.1 cm ² , P < .001). We found a moderate association between TMT and SMA in the patients with normal muscle status (Spearman’s rho 0.521, P < .001), and a strong association in the patients at risk of sarcopenia (Spearman’s rho 0.678, P < .001). Conclusion Our results confirm the use of TMT as a surrogate marker of total body skeletal muscle mass in glioblastoma, especially in frail patients at risk of sarcopenia. TMT can be used to identify patients with muscle loss early in the disease process, which enables the implementation of adequate intervention strategies.
 
A bar plot presenting the number of interventions in patients with solitary and multiple meningioma
Extent of resection and utility of adjuvant treatment with recurrence rates stratified by each
A Recurrence-free survival and B overall survival stratified by multiplicity of meningioma
Recommended management strategies for the management of patients with multiple meningioma at presentation
Treatment details for the study cohort
Background Sporadic multiple meningioma are uncommon. Population-based data suggests that these patients have a reduced overall survival when compared to patients with solitary meningioma. The aim of this study was to investigate the clinical outcomes in multiple and solitary meningioma. Methods A single-center matched cohort study (2008–2018) was performed. Patients with synchronous multiple meningioma at presentation, with no history of prior intracranial radiation, concurrent hormone replacement therapy or features of NF2-schwannomatosis were included. Eligible patients were matched 1:1 to patients with solitary meningioma. Outcomes of interest were occurrence of an intervention, recurrence, new meningioma development and mortality. Results Thirty-four patients harboring 76 meningioma at presentation were included. Mean age was 59.3 years (SD = 13.5). Thirty-one (91.2%) were female. The median number of meningioma per patient was 2 (range 2–6). Eighteen patients (52.9%) were symptomatic at presentation. Median overall follow-up was 80.6 months (IQR 44.1–99.6). Compared to patients with a sporadic meningioma, there was no difference in intervention rates (67.6% vs 70.6%, P = 0.792). Eight patients (34.8%) with a multiple meningioma had a WHO grade 2 meningioma compared to 7 (29.2%) with a solitary meningioma (P = 0.679). Median recurrence-free survival was 89 months (95% CI 76–104) with no difference between the two groups (P = 0.209). Mean overall survival was 132 months (95% CI 127–138) with no difference between the two groups (P = 0.860). One patient with multiple meningioma developed two further new meningioma 36 months following diagnosis. Conclusion Sporadic multiple meningioma may not have worse clinical outcomes. Management of patients with sporadic multiple meningioma should be tailored towards the symptomatic meningioma or high-risk asymptomatic meningioma.
 
Brain areas maximally invaded by the tumor in the DEX A and P B groups are shown in the overlays on coronal, sagittal, and axial sections of the T1 MRIcro template. The legend shows the color corresponding to the different frequencies of the participants’ lesion overlays, from purple, least frequent, to blue, most frequent. Images are displayed in radiological convention. C V/C levels: percentage of patients in the DEX and P group assigned to each level. Patients in the DEX group were more frequently assigned to level 1–3 as compared to those in the P group
Purpose In awake surgery, the patient is sedated, but is also required to be sufficiently alert and collaborative during extensive neurocognitive testing. In the present preliminary report of a retrospective single-center study, a continuous series of 168 patients who underwent awake surgery for brain tumor located near eloquent areas, was investigated to observe the effect of dexmedetomidine (n = 58) compared with propofol (n = 110) on vigilance and collaboration required to perform extensive intra-operatory Real Time Neuropsychological Testing (RTNT). Methods We assigned a score to each patient, by using a scale that combines vigilance and collaboration in a 5 levels score (the higher score denoting higher level). Results The median interquartile range was significantly lower (range 3–5) for the dexmedetomidine group compared to the propofol one (range 4–5, p = .044). Patients with intra-operative seizures (p = .014) and/or electrocorticographic slow/epileptiform activity (p = .042), and patients in the propofol group who showed increased heart rate (p = .032) were those who obtained the lower scores (lower vigilance and collaboration level). Conclusion The study shows that the effect of dexmedetomidine or propofol -based conscious sedation on ability to perform Real Time Neuropsychological Testing during awake surgery for supratentorial tumor resection is different. Although both permit high mean levels of vigilance and collaboration, the patient who received dexmedetomidine was more likely to show lower vigilance and collaboration during RTNT.
 
PRISMA flow diagram of literature search strategy in PubMed and ClinicalTrials.gov
Left temporal pre-operative target (red) and the actual Gamma Knife treatment plan (yellow; 27 Gy prescription dose, 3 fractions) based on the T1 post contrast MRI images in the coronal a, transverse b, and sagittal c views. This patient was treated with neo-adjuvant SRS prior to surgical resection
Left temporal post-operative cavity (blue) with an added 1 mm. margin (pink) and mock Gamma Knife plan (yellow; 27 Gy prescription dose, 3 fractions) based on the T1 post contrast MRI images in the coronal a, transverse b, and sagittal c views. This patient was treated with neo-adjuvant SRS prior to surgical resection and is the same patient in Fig. 2
PurposeFollowing surgical resection of brain metastases (BMs), adjuvant stereotactic radiosurgery (SRS) has become the standard of care post-operative cavity irradiation. Recent studies, however, have demonstrated that with the current sequence of surgery and radiation, risk of leptomeningeal disease (LMD) and radiation necrosis (RN) remains high. Pre-operative, or neoadjuvant, SRS (nSRS) has been proposed as an alternative treatment strategy which not only minimizes local recurrence (LR) but also LMD and RN. It is thought that nSRS sterilizes the tumor, allowing for minimal spillage of viable tumor cells during resection, creating less favorable conditions for LMD. Furthermore, nSRS allows for easier contouring and decreased margin irradiation during planning and treatment, respectively, diminishing the risk of symptomatic RN. While nSRS has already been adopted for treating other extra-cranial tumors, its role in treating BMs is yet to be defined. We aim to summarize recent studies in nSRS usage for BMs and the rationale of this treatment strategy.Methods We performed a search for articles regarding nSRS for BMs published in PubMed from 2018 to 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We summarized a total of 14 retrospective reviews, case series, dose/timing studies, and ongoing Phase II & III clinical trials. Conclusion In this review, we describe the findings of current studies and identify prospective clinical trials with the aim of understanding the efficacy of nSRS over current treatment standards. Herein, we also discuss the theoretical advantages and limitations of nSRS (both biologic and clinical) to help guide future clinical investigations.
 
PurposeThe incidence of intracranial metastatic disease (IMD) in patients with gastrointestinal (GI) cancers is rising. Expression of the erythroblastic oncogene B-2 (ERBB2) is associated with an in increased risk of IMD in patients with breast cancer. The implications of ERBB2 expression for IMD risk in patients with GI cancers is less clear. The objective of this systematic review was to determine the incidence of IMD and OS in patients with ERBB2+ gastrointestinal cancers.MethodsA literature search of MEDLINE, EMBASE, CENTRAL, and grey literature sources was conducted from date of database inception to July 2021. Included studies reported outcomes on patients with IMD secondary to ERBB2 GI cancers.ResultsFourteen cohort studies met inclusion criteria, of which thirteen were retrospective. Eleven studies reported on gastric, esophageal, or gastroesophageal junction cancers. Three studies directly compared incidence of IMD based on ERBB2 status and among these, ERBB2+ patients had a higher incidence of IMD. One study indicated that ERBB2+ patients had significantly longer OS from the times of primary cancer (P = .015) and IMD diagnosis (P = .01), compared with patients with ERBB2− disease.Conclusions In this systematic review, patients with ERBB2+ GI cancer were more likely to develop IMD. Future study is required on the prognostic and predictive value of ERBB2 status in patients with GI cancers.
 
Etiopathogenesis of hair loss in children underwent oncological treatments
Original CT treatment plan scalp contouring. A Saggital and (B) Coronal view, whole-scalp ROI is pink colored and nape ROI is yellow colored. The thickness of skin contouring ranged from 3 to 5 mm based on the thickness of the skin. To determine the deep contour of the scalp we used the bone window, for the outer limit the soft tissue window
Purpose Our aim was to determine the main risk factors related to the occurrence of permanent alopecia in childhood medulloblastoma (MB) survivors. Methods We retrospectively analyzed the clinical features of all consecutive MB survivors treated at our institute. We divided the patients into 3 groups depending on the craniospinal irradiation (CSI) dose received and defined permanent alopecia first in terms of the skin region affected (whole scalp and nape region), then on the basis of the toxicity degree (G). Any relationship between permanent alopecia and other characteristics was investigated by a univariate and multivariate analysis and Odds ratio (OR) with confidence interval (CI) was reported. Results We included 41 patients with a mean10-year follow-up. High dose CSI resulted as an independent factor leading to permanent hair loss in both groups: alopecia of the whole scalp (G1 p-value 0.030, G2 p-value 0.003) and of the nape region (G1 p-value 0.038, G2 p-value 0.006). The posterior cranial fossa (PCF) boost volume and dose were not significant factors at multivariate analysis neither in permanent hair loss of the whole scalp nor only in the nuchal region. Conclusion In pediatric patients with MB, the development of permanent alopecia seems to depend only on the CSI dose ≥ 36 Gy. Acute damage to the hair follicle is dose dependent, but in terms of late side effects, constant and homogeneous daily irradiation of a large volume may have a stronger effect than a higher but focal dose of radiotherapy.
 
PRISMA flow diagram of the search algorithm and exclusion criteria used in this review
Graph of overall fluorescence positive and negative samples by tumor primary site. NSCLC non-small cell lung cancer, SCLC small cell lung cancer, GI gastrointestinal, GU genitourinary, 5-ALA 5-aminolevulinic acid
Purpose 5-aminolevulinic acid (5-ALA) has demonstrated its utility as an intraoperative imaging adjunct during fluorescence guided resection of malignant gliomas. However, literature regarding 5-ALA-guided resection for brain metastases is limited. We conducted a systematic review to evaluate the efficacy of 5-ALA fluorescence for resection of metastatic brain tumors. Methods PubMed was queried for studies involving 5-ALA and brain metastases, and results were screened following PRISMA guidelines. Articles related to 5-ALA and brain metastasis were further assessed based on inclusion and exclusion criteria and results were analyzed for 5-ALA fluorescence rates stratified by tumor primary sites and histological subtypes. Results Of 421 identified search results, 10 studies were included and a total of 631 patients analyzed. Of these studies, 60% were retrospective in design. The reported rates of 5-ALA fluorescence in included brain metastases ranged from 27.6 to 86.9%, with variability across and within tumor types. No studies concluded improved operative outcomes or survival outcomes related to 5-ALA use. Conclusions Current studies regarding 5-ALA fluorescence in brain metastases are limited and do not confirm efficacy for improving extent of resection or post-operative survival. Fluorescence is variable across and within tumor types. Further studies are necessary to evaluate whether specific tumors may benefit from 5-ALA FGS or if changes in delivery protocols or fluorescence quantification may affect intraoperative utility.
 
Press Ganey results for Telemedicine and In-Person visits. (A) Press Ganey results were divided into 4 separate categories: Access, Provider, Telemedicine Technology, and Overall Assessment. The survey results were compared by patient gender, age, insurance type and surgical vs. medical specialty for both telemedicine visits as well as in-person visits. (B) Direct comparisons between telemedicine and in-person survey results were performed for Access, Provider, and Overall Assessment. * = P ≤ 0.05, ** = P ≤ 0.01, *** = P ≤ 0.001
Purpose Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person visits within a Neuro-Oncology Program to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. Methods 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) by surgical and medical neuro-oncology patients between 04/01/2020 and 06/30/2021 were reviewed. Survey results were divided into 4 categories (Access, Provider, Technology (telemedicine only), and Overall Satisfaction). Results were analyzed for the impact of telemedicine versus in-person visits, and gender, age, insurance, and specialty. Cost savings were calculated based on potential travel distance and lost productivity. Results Survey results from telemedicine visits demonstrated that patients with private insurance returned higher scores in the Provider (p = 0.0089), Technology (p = 0.00187), and Overall (p = 0.00382) categories. Surgical patients returned higher scores for Access (p = 0.0015), Technology (p = 0.0002), and Overall (p = 0.0019). When comparing telemedicine to in-person scores, in-person scored higher in Provider (p = 0.0092) for all patients, while in-person scored higher in Access (p = 0.0252) amongst surgical patients. Cost analysis revealed that telemedicine allowed patients to save an average of 4.1 to 5.6 h per visit time and a potential cost savings of up to $223.3 ± 171.4. Conclusion Telemedicine yields equivalent patient satisfaction when employed in surgical as compared to medical Neuro-Oncology patients with the potential to lessen the financial and time burden on neuro-oncology patients.
 
Purpose Brain radiotherapy combined with concomitant and six cycles of adjuvant temozolomide (TMZ) is the standard treatment for newly diagnosed high-grade gliomas (HGGs). However, the optimal number of cycles of TMZ is still controversial. We conducted this retrospective cohort study to evaluate whether prolonging adjuvant TMZ beyond six cycles resulted in better survival outcomes. Methods Patients with high-grade gliomas treated with standard brain radiotherapy combined with TMZ were retrospectively analysed. The duration of adjuvant TMZ ranged from 6 to 12 cycles. Those with 6 cycles of adjuvant TMZ were defined as the standard STUPP group, and those with 7–12 cycles were called the extended STUPP group. Median progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The Cox proportional hazards model was adopted to estimate the Hazard ratio (HR) associated with PFS and OS. Results From September 2011 to May 2021, 372 patients were eligible (143 in the standard group, 229 in the extended group). Patients who received extended STUPP had better PFS and OS compared with standard STUPP. The median PFS for the standard STUPP group was 12 months and for the extended STUPP group 22 months (log-rank P < 0.001). The median OS for the standard STUPP group and extended STUPP group were 12 months and 36 months, respectively (log-rank P < 0.001). In the subgroup analysis, the two treatments did not differ in IDH-mutated patients, while patients with IDH wild-type had a significantly better response to extended treatment than to standard treatment (PFS: log-rank P = 0.004; OS log-rank P = 0.001). Patients with MGMT promoter methylation treated with extended STUPP obtained longer PFS and OS than those treated with standard STUPP (PFS: log-rank P = 0.015; OS log-rank P = 0.010). Adverse events including leukopenia (P < 0.001), thrombocytopenia (P = 0.090), fatigue (P < 0.001) and nausea/vomiting (P = 0.004) were more frequent in the extended group. Conclusion Extended TMZ treatment was superior to standard 6-cycle TMZ for both PFS and OS. The incidence of toxicities in extended group was higher but tolerable.
 
PRISMA diagram for systematic search
Overall survival (A, B) and progression-free survival (C, D)
Individual and pooled OS (A) and PFS (B) from studies of HF-RT in young and fit patients with GBM
Purpose Shorter hypofractionated radiation therapy (HF-RT) schedules may have radiobiological, patient convenience and healthcare resource advantages over conventionally fractionated radiation therapy (CF-RT) in glioblastoma (GBM). We report outcomes of young, fit GBM patients treated with HF-RT and CF-RT during the COVID-19 pandemic, and a meta-analysis of HF-RT literature in this patient subgroup. Methods Hospital records of patients with IDH-wildtype GBM treated with HF-RT (50 Gy/20 fractions) and CF-RT (60 Gy/30 fractions) between January 2020 and September 2021 were reviewed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariable analysis was performed using Cox regression analysis. A systematic search and meta-analysis of studies from January 2000 to January 2022 was performed. Results 41 patients were treated (HF-RT:15, CF-RT:26). For both HF-RT and CF-RT groups, median age was 58 years and 80–90% were ECOG 0–1. There were more methylated tumours in the HF-RT group. All patients received concurrent/adjuvant temozolomide. At 19.2 months median follow-up, median OS was 19.8 months and not-reached for HF-RT and CF-RT (p = 0.5), and median PFS was 7.7 and 5.8 months, respectively (p = 0.8). HF-RT or CF-RT did not influence OS/PFS on univariable analysis. Grade 3 radionecrosis rate was 6.7% and 7.7%, respectively. 15 of 1135 studies screened from a systematic search were eligible for meta-analysis. For studies involving temozolomide, pooled median OS and PFS with HF-RT were 17.5 and 9.9 months (927 and 862 patients). Studies using shortened HF-RT schedules reported 0–2% Grade 3 radionecrosis rates. Conclusion HF-RT may offer equivalent outcomes and reduce treatment burden compared to CF-RT in young, fit GBM patients.
 
Individual evolution of the maximum tumor diameter of the tumor remnant after surgery until the last revision in 20 patients treated with cabergoline (left) and in 40 patients under active surveillance (right)
Clinical response rates (stable disease, partial response, and progression) of tumor remnant after surgery in patients treated with cabergoline (CAB group, n = 22) and patients followed with active surveillance (OBS group, n = 40) (chi-square 1.71, p = 0.42)
Clinical response rates (stable disease, partial response, and progression) of tumor remnant after surgery in patients treated with CAB (n = 186) and patients followed with active surveillance (OBS group, n = 157) obtained from literature data [8] together with those of our patients (chi-square 53.32, p < 0.00001)
Background In recent years, dopamine agonists (DAs) have become an attractive therapeutic option to prevent both tumor growth and post-surgical tumor remnant growth in clinically non-functioning pituitary adenoma (NFPA). Aim To analyze our experience on the effect of cabergoline (CAB) on tumor remnant after initial surgery in NFPA patients. Patients and Methods A retrospective and multicenter study of NFPA patients with tumor remnant after surgery treated with CAB was performed. Results From a total of 142 NFPA patients (79 men, 55.2%; mean age 57.2 ± 14.2 year) who underwent surgery, we selected 62/142 (43.7%) patients (32 men, 51.6%; mean age 59.3 ± 13.9 year) with tumor persistence (TP) after surgery. In 22/62 (35.5%) TP patients CAB was used (CAB group), while the rest of the patients (40/62, 64.5%) underwent active surveillance [observation (OBS) group)]. The maximum diameter of the tumor remnant did not change significantly in either the CAB group [11.5 (6.0-16.9) mm vs. 12.0 (7.0–15.0) mm, p = 0.85) or the OBS group [8.5 (6.0-13.7) mm vs. 9.0 (6.2–14.0) mm, p = 0.064) at the end of the follow-up [13 (10.5–17) vs. 77.5 (50.2-107.2) months, CAB vs. OBS group; p < 0.001]. At the end of the treatment period with CAB most of the patients (n = 20/22, 90.9%) showed no progression of the tumor remnant [stable disease, SD (n = 17/22, 77.2%) and partial response, PR (n = 3/22, 13.6%)], while 2/22 patients (9.1%) exhibited progression. Similar response rates were observed in the OBS group [SD (n = 32/40, 80%), PR (n = 2/40, 5%), and progression (n = 6/40, 15%)]. Although no statistically significant differences (p = 0.42) were found in these responses, the percentage of progression was 1.65 times higher in the OBS group compared to the CAB group. On the contrary, the percentage of PR was 2.72 times higher in the CAB group compared to the OBS group, despite a significantly shorter follow-up period in the CAB group. Conclusion Although the present study showed no significant differences in the type of tumor response between the CAB and OBS groups of patients, the percentage of PR was higher and that of progression lower in the CAB group compared to the OBS group. This finding does not rule out a potential therapeutic benefit of CAB in the management of tumor remnant in patients with NFPA undergoing surgery.
 
Percentage incidence of distant and local recurrence in our study compared to the EF-14 secondary analysis and the historically observed rates. The rates of local recurrence are 92%, 82%, and 78% for the historic, EF-14, and our study cohorts respectively. Meanwhile, the rates of distant recurrence are 8%, 18%, and 22% for the historic, EF-14, and our study cohorts respectively
Newly diagnosed right parietal mass (a), Post-operative MRI (b), Infratentorial recurrence (c)
Newly diagnosed left parasagittal mass (a), Post-operative MRI (b), Distant recurrence (c)
Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression. Materials and Methods This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion. Results Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19–77 years). Median KPS was 90 (70–100). Median follow-up was 15.2 months (1.7–23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26–6.95 cm). One infratentorial progression was noted. Conclusions We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding. Trial Registration Clinicaltrials.gov Identifier NCT03477110.
 
CD95 and CD95L expression in mouse glioma cells. a. SMA-497, SMA-540, SMA-560 or GL-261 cells were assessed for expression of Cd95 by PCR using Hprt1 as endogenous control. b. Protein levels were assessed by flow cytometry. c. To assess Cd95l mRNA expression, two primer pairs, one targeting the first exon of the complete Cd95l coding sequence and one targeting the fourth exon of the complete Cd95l coding sequence, were used. d. CD95L protein levels were assessed by flow cytometry. Activated splenocytes (2 µg/ml concanavalin A) were included as positive control for CD95 protein and Cd95 mRNA and for CD95l mRNA. Data in a,c are presented as mean and SD. In c, a.t. indicates CT values above reliability threshold, CT>32.
CD95L expression in murine gliomas in vivo. a. Diagram of the two known murine Cd95l transcript variants and their sequence correspondence with the canonical Cd95l coding sequence (Cd95l CDS) and the putative murine CD95L and CD95Ls protein domains (created with BioRender.com). Three primer pairs (PP) used for the analysis of Cd95l transcript expression in vivo and their approximate amplifying regions in the transcript variants they are predicted to amplify are depicted. The CDS sequence, transcript elements, protein sequences and domain correspondence depiction were based on the data annotated in the Ensembl and UniProt databases [29, 35]. The 3D protein structures are AlfaFold predictions. The CD95L structure was extracted from the AlphaFold database [36] and the CD95Ls 3D structure was generated using the AlphaFold Colab notebook [37]. Structure coloring indicates model confidence (dark blue, pLDDT > 90; light blue, pLDDT 90 − 70; yellow, pLDDT 70 − 50; orange, pLDDT < 50). CD, death domain; TMD, transmembrane domain; ECD, extracellular domain; PRD, proline-rich domain; SA, self-assembly domain; THD, TNF homology domain. b,c. Cells were maintained in vitro or implanted in syngeneic mice and tumors from end-stage glioma-bearing mice were isolated. Expression of Cd95l mRNA in tumors and the surrounding tumor-bearing brain tissue (C57BL/6 brain and VM/Dk brain) was analyzed by RT-qPCR using primer pairs targeting the first exon of Cd95l or the sequence spanning the third and four exons of the complete Cd95l coding sequence (b) or a primer pair targeting the fourth exon of Cd95l (c). Hprt1 was used as internal control. Three tumor-bearing mice (in vivo 1, in vivo 2, in vivo 3) per model were studied. Data are represented as mean and SD (a.t., CT values above reliability threshold, CT>32). d. iRFP720-labelled GL-261 cells (GL-261 iRFP720+) were implanted in syngeneic mice. Tumors from end-stage mice were isolated and analyzed by flow cytometry. Flow cytometry histograms showing cell surface CD95L protein levels in GL-261 cells gated based on iRFP720 positivity are depicted. SFI, specific fluorescence index (median fluorescence intensity of anti-CD95L antibody, black ÷ median fluorescence intensity of isotype control, grey).
CD95 and CD95L CRISPR knockout (KO) in mouse glioma cells. Cd95 or Cd95l genes were knocked out via CRISPR/Cas9. a. Clonal CD95 KO cells were assessed for expression of the Cd95 transcript sequence spanning two predicted double-strand DNA break sites by RT-qPCR using Hprt1 as endogenous control and of protein by cell surface flow cytometry. RT-qPCR data are expressed as mean and SD. SFI, specific fluorescence index (median fluorescence intensity of experimental antibody ÷ median fluorescence intensity of isotype control). b. Naïve, CRISPR control or CD95 KO cells were stimulated with 10 or 1000 ng/ml exogenous CD95L (Mega-Fas-Ligand, MFL) in the absence or presence of cycloheximide (CHX, 10 µg/ml) for 6 h and assessed for Ac-DEVD-amc-cleaving (DEVDase) activity. As a positive control, cells were treated with 1 µM staurosporine (stauro). As a negative control, cells were treated with 10 µM zVAD-fmk in combination with staurosporine. A representative independent experiment is shown for each cell line. Data are expressed as mean and SD of six replicates. Statistical significances were assessed by two-way ANOVA followed by Bonferroni’s post hoc test (**p < 0.01, ****p < 0.0001 versus vehicle; ####p < 0.0001 versus CHX; +p < 0.05, ++++p < 0.0001 versus stauro). A.F.U., arbitrary fluorescence units. c. Clonal CD95L KO cells were assessed for expression of the Cd95l transcript sequence targeted by a sgRNA directing a Cas9-mediated double-strand DNA break in the fourth exon of Cd95l by RT-qPCR using Hprt1 as endogenous control. Data are expressed as mean and SD. Naïve refers to non-transfected cells, and CRISPR control to cells transfected with non-targeting sgRNA/pSpCas9(BB)-2 A-GFP plasmids.
Effect of CD95 and CD95L knockout (KO) in SMA-497 cell growth and T cell killing in vitro. a,b. The growth of CRISPR control, CD95 KO or CD95L KO SMA-497 cells was estimated by crystal violet staining in limiting dilution assays of cells grown in adherence conditions in the presence of fetal calf serum (a) or by MTT assay in cells cultured as spheres in suspension in the absence of fetal calf serum, but with EGF and FGF supplementation (b). c,d. Cell growth of adherent CD95 KO (clone 6) or CD95L KO (clone 3) SMA-497 cells transfected with Cd95 or Cd95l, respectively, was estimated in limiting dilution assays by crystal violet staining. Data in a-d are expressed as mean and SEM of representative experiments. Statistical significances (main column effect) were determined by means of a two-way ANOVA test followed by Bonferroni’s post hoc test. Data were reproduced in three independent experiments. e. Specific killing of activated splenocytes after 24 h co-culture with CRISPR control, CD95L KO (clone 3) or Cd95l-transfected CD95L KO (clone 3) SMA-497 cells. Data in e are expressed as mean and SD. Statistical significances were calculated by one-way ANOVA followed by Bonferroni’s post hoc test. A.U., arbitrate units; ns, not significant; ****, p < 0.0001.
Effect of CD95 and CD95L knockout (KO) in the SMA-497 model in vivo. a. Syngeneic (immunocompetent) VM/Dk or athymic (immunocompromised) Foxn1nu mice were orthotopically implanted with control (naïve and CRISPR control), CD95 KO (clones 5 and 6) or CD95L KO (clones 3 and 5) SMA-497 cells (illustration created with BioRender.com). b. Tumor volumes from animals sacrificed at the first onset of symptoms were determined by hematoxylin/eosin staining (scale bar = 1 mm). Data are expressed as mean and SD of n = 4 VM/Dk mice. Statistical significances between CD95 KO or CD95L KO and control tumor-bearing brains were determined by means of a one-way ANOVA test followed by Bonferroni’s post hoc test. c,d. End-stage survival was recorded. Statistical significances between CD95 KO or CD95L KO glioma-bearing mice and control glioma-bearing mice within the same mouse strain were determined by means of a log-rank test. Median survival in days provided in brackets (n = 7 mice per group). *, p < 0.05; **, p < 0.01; ***, p < 0.001.
Purpose Glioblastoma is the most common brain tumor in adults and is virtually incurable. Therefore, new therapeutic strategies are urgently needed. Over the last decade, multiple growth-promoting functions have been attributed to CD95, a prototypic death receptor well characterized as an apoptosis mediator upon CD95L engagement. Strategic targeting of non-apoptotic or apoptotic CD95 signaling may hold anti-glioblastoma potential. Due to its antithetic nature, understanding the constitutive role of CD95 signaling in glioblastoma is indispensable. Methods We abrogated constitutive Cd95 and Cd95l gene expression by CRISPR/Cas9 in murine glioma models and characterized the consequences of gene deletion in vitro and in vivo. Results Expression of canonical CD95 but not CD95L was identified in mouse glioma cells in vitro. Instead, a soluble isoform-encoding non-canonical Cd95l transcript variant was detected. In vivo, an upregulation of the membrane-bound canonical CD95L form was revealed. Cd95 or Cd95l gene deletion decreased cell growth in vitro. The growth-supporting role of constitutive CD95 signaling was validated by Cd95 re-transfection, which rescued growth. In vivo, Cd95 or Cd95l gene deletion prolonged survival involving tumor-intrinsic and immunological mechanisms in the SMA-497 model. In the GL-261 model, that expresses no CD95, only CD95L gene deletion prolonged survival, involving a tumor-intrinsic mechanism. Conclusion Non-canonical CD95L/CD95 interactions are growth-promoting in murine glioma models, and glioma growth and immunosuppression may be simultaneously counteracted by Cd95l gene silencing.
 
Altered responses to DNA damage in IDH-mutant gliomas. Examples of mechanisms related to (A) gene expression, (B) sensitivity to alkylating agents, (C) homologous recombination, and (D) oxidative stress. Dashed lines indicate indirect effects. BCAAs: branched-chain amino acids; ROS: reactive oxygen species
Purpose Since the discovery of IDH mutations in glioma over a decade ago, significant progress has been made in determining how these mutations affect epigenetic, transcriptomic, and metabolic programs in brain tumor cells. In this article, we summarize current understanding of how IDH mutations influence DNA damage in glioma and discuss clinical implications of these findings. Methods We performed a thorough review of peer-reviewed publications and provide an overview of key mechanisms by which IDH mutations impact response to DNA damage in gliomas, with an emphasis on clinical implications. Results The effects of mutant IDH on DNA damage largely fall into four overarching categories: Gene Expression, Sensitivity to Alkylating Agents, Homologous Recombination, and Oxidative Stress. From a mechanistic standpoint, we discuss how mutant IDH and the oncometabolite (R)-2HG affect each of these categories of DNA damage. We also contextualize these mechanisms with respect to ongoing clinical trials. Studies are underway that incorporate current standard-of-care therapies, including radiation and alkylating agents, in addition to novel therapeutic agents that exert genotoxic stress specifically in IDH-mutant gliomas. Lastly, we discuss key unanswered questions and emerging data in this field that have important implications for our understanding of glioma biology and for the development of new brain tumor therapies. Conclusion Mounting preclinical and clinical data suggest that IDH mutations alter DNA damage sensing and repair pathways through distinct mechanisms. Future studies are needed to deepen our understanding of these processes and provide additional mechanistic insights that can be leveraged for therapeutic benefit.
 
Flow chart of the screening procedure
Representative magnetic resonance images of a CR in intracranial lesion before and after treatment. A Before treatment. B After treatment
Waterfall plot of intracranial and extracranial changes in patients with measurable intracranial lesions
Kaplan–Meier survival analysis. A OS. B Intracranial PFS. C PFS. OS: Overall survival; PFS: Progression-free survival; NR: Not reached
Kaplan–Meier survival analysis for overall survival (OS) and intracranial progression-free survival (PFS) based on significant predictors. OS analysis: A Multiple BMs vs. Single BMs. B Without high disease burden vs. With high disease burden. C 1–2 lines prior systemic therapy vs. ≥ 3 lines prior systemic therapy. Intracranial PFS: D Multiple BMs vs. Single BMs. E Without high disease burden vs. With high disease burden. F Without prior intracranial RT vs. With prior intracranial RT. NR: Not reached; RT: Radiotherapy; BMs: Brain metastases
Background Previous studies showed that both immune checkpoint inhibitors (ICIs) and anlotinib have central nervous system (CNS) efficacy. This study aimed to evaluate the efficacy and safety of ICIs combined with anlotinib in small cell lung cancer (SCLC) patients with brain metastases (BMs). Methods We retrospectively reviewed SCLC patients with CNS metastases confirmed by brain magnetic resonance imaging (MRI). Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and Response assessment in neuro-oncology brain metastases (RANO-BM) were used to evaluate treatment response to ICIs plus anlotinib. Kaplan–Meier analysis and Cox regression analysis were performed to determine patient’s prognosis. Results Sixty-six patients with baseline BMs were included. For patients with measurable intracranial lesions, the intracranial objective response rate (ORR) was 29.2% based on RECIST 1.1 criteria and was 27.1% based on RANO-BM criteria. The median intracranial progression-free survival (PFS) was 9.0 months (95% confidence interval [CI], 6.5–11.5 months). The median overall survival (OS) was 13.4 months (95% CI, 10.7–20.5 months). Multivariate Cox regression analysis showed that high disease burden (hazard ratio [HR] = 4.83, P < 0.001), multiple BMs (HR = 2.71, P = 0.036), and more than or equal to 3 prior lines of therapy (HR = 2.56, P = 0.023) were independent negative predictors of OS. The overall incidence of treatment-related adverse events (TRAEs) was 75.8%, and grade 3–4 TRAEs were reported in 19.7% of patients. Conclusions Our results suggested that ICIs plus anlotinib had potent CNS efficacy with tolerable toxicity and could be a promising treatment option for SCLC patients with BMs.
 
Voxel-wise heatmap of lesion presence Note. The maximum amount of overlapping lesions was n = 21. The heatmap shows yellow to red areas where lesions were mostly occurring (median = 5). The majority of lesions affected the left inferior temporal, left insular, right superior temporal and anterior cingulate cortex. Images are shown according to radiological convention
Voxel-wise p-map for predictions of verbal memory scores Note. This p-map shows green to red voxels where lesions were significantly associated with immediate and delayed verbal memory scores (as estimated with HVLT-A and HVLT-B). Panel A shows the regions associated with immediate verbal memory. Panel B shows the regions associated with delayed verbal memory. Red indicates the clusters that were significant at cluster level (affecting the left superior temporal gyrus and temporal pole). Images are shown according to radiological convention
Voxel-wise p-map for predictions of processing speed and cognitive flexibility performance Note. This p-map shows green to red voxels where lesions were significantly associated with processing speed scores (as estimated with TMT-A) and cognitive flexibility scores (as estimated with TMT-B), in panels A and B, respectively. Red indicates the clusters that were significant at cluster level. In panel A, these clusters were located surrounding the right temporo-parietal junction, extending to the dentate gyrus of the hippocampus and fornix. In panel B, no voxels were significant at cluster level. Images are shown according to radiological convention
Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p < .001 and p < .05 for voxel- and cluster-level, resp.). Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.
 
(A) Representative images of a DTI scan are presented for two different axial slices from the same patient (I & II). The regions of interest (ROI) for the analysis of our first cohort A are color labeled and consist of the marginal tumor zone (yellow), white matter adjacent to the tumor (dark blue), ipsilateral (red) and contralateral (green) cortex as well as ipsilateral (cyan) and contralateral (magenta) white matter. (B) Representative slices of a T1-MPRAGE image of a patient with GBM, IDH-wildtype (left), and a T2-weighted image of a patient with astrocytoma, IDH-mutant, CNS WHO Grade 2 (right) are shown. Colored circles illustrate the definition of regions of interest (ROI) for our second cohort B. In GBM patients and IDH-mutant astrocytoma CNS WHO Grade 4, three spheric ROIs were defined in each contrast enhancement (red), necrosis (blue), peritumoral white matter (green), edema (yellow), the area contralateral to the tumor in the opposite hemisphere (violet) as well as ipsi- and contralateral controls frontal or occipital depending on tumor position (orange, left image). In all other tumor entities (right image), three spheric ROIs were defined in each non-enhancing tumor (pink), marginal non-enhancing tumor zone (brown), peritumoral white matter (green), edema (not present), the area contralateral to the tumor in the opposite hemisphere (violet) as well as ipsi- and contralateral controls frontal or occipital depending on tumor position (orange) and contrast enhancement/ necrosis if present
The bar chart demonstrates the mean diffusivity and fractional anisotropy (mean ± SD) for different regions of interest for the exploratory cohort A. These were the marginal zone of the tumor (TU), white matter adjacent to the tumor (AWM), ipsilateral cortex (IC) and white matter (IWM) as well as contralateral white matter (CWM) and cortex (CC). Data was dichotomized into patients with and without history of seizures. Differences between these two groups were tested for statistical significance (*) in different regions of interest
Bar charts illustrate the distribution of mean diffusivity (MD) of key regions of interest in cohort A (A) and cohort B (B) between different glioma entities separated for seizure status. Bars represent the mean; absolute units are 10− 6 mm²/s
Introduction Structural white matter changes associated with certain epilepsy subtypes have been demonstrated using diffusion tensor imaging (DTI). This observational study aims to identify potential water diffusion abnormalities in glioma patients with associated seizures. Methods Two cohorts from two centers were analyzed independently: (A) Prospectively recruited patients diagnosed with glioma who received preoperative DTI to measure mean diffusivity (MD) and fractional anisotropy (FA) in regions-of-interest (ROIs) including the marginal tumor zone (TU), adjacent peritumoral white matter as well as distant ipsilateral and contralateral white matter and cortex. Data were compared between patients with and without seizures and tested for statistical significance. (B) A retrospective cohort using an alternative technical approach sampling ROIs in contrast enhancement, necrosis, non-enhancing tumor, marginal non-enhancing tumor zone, peritumoral tissue, edema and non-tumorous tissue. Results (A) The prospective study cohort consisted of 23 patients with 12 (52.2%) presenting with a history of seizures. There were no significant seizure-associated differences in MD or FA for non-tumor white matter or cortical areas. MD-TU was significantly lower in patients with seizures (p = 0.005). (B) In the retrospective cohort consisting of 46 patients with a seizure incidence of 50.0%, significantly decreased normalized values of MD were observed for non-enhancing tumor regions of non-glioblastoma multiforme (GBM) cases in patients with seizures (p = 0.022). Conclusion DTI analyses in glioma patients demonstrated seizure-associated diffusion restrictions in certain tumor-related areas. No other structural abnormalities in adjacent or distant white matter or cortical regions were detected.
 
ABC transporter expression. Comparison of ABCB1 (a), ABCC1 (b), ABCC3 (c) and ABCG2 (d) mRNA levels (normalized relative quantity) in 95 newly diagnosed, 64 recurrent GBM and in 18 non-tumoral tissue samples. *p < 0.05; **p < 0.01; ***p < 0.001; #p < 0.0001; ns not significant
ABC transporter expression. Comparison of mRNA levels (normalized relative quantity) of ABCB1, ABCC1, ABCC3 and ABCG2 in 95 newly diagnosed (a) and in 64 recurrent GBM (b). Graphics “c” and “d” are zooms of graphics “a” and “b” respectively so that differences in the expression levels of ABCB1, ABCC1, ABCC3 are more apparent. **p < 0.01; ***p < 0.001; #p < 0.0001; ns not significant
Correlation of ABC transporters expression level with newly diagnosed GBM patient outcome. Kaplan–Meier estimates of overall survival in newly diagnosed GBM according to ABCB1 (a), ABCC1 (b), ABCC3 (c) and ABCG2 (d) expression
Correlation of ABC transporters expression level with newly diagnosed GBM patient outcome. Kaplan–Meier estimates of progression-free survival in newly diagnosed GBM according to ABCB1 (a), ABCC1 (b), ABCC3 (c) and ABCG2 (d) expression
Purpose Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumors in adults. Patients invariably relapse during or after first-line therapy and the median overall survival is 14.6 months. Such poor clinical response is partly ascribed to the activity of ATP-binding cassette (ABC) transporters. The activity of these proteins, severely reduces the amount of therapeutics that penetrates the tumor cells. We hypothesized that ABC transporter expression could correlate with survival surrogates. In this study, we assessed the expression of four commonly expressed ABC transporters in GBM samples and investigated if mRNA levels could serve as a prognostic biomarker. Methods Human specimens were analyzed by qPCR to assess ABCB1, ABCC1/3 and ABCG2 expression. Kaplan-Meier and multivariate analyses were then used to evaluate the correlation with overall survival (OS) and progression-free survival (PFS). Results Our cohort included 22 non-tumoral samples as well as 159 GBM tumor specimens. ABC transporters were significantly more expressed in GBM samples compared to non-tumoral tissue. Moreover ABCC1 and 3 mRNA expression were significantly increased at recurrence. Statistical analyses revealed that increased expression of either ABCC1 or ABCC3 did not confer a poorer prognosis. However, increased ABCC1 mRNA levels did correlate with a significantly shorter PFS. Conclusion In this manuscript, the analyses we conducted suggest that the expression of the four ABC transporters evaluated would not be suitable prognostic biomarkers. We believe that, when estimating prognosis, the plethora of mechanisms implicated in chemoresistance should be analyzed as a multi-facetted entity rather than isolated units.
 
Kaplan Meier plot of survival of this cohort of long term survivors after stereotactic radiosurgery for brain metastases
A Cumulative incidence plot of distant brain failure over time in this cohort of long term survivors after stereotactic radiosurgery for brain metastases. B Scatter plot of final brain metastasis velocity versus number of metastases at first stereotactic radiosurgery (SRS) in this cohort of long term survivors after SRS for brain metastases
Purpose Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. Methods This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). Results Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). Conclusion Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.
 
Brain MRI of children with a brainstem tumor. A T2-weighted Sagittal FLAIR MRI image showing a tumor located in the medulla oblongata. B T1-weighted Sagittal FLAIR MRI image showing a tumor located in the midbrain. C and a tumor located in pons D DIPG extending to the midbrain. E DIPG extending to the cerebellum. F DIPG extending to the medulla oblongata. The white arrows point to the tumor body
Patient screening flow chart
Purpose It remains unclear as to whether patients with brainstem tumor experience complex neuropsychiatric problems. In this cohort study, we specifically investigated behavioral, emotional and cognitive symptoms in pediatric patients with brainstem glioma and healthy individuals. Methods A total of 146 patients with pediatric brainstem tumors (aged 4–18 years old) and 46 age-matched healthy children were recruited to assess their behaviors and emotions examined by the Child Behavior Checklist. A variety of clinical factors were also analyzed. Results There were significant differences in most behavioral and emotional symptoms between pediatric patients and healthy subjects. Moreover, patients with pons tumors exhibited significantly higher scores than patients with medulla oblongata tumors (p = 0.012), particularly in concerning the syndrome categories of Withdrawn (p = 0.043), Anxious/depressed symptoms (p = 0.046), Thought Problems (p = 0.004), Attention deficits (p = 0.008), Externalizing problems (p = 0.013), and Aggressive behavior (p = 0.004). A tumor body located in the pontine (p = 0.01, OR = 4.5, 95% CI = 1.4–14.059) or DIPG in the midbrain (p = 0.002, OR = 3.818, 95% CI = 1.629–8.948) appears to act as a risk factor that is associated with more problems in patients with neuropsychiatric symptoms. Conclusions Pediatric patients with brainstem tumors exhibit severe behavioral and emotional problems. Tumor invades the pontine and midbrain act a risk factor with more problems. It suggests that structural and functional abnormalities in the brainstem will cause prolonged behavioral problems and emotional-cognitive dysfunctions in young children.
 
Functional outcomes in patients with left-sided eloquent GB one month after stereotactic biopsy under GA, resection under GA or resection during AC: (A) Functional language outcome and (B) functional motor outcome. Four outcome levels were defined: preserved (patients remaining asymptomatic), unrecovered (patients retaining their preoperative deficits), improved (patients with an improvement of preoperative deficits) and, worse (patients whose functional status has deteriorated, with the acquisition of new motor and/or language deficits or a worsening of their preoperative deficits)
Kaplan-Meier curves for the survival of patients with left-sided eloquent GB stratified by three surgical approaches: biopsy under GA, resection under GA and resection during AC (A: PFS; B: OS). Abbreviations: PFS, progression-free survival; OS, overall survival
Purpose Neurosurgeons use three main surgical approaches for left-sided glioblastoma (GB) in eloquent areas: biopsy, tumor resection under general anesthesia (GA), and awake craniotomy (AC) with brain mapping for maximal safe resection. We performed a retrospective study of functional and survival outcomes for left-sided eloquent GB, comparing these surgical approaches. Methods We included 87 patients with primary left-sided eloquent GB from two centers, one performing AC and the other biopsy or resection under GA. We assessed Karnofsky performance score (KPS), language and motor deficits one month after surgery, progression-free survival (PFS) and overall survival (OS). Results The 87 patients had a median PFS of 8.6 months [95% CI: 7.3–11.6] and a median OS of 20.2 months [17-3-24.4], with no significant differences between the three surgical approaches. One month after surgery, functional outcomes for language were similar for all approaches, but motor function was poorer in the biopsy group than in other patients. The proportion of patients with a KPS score > 80 was higher in the resection with AC group than in the other patients at this timepoint. Conclusion We detected no real benefit of a resection with AC over resection under GA for left-sided eloquent GB in terms of survival or functional outcomes for language. However, given the poorer motor function of biopsy patients, resection with AC should be proposed, when possible, to patients ineligible for surgical resection under GA, to improve functional outcomes and patient autonomy.
 
Consort diagram. All neurooncological patients who died while admitted in hospital or within 7 days after discharge were considered. Patients with solely infratentorial tumor manifestations were excluded. Of those left, only patients who received an EEG within 45 days prior to death were included.
EEG and clinical observations within 45 days prior to death (n = 68). Incidence of seizures determined by EEG analysis (1) and clinical observation (2) as well as the state of awareness of patients during the EEG recording (3)
clinical and EEG findings within 45 days prior to death. Epileptic seizures within 45 days prior to death in brain tumor patients combining clinical and electrophysiological findings
Purpose Seizures pose a significant burden in patients with primary and secondary brain tumors during the end-of-life period. A wide range of 6 to 56% of clinically observed epileptic seizures at the end of life has been reported. We aimed to analyse the incidence of epileptic seizures at the end of life in brain tumor patients more accurately using not only clinical but also electrophysiological findings. Methods This retrospective, single center study included brain tumor patients who died during the stay on the ward or within 7 days after discharge between 01/2015 and 08/2020. Clinical observation of seizures derived from the original medical records and EEG findings (within 45 days prior to death) were analyzed to determine the incidence of seizures in that period. Results Of the 68 eligible patients, 50 patients (73.5%) suffered from seizures within 45 days prior to death, of which n = 24 had a status epilepticus. The diagnosis of seizures/ status epilepticus was determined either by the presentation of clinical signs in 45 patients and if not, by the detection of a (possible) non-convulsive status epilepticus in the EEG of five patients. Conclusion In the presence of neurologically trained staff and with the frequent use of routine EEG, we were able to identify seizures and to distinguish status epilepticus from encephalopathy/ hypoactive delirium. We detected a higher incidence of seizures and status epilepticus at the end of life in neurooncological patients than previously reported.
 
PFS (A), and OS (B) by H3K27me3 in recurrent grade 1&2 meningiomas
PFS (A), and OS (B) by H3K27me3 in recurrent grade 1 meningiomas, PFS (C), and OS (D) by H3K27me3 in recurrent grade 2 meningiomas
Representative case of H3K27me3 expression loss during tumor progressions. A 46-year-old male patient with a recurrent meningioma received tumor resection in 2011. Axial (A) and sagittal (B) T1-contrast MRI demonstrated a recurrent, right ventricular meningioma. Postoperative pathology demonstrated an atypical histology (C, H&E) with retained H3K27me3 expression (D). The patient experienced tumor recurrence five years after surgery and had another surgery in 2016. Axial (E) and sagittal (F) T1-contrast MRI demonstrated tumor recurrence at the same location. Postoperative pathology demonstrated an atypical histology (G, H&E) with negative H3K27me3 expression (H)
Purpose To determine if loss of H3K27me3 could predict higher risk of re-recurrence in recurrent meningiomas. Methods A retrospective, single-center cohort study was performed for patients who underwent resection of recurrent grade 1 (N = 132) &2 (N = 32) meningiomas from 2009 to 2013. Association of H3K27me3 staining and clinical parameters was analyzed. Additionally, H3K27me3 staining was performed from 45 patients whose tumors recurred and were resected during the follow-up, to evaluate H3K27me3 change during tumor progression. Survival analysis was performed as well. Results Loss of H3K27me3 expression was observed in 83 patients, comprising 63 grade 1 (47.7%) and 20 grade 2 patients (62.5%). Both grade 1 (p < 0.001) and grade 2 recurrent meningiomas (p < 0.001) had a higher frequency of H3K27me3 loss, compared to de novo meningiomas. 8 of 27 tumors with retained H3K27me3 lost H3K27me3 during re-recurrence (29.6%), while no gain of H3K27me3 was observed in progressive disease from 18 tumors with H3K27me3 loss. Loss of H3K27me3 expression was associated with an earlier re-recurrence in recurrent meningiomas grade 1 and 2 (p < 0.001), and was an independent prognostic factor for PFS in recurrent grade 1 meningiomas (p = 0.005). Conclusion Compared to primary meningiomas, recurrent meningiomas more predominantly had loss of H3K27me3 expression, and further loss can occur during the progression of recurrent tumors. Our results further demonstrated that loss of H3K27me3 predicted shorter PFS in recurrent grade 1 and grade 2 meningiomas. Our work thus supports clinical testing of H3K27me3 in recurrent meningiomas WHO grade 1 and 2.
 
Histogram depicting time to surgery from the initial clinical encounter
Kaplan–Meier Curve for probability of recurrence for incidental and their matched symptomatic meningioma cohort
Purpose The management of incidentally discovered meningioma remains controversial. We sought to compare outcomes following surgical resection of incidental meningioma to a matched cohort of symptomatic meningiomas. Methods A retrospective single-center case–control study was conducted for patients undergoing resection of incidental meningioma from 2000 to 2019. A 1:1 case–control matching for incidental and symptomatic meningioma was performed using the following variables: age at initial visit, gender, tumor location/size, and presence of peritumoral edema. Primary outcomes included (1) WHO grading/histopathological subtype/MIB-1 index, (2) extent of resection (gross total resection or subtotal resection), and (3) recurrence. Outcomes were compared between groups using descriptive/bivariate analyses. Results A total of 91 incidental meningiomas were analyzed. Trauma was the most common reason (n = 19, 21%) to obtain imaging, and tumor size the leading reason to operate (n = 37, 41%). Median time-to-surgery from initial clinical encounter was 5-months (Q1:3, Q3:16.5). More incidental meningioma patients (n = 47, 52%) were privately insured compared to their matched symptomatic cohort (n = 30, 33%) (P = 0.006). Patients with incidental meningioma had significantly higher mean Karnofsky Performance Scale at time-of-surgery (93.2, SD:11.1 vs. 81.4, SD:12.7) (P < 0.001). There were no significant differences in primary/secondary outcomes between the groups. Incidental meningioma was not associated with recurrence on Cox proportional hazards analysis (HR: 0.795, 95%CI: 0.3–2.1, P = 0.637). Conclusion Matched case–control analysis demonstrated no significant differences in clinical, histopathological, and functional outcomes following resection of incidental and symptomatic meningioma. While non-operative management with close follow-up and serial imaging is preferred for incidental meningiomas, those undergoing resection when indicated can anticipate similar safety and efficacy as symptomatic meningiomas.
 
The molecular pathological grading process for WHO grade 2 meningioma
Kaplan-Meier survival curves showing correlation of the factors of extent of resection (first row) and molecular risk grading (second row) with patients’ PFS (first column), OS (second column) and MPFS (third column)
Purpose A molecular pathological grading method was tested in WHO grade 2 meningiomas to judge whether this molecular grading can more accurately evaluate meningioma biological behaviour. Methods The medical records and paraffin-embedded tissues of surgically resected WHO grade 2 meningioma patients in our department from January 1, 2010, to December 31, 2020, were collected. The molecular pathological risk grading suggested by Sahm et al. was adopted and the patients were graded as low, intermediate and high risk. Progression-free survival (PFS), malignant progression-free survival (MPFS) and overall survival (OS) were analysed. Univariate and multivariate analysis were performed to determine the relationship between molecular risk grading and patient survival. Results Of the 98 patients, 13 (13.2%) were graded as low risk, 63 patients (64.3%) were graded as intermediate risk, and 22 patients (22.4%) were graded as high risk. With increasing molecular risk grade, the rates of tumour recurrence, malignant progression and mortality increased significantly (P < 0.05). Multivariate analysis showed that molecular risk grading was negatively associated with PFS (HR 0.018, 95% CI 0.003–0.092), MPFS (HR 0.040, 95% CI 0.006–0.266) and OS (HR 0.088, 95% CI 0.016–0.472) (P < 0.01), and gross total resection (Simpson grade I–III) significantly prolonged PFS (HR 5.882, 95% CI 2.538–13.699) and OS (HR 2.611, 95% CI 1.117–7.299) (P < 0.05). Conclusion Sahm et al.’s molecular risk grading can further refine the classification of WHO grade 2 meningiomas and more accurately evaluate their biological behaviour and patient prognosis.
 
a Kaplan–Meier curve depicting 12-month OS across all patients. b Kaplan–Meier curve comparing 12-month OS between subgroups stratified by presence of any lesion hemorrhage. c Kaplan–Meier curve depicting LC at 12-months after radiosurgical treatment across all treated MBM. d Kaplan–Meier curve comparing LC at 12-months after radiosurgical treatment in the presence of none, pre-treatment, and post-treatment hemorrhage. OS overall survival, LC local control, MBM melanoma brain metastases
Purpose To assess, for intact melanoma brain metastases (MBM), whether single-fraction stereotactic radiosurgery (SRS) versus fractionated stereotactic radiotherapy (fSRT) is associated with a differential risk of post-treatment lesion hemorrhage (HA) development. Methods A single institution retrospective database review identified consecutive patients with previously unresected MBM treated with robotic SRS/fSRT between 2013 and 2021. The presence of lesion HA was determined by multi-disciplinary imaging review. Dosimetric variables were reported as biologically effective doses using an α/β ratio of 2.5 (BED2.5). Statistical analysis was performed using mixed effect logistic regression for post-treatment HA and Cox frailty modeling for local control (LC). Results The cohort included 48 patients with 226 intact MBM treated with SRS/fSRT. Of lesions without prior HA, 63 of 133 lesions (47.4%) receiving SRS demonstrated evidence of post-treatment HA versus 2 of 24 lesions (8.3%) treated with fSRT (p = 0.01). A larger maximum BED2.5 was observed in lesions developing HA compared to no HA (238.3 Gy vs. 211.4 Gy; p = 0.022). 12-month LC was 65.7% (95% CI 37.2–87.3%) and 77.5% (95% CI 58.5–91.2%) for lesions demonstrating pre-treatment and post-treatment HA, respectively, with no local failure events observed within 12 months for non-hemorrhagic lesions (p < 0.001). Conclusion We found an increased incidence of post-treatment HA for intact MBM receiving a larger maximum BED2.5, which was significantly higher for single fraction treatments within our cohort. The presence of lesion HA, either pre- or post-treatment, was indicative of inferior LC. Further investigations of optimal dose and fractionation schedules for treatment of MBM in the era of immunotherapy are warranted.
 
Distribution of cases within the analyzed single-center cohort of 191 patients treated with pediatric LGG at our institution between 2006 and 2020
A Comparison of pre- and postoperative mean tumor growth rates showed a significant deceleration of tumor growth after 1st, 2nd and 3rd IR (Kruskal–Wallis test, p = 0.001, bars show mean and 95% CI). Pairwise Mann–Whitney tests showed significant difference of mean preoperative growth velocity and mean growth rate following 1st IR (p < 0.02), 2nd IR (p = 0.015) and 3rd IR (p < 0.001). B Results remained significant after excluding patients undergoing (neo)adjuvant treatment (Kruskal–Wallis test, p = 0.037, bars show mean and 95% CI). C Intra-patient comparison of individual tumor growth rates before and after IR. Tumor growth rates decreased by an average of 84.7% (p = 0.0024)
A Linear regression including 71 cases of incomplete resection showed a minor, thus significant negative correlation between extent of resection and postoperative growth rates (R = − 0.02, R squared = 0.07, p = 0.027). B A significant correlation between resection extent (%) and percental reduction of growth velocity after STR could be shown in 16 patients not receiving (neo)adjuvant treatment (R = 0.974, R squared = 0.719, p < 0.001). C Linear regression analysis revealed a significant impact of residual tumor burden post incomplete resection on postoperative growth velocity (R = 0.025, R squared = 0.3, p < 0.001). D Comparing mean residual tumor volumes of cases with measurable tumor growth vs tumor residuals with no signs of growth during the observation period post IR showed a significant difference of mean tumor volumes (9.308 cm³ [n = 19] vs 2.308 cm³ [n = 55], p = 0.011)
A Comparison of postoperative growth velocities of BRAF V600E mutant LGG and BRAF wild-type LGG showed significant difference of means (0.123 cm³/month and 0.016 cm³/month). B Comparative analysis of pre- and postoperative tumor growth rates in BRAF-KIAA1549 fusion positive and negative LGG showed no significant differences of means (p = 0.17 and p = 0.09, respectively)
Purpose Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. Methods Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. Results Mean preoperative TGV of 0.264 cm³/month showed significant deceleration of tumor growth to 0.085 cm³/month, 0.024 cm³/month and −0.016 cm³/month after 1st, 2nd, and 3rd IR, respectively (p < 0.001). Results remained significant after excluding patients undergoing (neo)adjuvant treatment. Resection extent showed correlation with postoperative reduction of TGV (R = 0.97, p < 0.001). ROC analysis identified a residual cut-off tumor volume > 2.03 cm³ associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm³/month vs. 0.016 cm³/month, p = 0.047). Conclusion This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.
 
Evolution of meningioma radiotherapy. A–B Figures reproduced from Friedman et al. 1977 [5]. A shows an early example of meningioma radiotherapy. Shown is a 2D film described as a verification “post film” showing a cylindrical irradiated volume targeting a large posterior fossa meningioma, treated sometime before 1963. This volume received a maximum dose of 8000 rad (80 Gy) in 42 days with 2MV photons, a significantly higher dose than reported by most investigators, past or present. This patient was reportedly alive and well 4 years post-radiation. B shows a diagram from the same historical publication showing a mock-up of a 2D technique using tangential fields with physical wedges for treatment of a parasagittal meningioma. C–D shows an axial post-contrast T1 MRI and IMRT plan delivering 59.4 Gy in 33 fractions, respectively, for a large 4.8 cm left frontoparietal meningioma. Gross total resection was achieved, and pathology revealed 5 mitoses per 10hpf, foci of necrosis, hypercellularity and small cell change. No brain invasion was identified, and Ki67 labeling index was 5%. Immunohistochemistry staining showed retained H3K27me and BAP1. An institutional targeted DNA sequencing panel revealed monosomy 22q and a pathogenic NF2 mutation, along with loss of 1p, 10p and 14q, consistent with high molecular risk. In D), the red line denotes the 59.4 Gy prescription isodose, and blue denotes the 50% isodose line. The target included a customized anisotropic margin of at-risk dura of up to 15 mm, and no explicit clinical target volume expansion into brain, given the absence of brain invasion. E–F shows an axial post-contrast T1 MRI of an imaging defined, presumed benign meningioma abutting the brainstem, which was treated with 54 Gy in 30 fractions (red isodose line). Treatment was well tolerated. G–H shows coronal post-contrast T1 MRI and IMRT plan delivering 59.4 Gy in 33 fractions, respectively, for a large, heterogenous and multilobulated meningioma of the posterior falx, which underwent a gross-total resection. Pathology revealed 11 mitoses per 10 high powered fields, elevated Ki67 labeling index of 7%, foci of necrosis, small cell change, consistent with WHO grade 2. Immunohistochemistry showed weak progesterone receptor staining in ~ 25% of cells and retained H3K27me3. An institutional targeted DNA sequencing panel showed no pathogenic SSVs, but chromosomes 22q (NF2), 1p, and 19q were lost, consistent with high molecular risk. The target included a customized anisotropic margin of up to 15 mm of at-risk falx and dura, including the sagittal dural sinus abutted by tumor. Treatment was well tolerated, and the patient remains disease free 1.5 years post-therapy
Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.
 
Incidence of major outcomes stratified by age group, mFI-5 frailty score, and RAI-A score for patients in the overall cohort of brain tumor patients who underwent neurosurgery in NSQIP database from 2015-2019, n=30,951
Graphic representation of multivariable effect sizes (OR with 95% CIs) of RAI-A and mFI-5 scores for postoperative outcomes of BTR patients from NSIQP database for years 2015–2019
Graphic representation of multivariable effect sizes (OR with 95% CIs) of RAI-A and mFI-5 scores for postoperative outcomes of BTR patients from NSIQP database for years 2015-2019 stratified into all brain tumors cohort, n =3 0,951, meningiomas cohort (n = 7,240), primary malignant brain tumors cohort (n = 12,550), and metastatic brain tumors cohort (n = 7,149)
Purpose To evaluate the independent effect of frailty, as measured by the Risk Analysis Index-Administrative (RAI-A) for postoperative complications and discharge outcomes following brain tumor resection (BTR) in a large multi-center analysis. Methods Patients undergoing BTR were queried from the National Surgical Quality Improvement Program (NSIQP) for the years 2015 to 2019. Multivariable logistic regression was performed to evaluate the independent associations between frailty tools (age, 5-factor modified frailty score [mFI-5], and RAI-A) on postoperative complications and discharge outcomes. Results We identified 30,951 patients who underwent craniotomy for BTR; the median age of our study sample was 59 (IQR 47–68) years old and 47.8% of patients were male. Overall, increasing RAI-A score, in an overall stepwise fashion, was associated with increasing risk of adverse outcomes including in-hospital mortality, non-routine discharge, major complications, Clavien-Dindo Grade IV complication, and extended length of stay. Multivariable regression analysis (adjusting for age, sex, BMI, non-elective surgery status, race, and ethnicity) demonstrated that RAI-A was an independent predictor for worse BTR outcomes. The RAI-A tiers 41–45 (1.2% cohort) and > 45 (0.3% cohort) were ~ 4 (Odds Ratio [OR]: 4.3, 95% CI: 2.1–8.9) and ~ 9 (OR: 9.5, 95% CI: 3.9–22.9) times more likely to have in-hospital mortality compared to RAI-A 0–20 (34% cohort). Conclusions and Relevance Increasing preoperative frailty as measured by the RAI-A score is independently associated with increased risk of complications and adverse discharge outcomes after BTR. The RAI-A may help providers present better preoperative risk assessment for patients and families weighing the risks and benefits of potential BTR.
 
Background Due to the differences in size and invasiveness when compared to non-giant macroadenomas (nGPAs), giant pituitary adenomas (GPAs) are considerably harder to resect. This study aimed to differentiate GPAs from nGPAs, based on the presenting complaints, surgical approaches, peri- and postoperative outcomes. Methods We retrospectively analyzed cases of pituitary macroadenomas that underwent surgical resection at a tertiary care hospital. GPAs were tumors greater than 4 cm in the largest dimension, while nGPAs were tumors smaller than 4 cm. 55 GPA patients and 70 nGPA patients from 2006 to 2017 were included. Demographic, perioperative, and post-operative outcomes were evaluated. Group comparisons for continuous variables were made using an independent t-test/Mann Whitney U test and categorical data was analyzed on Chi-square/Fisher exact test; a p-value of < 0.05 was considered significant. Results Visual deterioration was the most common complaint, reported by 61.4% of nGPA patients and 81.8% of GPA patients. The mean extent of gross total resection was 47.1% in nGPA patients and 18.2% in GPA patients (p = 0.001). After surgery, tumor recurrence was seen in 1.4% of nGPA patients and 18.2% of GPA patients (p = 0.001). First re-do surgery was required in 5.7% of nGPA patients and 25.5% of GPA patients (p = 0.004). Conclusion Compared to nGPAs, GPAs are more likely to present with a higher number of preoperative symptoms, and lesser chances of gross total tumor resection. GPAs are also associated with a higher rate of recurrence, which results in more follow-up procedures. Larger, multi-center longitudinal studies need to be done to validate these findings.
 
The workflow of the study population
T1 contrast-enhanced MRI of patients with preoperative gamma knife treatment. A, B and C represent each patient. 1 and 2 represent MRI before gamma knife treatment and microsurgical resection, respectively
Purpose We aimed to explore the influence of preoperative gamma knife treatment on the clinical effect of microsurgical resection of vestibular schwannoma. Methods The data of patients who underwent vestibular schwannoma resection in our hospital between November 2010 and December 2019 were retrospectively collected. According to the data collected retrospectively and the inclusion and exclusion criteria, we selected these patients and divided them into Group A (with preoperative gamma knife treatment) and Group B (without preoperative gamma knife treatment). The pre/postoperative clinical manifestations, neurological function grade, postoperative complications, tumor recurrence and increase were collected and compared between the two groups. Results There were 40 and 823 patients enrolled in Groups A and B, respectively. There were no significant differences in the general condition, tumor size and side, or neurological performance of the patients in those two groups before the operation. At the last follow-up, the number of patients with poor facial nerve function was 15 (39.5%) in Group A and 170 (20.7%) in Group B (P = 0.021 < 0.05). In Group A and Group B, disequilibrium occurred in 14 (36.8%) patients and 124 (15.1%) patients, respectively, after the operation (P = 0.012 < 0.05). Seven (17.5%) patients had pneumonia in Group A, and 21 (2.6%) patients had pneumonia in Group B (P = 0.04 < 0.05) after the operation. Conclusion When a patient with vestibular schwannoma undergoes microsurgical surgery, the preoperative history with gamma knife treatment may make recovery from postoperative facial paralysis difficult for the patients, making them more prone to suffer from postoperative disequilibrium and postoperative pneumonia.
 
Purpose In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared with lomustine, in glioblastoma (GBM) patients at first progression after chemoradiation. Recently, some real-life trials showed similar impact on survival but a higher rate of adverse events than in REGOMA, thus raising concerns over tolerability. The aim of this study was to assess the efficacy and tolerability of a lower intensity regorafenib regimen. Patients and methods Regorafenib daily dose was gradually increased from 80 to 160 mg across the first 2 cycles. Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death. Results Sixty-six GBM patients were included. Median age was 60.0 years. Median PFS and OS following regorafenib were 2.7 and 7.1 months, respectively. Best RANO response to regorafenib were partial response (PR) in 10 (15.1%), stable disease in 17 (25.8%), and progressive disease in 39 (59.1%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade 3–4 toxicity. In a multivariable analysis, higher age and absence of MGMTp methylation were significantly associated with poorer disease control after regorafenib. Conclusions Our study is the largest observational real-life study on the use of regorafenib. Our lower intensity regimen proved as effective as the standard 160 mg daily schedule (mPFS and mOS being 2.7 vs 2.0 months and 7.1 vs 7.4 months in our study vs REGOMA, respectively). Moreover, we observed a higher rate of PRs as compared with REGOMA (15.0% vs 3.0%).
 
NMDAR signaling controls the effect of TMZ via MGMT expression. a Representative images of immunoblots and graph about the expression of MGMT in T98G cells treated with 100 µM NMDA and 10 µM glycine for 12, 24 and 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05 vs. 0 h group (Dunnett’s test). b Graph showing the expression of MGMT mRNA level in T98G cells treated with 100 µM NMDA and 10 µM glycine for 12, 24 and 48 h. Data are shown as mean ± SEM (n = 4). ***p < 0.001 vs. 0 h group (Dunnett’s test). c Representative images of immunoblots and graph showing the expression of phosphorylated NF-κB protein level in T98G cells treated 100 µM NMDA and 10 µM glycine for 12, 24 and 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05 vs. 0 h group (Dunnett’s test). d Graph showing cell viability of T98G cells treated with 100 µM NMDA/10 µM glycine and/or 200–600 µM TMZ for 48 h. Data are shown as mean ± SEM (n = 6). **p < 0.01, ***p < 0.001 vs. Control group, ##p < 0.01 vs. Control + NMDA + glycine group, $$p < 0.01 vs. 400 µM TMZ group and ††p < 0.01 vs. 600 µM TMZ group (Games-Howell test). e Representative images of colony formation assay and graph showing the colony numbers of T98G cells treated with 300 µM TMZ and/or 100 µM NMDA/10 µM glycine for 48 h and cultured for 10 days. Data are shown as mean ± SEM (n = 6). **p < 0.01 vs. Control group and ##p < 0.01 vs. 300 µM TMZ group (Tukey’s test). Scale bar = 10 mm. f Representative images of immunoblots and graph showing the expression of NMDAR1 or MGMT in T98G cells transfected with NMDAR1 shRNA. Data are shown as mean ± SEM (n = 5). *p < 0.05 vs. Negative Control; NC shRNA group (Student’s t-test). g Graph showing cell viability of T98G cells transfected with NMDAR1 shRNA and/or treated with 300 µM TMZ for 48 h. Data are shown as mean ± SEM (n = 6). **p < 0.01 vs. control + NC shRNA group) and #p < 0.05 vs. TMZ + NC shRNA group (Tukey’s test)
Memantine suppress the expression of MGMT. (a, b) Representative images of immunoblots and graph showing the expression of a MGMT protein level and b MGMT mRNA level in T98G cells treated with memantine in concentration-dependent (0.4, 4, 40 µM) for 48 h. a Data are shown as mean ± SEM (n = 6). *p < 0.05 vs. Control group (Dunnett’s test). b Data are shown as mean ± SEM (n = 6). ***p < 0.001 vs. Control group (Dunnett’s test). c–e Representative images of immunoblots and graph showing the expression of d MGMT and e phosphorylated NF-κB in T98G cells treated with memantine for 0, 12, 24 and 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05 vs. 0 h treatment group (Dunnett’s test). f Graph showing the expression of MGMT mRNA level in T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). ***p < 0.001 vs. Control group and #p < 0.05 vs. 300 µM TMZ group (Games-Howell’s test)
The effect of combining MEM with TMZ on cell viability of GBM cells. a Graph showing cell viability of T98G cells treated with 100–400 µM TMZ and/or 10–60 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). **p < 0.01, ***p < 0.001 vs. Control group (Dunnett’s test) and ###p < 0.001 vs. 300 µM TMZ group (Tukey’s test). b Graph showing cell viability of T98G cells treated with 30, 100 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05 vs. 40 µM MEM group (Tukey’s test) and $p < 0.05 vs. 100 µM TMZ group (Tukey’s test). c Graph showing cell viability of GL261cells treated with 10–50 µM TMZ and/or 10–50 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). **p < 0.01 vs. Control group (Dunnett’s test) and ##p < 0.01 vs. 300 µM TMZ group (Tukey’s test). d Graph showing cell viability of U87MG cells treated with 10–50 µM TMZ and/or 1–20 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 vs. Control group (Tukey’s test). d Graph showing cell viability of U87 cells treated with 10–50 µM TMZ and/or 1–20 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 vs. Control group (Tukey’s test). d Graph showing cell viability of GL261 cells treated with 10–50 µM TMZ and/or 1–20 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05, **p < 0.01 vs. Control group (Dunnett’s test). e Representative images of colony formation assay and graph showing the colony numbers of T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h and cultured for 10 days. Data are shown as mean ± SEM (n = 6). *p < 0.05 vs. Control group and ###p < 0.001 vs. 300 µM TMZ group (Games Howell’s test). Scale bar = 10 mm
The effect of combining MEM with TMZ on cell death of GBM cells. a Representative images of cell death assay and graph showing the ratio of cell death in T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). ***p < 0.001 vs. Control group and ###p < 0.001 vs. 300 µM TMZ group (Tukey’s test). The scale bar is 100 µm. b Representative images of TUNEL assay and graph showing the TUNEL positive cell rate of T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 5). *p < 0.05 vs. Control group and ##p < 0.01 vs. 300 µM TMZ group (Games Howell’s test). Scale bar = 100 µm. c Graph showing the caspase3/7 activity of T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). ***p < 0.001 vs. Control group and ###p < 0.001 vs. 300 µM TMZ group (Tukey’s test)
The effect of combining MEM with TMZ on the expression of some proteins in T98G cells. a, d Representative images of immunoblots. b, c, e, f Graphs showing the expression of b cleaved-PARP c cyclinD1 e bcl-2 f p-H2A.X in T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 6). *p < 0.05, ***p < 0.001 vs. Control group and #p < 0.05, ##p < 0.01, ###p < 0.001 vs. 300 µM TMZ group (Tukey’s test). The two bands of bcl-2 were quantified together. g Representative images of p-H2A.X foci and graphs showing the ratio of p-H2A.X foci positive cells in T98G cells treated with 300 µM TMZ and/or 40 µM MEM for 48 h. Data are shown as mean ± SEM (n = 3). *p < 0.05 vs. Control group and ##p < 0.01 vs. 300 µM TMZ group (Tukey’s test). The ratio of p-H2A.X foci positive cells was quantified as cells with 10 or more p-H2A.X foci present. Scale bar = 20 µm
Purpose The alkylating agent temozolomide (TMZ) has a significant impact on the prognosis of glioblastoma (GBM) patients. Therefore, maximizing TMZ efficacy is important for GBM treatment. Many reports have shown that glutamate signaling promotes GBM progression via glutamate receptors, including N-methyl-D-aspartate receptors (NMDARs). Although NMDARs promote cell migration and invasion of GBM cells, their role in TMZ resistance remains unclear. Therefore, we focused on NMDAR signaling and investigated its effects on TMZ resistance. Methods We investigated the effect of NMDAR signaling on O⁶-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that induces chemoresistance to TMZ, using quantitative real-time polymerase chain reaction and western blotting in human GBM T98G cells. In addition, we used memantine (MEM), an NMDAR antagonist, to investigate the cytotoxic effect of TMZ/MEM combination and its detailed mechanism. Results Activation of NMDAR by N-methyl-D-aspartate (NMDA) elevated MGMT expression and suppressed the effect of TMZ in T98G cells. In contrast, knockdown of NMDAR by NMDAR1 shRNA decreased MGMT expression and enhanced the effect of TMZ in T98G cells. The cytotoxic effect of TMZ was enhanced by MEM in T98G cells. Inhibition of NMDAR by MEM decreased MGMT expression and increased DNA alkylation by TMZ. Conclusion NMDAR signaling induced chemoresistance of TMZ via the upregulation of MGMT expression in GBM cells. Furthermore, MEM inhibited TMZ-induced MGMT upregulation and increased the cytotoxic effect of TMZ on MGMT-positive cells. This study demonstrates that the combination of TMZ and MEM could be a new therapeutic strategy for MGMT-positive GBM. Graphical abstract Overview of this study. NMDAR signaling controls the expression of MGMT and the cytotoxic effect of TMZ.
 
Anomaly matrix of the sensorimotor network of patient 6. Anomaly matrices represent the connectivity between sets of parcellations. White squares indicate connectivity within the normal range, black squares too variable to determine a normal range. The colour scale on the right-hand side of the matrix is a measure of connectivity compared to the normal range. Redness represents hyperconnectivity and blueness represents hypoconnectivity. The higher proportion of hypo-connected parcels on the right-hand side and a higher proportion of hyper-connected parcels on the left align with the patient’s symptom of left sided weakness following the removal of a grade I brainstem ganglioglioma
EQ-5D, motor scales, and BDI. A EQ-5D (Scale − 1–1) for QoL after treatment and follow-up compared to baseline. EQ-5D scores were increased for patients after rTMS (p = 0.0024, Wilcoxon test, N = 12) and follow-up (p = 0.0039 Wilcoxon test, N = 10) as compared to baseline. B and C Patients who had rTMS treatment within 1 year of surgery had greater magnitudes of change in EQ-5D scores between baseline and post-treatment (p = 0.0303, Mann–Whitney test, N = 2–10) and during follow-up (p = 0.0222, Mann–Whitney test, N = 2–8) compared to patients who underwent rTMS treatment after more than 1 year following surgery. D Nine patients were administered the LEFS (Scale 0–80) after treatment (mean ± SD, 4.6 ± 4.7), and seven individuals were administered the LEFS during follow-up (9.9 ± 10.2). E The UEFS (Scale 0–80) scores of eight patients after treatment (7.4 ± 10.1) and six patients during follow-up (10.7 ± 12.0). F Patient 10 was administered the BDI (Scale 0–63), showing a 47% reduction in BDI and an 88% reduction in BDI during follow-up compared to baseline
Patient MRI with rTMS targets. A–C Hypobulia and prefrontal cognitive initiation “axis.” Patient 12 developed severe hypobulia after right frontal tumor removal. The prefrontal cognitive initiation “axis,” responsible for goal initiation, comprises of the DMN, Salience network, and supplementary motor area (SMA) and is connected by the cingulum and frontal aslant tract [20]. Right sagittal (A) and left sagittal view (B) of the MRI scan showing the Salience, DMN, and SMA. C Right sagittal view of the three rTMS target. The R6ma, RPGi, and RTGd rTMS targets are labeled with green and blue tractography connecting parcellations. Two of the three rTMS targets for this patient were within the prefrontal cognitive initiation “axis”: RPGi and R6Ma. While R6Ma of the sensorimotor network is proximal to the tumor resection site, RPGi is within the DMN but outside of the immediate region of the resection site. D–F rTMS target contralateral to tumor site. An axial (D), coronal (E), and sagittal (F) view of rTMS targets superimposed on top of the MRI of Patient 1 who had a right temporal lobe craniotomy. rTMS targets include L1 of the left primary somatosensory cortex and R6d of right dorsal premotor cortex. G–I rTMS targets outside of tumor resection site. A coronal (G), sagittal (H), and axial (I) view of rTMS targets superimposed on top of the MRI of Patient 4. Patient 4 had a resection of the thalamus and had rTMS targets in the ventral premotor cortex (L6v and R6v) and the primary somatosensory cortex (L4)
Purpose Deficits in neuro-cognitive function are not uncommon for patients who have undergone surgical removal of brain tumors. Our goal is to evaluate the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a non-invasive tool for the treatment of neuro-cognitive dysfunctions following craniotomy. Methods We present a retrospective review of individualized rTMS in twelve patients from Cingulum Health from December 2019 to July 2021 who presented with neuro-cognitive deficits following craniotomy. Multiple cortical targets were selected based on the patient’s neurological disorder, associated networks, and anomalies in the functional connectivity of the brain as determined by machine-learning. TMS treatment was performed for five consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient’s deficit were assessed prior to, after, and during two-month follow-up of rTMS treatment. Results Nine patients had unilateral functional deficits in either upper, lower, or both limbs. One patient reported post-operative depression, another experienced short term memory difficulties, and a third reported hypobulia. All twelve patients reported significantly improved EQ5D after rTMS treatment and during follow-up. More than half of the patients with lower and upper functional deficits had a 9-point improvement during follow-up. In the patient who developed depression, an 88% reduction in depressive symptoms based on the Beck’s Depression Inventory (BDI) was observed during follow-up. No adverse events, such as seizures, occurred. Conclusion The personalized functional connectivity approach to rTMS treatment may be effective and safe for patients with post-craniotomy neuro-cognitive dysfunction.
 
Progression-free survival (PFS)(A) and overall survival (OS)(B) of central neurocytoma patients in two groups. RT radiotherapy
Progression-free survival (PFS)(A) and overall survival (OS)(B) of central neurocytoma patients in four groups. GTR Gross total resection, STR subtotal resection, RT radiotherapy
Progression-free survival (PFS) (A, C, E) and overall survival (OS) (B, D, F) of central neurocytoma patients according to univariate analysis. GTR Gross total resection, STR subtotal resection, LI labeling index
Log-Rank test for univariate analysis and multivariable Cox regression for multivariate analysis of PFS (A) and OS (B) in central neurocytoma patients. OS Overall survival, PFS progression-free survival, CI confidence interval, KPS Karnofsky performance status, GTR Gross total resection, STR subtotal resection, RT radiotherapy, LI labeling index
Purpose To investigate the efficacy and safety of adjuvant radiotherapy (RT) in patients with central neurocytoma (CN). Methods The study included 68 patients with CN retrospectively, was further divided into surgery + RT group (31 patients) and surgery alone group (37 patients). Progression-free survival (PFS), overall survival (OS), and adverse reactions (AEs) were compared between the two groups. Results The median follow-up duration was 82.2 (interquartile range, 64.7-104.5) months. Patients in the surgery + RT group tended to have longer PFS than those in the surgery alone group (5-year PFS rate: 92.7% vs. 86.3%; P = 0.074). There was no significant difference in OS between the two groups (5-year OS rate: 96.8% vs. 94.3%; P = 0.639). Subgroup analysis revealed a significant improvement in PFS in patients receiving RT after surgery in patients who underwent subtotal resection (STR) (P = 0.045). In the overall population, univariate multivariate analysis revealed that gross total resection (GTR) (P = 0.002), tumor location in the unilateral ventricle (P = 0.008), and MIB-1 (Ki-67) labeling index (LI) < 5% (P = 0.009) were favorable independent prognostic factors for PFS. Whereas tumor location in the unilateral ventricle (P = 0.043) was a favorable independent prognostic factor for OS. Moreover, RT patients experienced AEs (Grade 1–2, well-tolerated). Conclusion Adjuvant RT in the treatment of CNs showed satisfactory safety, and postoperative RT could improve PFS in STR patients. Furthermore, GTR, tumor development in the unilateral ventricle, and MIB-1 LI < 5% were found to be favorable factors affecting the prognosis of CNs.
 
Representative examples of DWI enhancement and contrast reviewed by neuroradiology. From left to right, images are from patient 6 (no/mild DWI), patient 1 (moderate DWI) and patient 10 (high DWI). Axial T1 post-contrast images are also left to right from patient 1 (avid homogenous) and patient 7 (avid heterogenous)
Purpose Pineal parenchymal tumor of intermediate differentiation (PPTID) is a neoplasm of pinealocyte origin and of intermediate differentiation (WHO grade 2 or 3). Treatment selection and prognostication is challenging for this rare, recently characterized tumor. In this single study, we review our clinical experience in patients with PPTID as well as pooled data from two other institutions. Methods This is a retrospective analysis of patients seen at Mayo Clinic, with additional data pooled from two similar studies at outside institutions for comparison and further analysis. Results Ten adult patients (6 male) were identified. Median age at diagnosis was 36 years (range 13–73 years). Patients were followed between 3 and 88 months with no reported deaths. The most common presenting symptom was headache, followed by nausea. Nine patients had local disease without neuroaxial dissemination at diagnosis, one of which had tumor recurrence at 36 months. Two patients underwent gross total resection (GTR) without adjuvant radiation without recurrence (PFS 4 and 46 months). In our combined analysis, we reviewed 36 patients from three different institutions. Four patients presented with disseminated disease. GTR was achieved for 16 patients. Twenty-eight patients received adjuvant radiation therapy and 16 patients experienced disease recurrence. Median overall survival was 44 months. Conclusion Our single institution experience and combined multi-institution analysis suggest GTR is associated with improved outcomes. The role of adjuvant radiation therapy and utility of CSI compared to focal RT is less unclear. Prospective study is required to identify optimal adjuvant therapy selection.
 
Top-cited authors
Tom Mikkelsen
  • Henry Ford Health System
Jeffrey Olson
  • Emory University
Minesh P Mehta
  • Baptist Health South Florida
Timothy C Ryken
  • Dartmouth–Hitchcock Medical Center
Michael W Mcdermott
  • University of California, San Francisco