Impact of contemporary regimens on the outcomes and toxicity of primary CNS lymphoma: a single-center retrospective analysis of 73 patients.

INTRODUCTION: Primary central nervous system lymphoma (PCNSL) is a rare disease with a dismal prognosis compared to its systemic large B-cell lymphoma counterpart. Real world data are limited, when considering a uniform backbone treatment. METHODS: A retrospective study of all adult patients treated sequentially with a high-dose methotrexate (HD MTX)-based regimen in a single tertiary medical center between 2003 and 2019. RESULTS: The 2015-2019 period differed from its predecessor in that most patients were treated with an HD MTX-based polychemotherapy regimen as opposed to HD MTX monotherapy (81% vs. 13%, P < .001), rituximab was given as standard of care (100% vs. 56%, P < .01), and most induction-responsive patients received consolidation treatment (70% vs. 18%, P = .01). The median progression-free and overall survival (OS) for the entire cohort (n = 73, mean age 64 years) was 9.9 and 29.8 months, respectively. Patients diagnosed between 2015 and 2019 had superior OS (P = .03) compared to those treated earlier. An interim partial response (PR) state, documented after two cycles of chemotherapy, was associated with increased incidence of progression, with only 33% of those patients achieving end-of-induction complete response. Twenty-three percent of patients developed thrombotic events and 44% developed grade 3-4 infections. HD MTX-based polychemotherapy induction was associated with both increase in thrombotic and infection incidence. CONCLUSIONS: Contemporary HD MTX-based combination therapies suggestively improved the outcomes for PCNSL, but at a cost of increased incidence of toxicity. Patients who achieve an interim PR status are at a high risk for treatment failure.

Interreader Variability of Dynamic Contrast-enhanced MRI of Recurrent Glioblastoma: The Multicenter ACRIN 6677/RTOG 0625 Study.

Purpose To evaluate factors contributing to interreader variation (IRV) in parameters measured at dynamic contrast material-enhanced (DCE) MRI in patients with glioblastoma who were participating in a multicenter trial. Materials and Methods A total of 18 patients (mean age, 57 years ± 13 [standard deviation]; 10 men) who volunteered for the advanced imaging arm of ACRIN 6677, a substudy of the RTOG 0625 clinical trial for recurrent glioblastoma treatment, underwent analyzable DCE MRI at one of four centers. The 78 imaging studies were analyzed centrally to derive the volume transfer constant (Ktrans) for gadolinium between blood plasma and tissue extravascular extracellular space, fractional volume of the extracellular extravascular space (ve), and initial area under the gadolinium concentration curve (IAUGC). Two independently trained teams consisting of a neuroradiologist and a technologist segmented the enhancing tumor on three-dimensional spoiled gradient-recalled acquisition in the steady-state images. Mean and median parameter values in the enhancing tumor were extracted after registering segmentations to parameter maps. The effect of imaging time relative to treatment, map quality, imager magnet and sequence, average tumor volume, and reader variability in tumor volume on IRV was studied by using intraclass correlation coefficients (ICCs) and linear mixed models. Results Mean interreader variations (± standard deviation) (difference as a percentage of the mean) for mean and median IAUGC, mean and median Ktrans, and median ve were 18% ± 24, 17% ± 23, 27% ± 34, 16% ± 27, and 27% ± 34, respectively. ICCs for these metrics ranged from 0.90 to 1.0 for baseline and from 0.48 to 0.76 for posttreatment examinations. Variability in reader-derived tumor volume was significantly related to IRV for all parameters. Conclusion Differences in reader tumor segmentations are a significant source of interreader variation for all dynamic contrast-enhanced MRI parameters. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Wolf in this issue.

Differentiation between vasogenic edema and infiltrative tumor in patients with high-grade gliomas using texture patch-based analysis.

BACKGROUND: High-grade gliomas (HGGs) induce both vasogenic edema and extensive infiltration of tumor cells, both of which present with similar appearance on conventional MRI. Using current radiological criteria, differentiation between these tumoral and nontumoral areas within the nonenhancing lesion area remains challenging. PURPOSE: To use radiomics patch-based analysis, based on conventional MRI, for the classification of the nonenhancing lesion area in patients with HGG into tumoral and nontumoral components. STUDY TYPE: Prospective. SUBJECTS: In all, 179 MRI scans were obtained from 102 patients: 67 patients with HGG and 35 patients with brain metastases. A subgroup of 15 patients with HGG were scanned before and following administration of bevacizumab. FIELD STRENGTH/SEQUENCE: Pre and postcontrast agent T1 -weighted-imaging (WI), T2 WI, FLAIR, diffusion-tensor-imaging (DTI), and dynamic-contrast-enhanced (DCE)-MRI at 3T. ASSESSMENT: A total of 225 histograms and gray-level-co-occurrence matrix-based features were extracted from the nonenhancing lesion area. Tumoral volumes of interest (VOIs) were defined at the peritumoral area in patients with HGG; nontumoral VOIs were defined in patients with brain metastasis. Twenty machine-learning algorithms including support-vector-machine (SVM), k-nearest neighbor, decision-trees, and ensemble classifiers were tested. The best classifier was trained on the entire labeled data, and was used to classify the entire data. STATISTICAL TESTS: Dimensional reduction was performed on the 225 features using principal component analysis. Classification results were evaluated based on the sensitivity, specificity, and accuracy of each of the 20 classifiers, first based on a training and testing dataset (80% of the labeled data) in a 5-fold manner, and next by applying the best classifier to the validation data (the remaining 20% of the labeled data). Results were additionally evaluated by assessing differences in dynamic-contrast-enhanced plasma-volume (vp ) and volume-transfer-constant (ktrans ) values between the two components using Mann-Whitney U-test/t-test. RESULTS: The best classification into tumoral and nontumoral lesion components was obtained using a linear SVM classifier, with average accuracy of 87%, sensitivity 86%, and specificity of 89% (for the training and testing data). Significantly higher vp and ktrans values (P < 0.0001) were detected in the tumoral compared to the nontumoral component. Preliminary classification results in a subgroup of patients treated with bevacizumab demonstrated a reduction mainly in the nontumoral component following administration of bevacizumab, enabling early assessment of disease progression in some patients. DATA CONCLUSION: A radiomics patch-based analysis enables classification of the nonenhancing lesion area in patients with HGG. Preliminary results were promising and the proposed method has the potential to assist in clinical decision-making and to improve therapy response assessment in patients with HGG. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 4 J. Magn. Reson. Imaging 2018.

Repeatability of dynamic contrast enhanced vp parameter in healthy subjects and patients with brain tumors.

PURPOSE: To study the repeatability of plasma volume (vp) extracted from dynamic-contrast-enhanced (DCE) MRI in order to define threshold values for significant longitudinal changes, and to assess changes in patients with high-grade-glioma (HGG). METHODS: Twenty eight healthy subjects, of which eleven scanned twice, were used to assess the repeatability of vp within the normal-appearing brain tissue and to define threshold values for significant changes based on least-detected-differences (LDD) of mean vp values and histogram comparisons using earth-mover's-distance (EMD). Sixteen patients with HGG were scanned longitudinally with eight patients scanned before and following bevacizumab therapy. Longitudinal changes were assessed based on defined threshold values in comparison to RANO criteria. RESULTS: The threshold values for significant changes were: LDD = 0.0024 (ml/100 ml, 21%) for mean vp and EMD = 4.14. In patients, in 20/24 comparisons, no significant longitudinal changes were detected for vp within the normal-appearing brain tissue. Concurring results were obtained between changes in lesion volume (RANO criteria) and LDD or EMD values in cases diagnosed with progressive-disease, yet in about 50% of cases diagnosed with partial-response preliminary results demonstrated significant increase in vp despite significant reductions in lesion volume. In two patients, these changes preceded progression detected at follow-up scans. In general, a good concordance was obtained between LDD and EMD. CONCLUSION: This study shows high repeatability of vp and provides threshold values for significant changes in longitudinal assessment of patients with brain tumors. Preliminary results suggest the use of vp-DCE parameter to improve assessment of therapy response in patients with high-grade-glioma.

Neurologic complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Cranial irradiation in childhood mimicking neurofibromatosis type II.

Neurofibromatosis type II (NF2) is a genetic disease characterized by bilateral vestibular schwannomas (VS) and other nerve system tumors. However, such tumors may be associated with environmental, rather than a genetic, etiology. Individuals fulfilling the clinical criteria of NF2 who had been treated by head ionized irradiation at a young age were compared for disease characteristics and molecular analysis with non-irradiated sporadic NF2 cases. In the study cohort, three of 33 sporadic adult cases fulfilling NF2 diagnostic criteria had a history of early age cranial irradiation exposure. None of the irradiated patients had bilateral VS compared with 73.3% of the non-irradiated individuals. One of the irradiated patients had no VS, while none of the non-irradiated NF2 cases had absence of VS. All of the irradiated individuals had brain meningiomas and thyroid tumors compared with 47% and 0%, respectively, of the non-irradiated individuals. Molecular analyses for NF2 mutations in blood of the irradiated individuals failed to detect disease-causing mutations. This study suggest that environmental factors may mimic NF2. Identifying such non-genetic cases fulfilling clinical criteria of the genetic disease may be crucial for the purposes of genetic counseling and patient management.

Changes in cerebral metabolism during ketogenic diet in patients with primary brain tumors: 1H-MRS study.

Normal brain cells depend on glucose metabolism, yet they have the flexibility to switch to the usage of ketone bodies during caloric restriction. In contrast, tumor cells lack genomic and metabolic flexibility and are largely dependent on glucose. Ketogenic-diet (KD) was suggested as a therapeutic option for malignant brain cancer. This study aimed to detect metabolic brain changes in patients with malignant brain gliomas on KD using proton magnetic-resonance-spectroscopy (1H-MRS). Fifty MR scans were performed longitudinally in nine patients: four patients with recurrent glioblastoma (GB) treated with KD in addition to bevacizumab; one patient with gliomatosis-cerebri treated with KD only; and four patients with recurrent GB who did not receive KD. MR scans included conventional imaging and 1H-MRS acquired from normal appearing-white-matter (NAWM) and lesion. High adherence to KD was obtained only in two patients, based on high urine ketones; in these two patients ketone bodies, Acetone and Acetoacetate were detected in four MR spectra-three within the NAWM and one in the lesion area -4 and 25 months following initiation of the diet. No ketone-bodies were detected in the control group. In one patient with gliomatosis-cerebri, who adhered to the diet for 3 years and showed stable disease, an increase in glutamin + glutamate and reduction in N-Acetyl-Aspartate and myo-inositol were detected during KD. 1H-MRS was able to detect ketone-bodies in patients with brain tumors who adhered to KD. Yet it remains unclear whether accumulation of ketone bodies is due to increased brain uptake or decreased utilization of ketone bodies within the brain.

NRG oncology RTOG 0625: a randomized phase II trial of bevacizumab with either irinotecan or dose-dense temozolomide in recurrent glioblastoma.

Angiogenesis, a hallmark of glioblastoma, can potentially be targeted by inhibiting the VEGF pathway using bevacizumab, a humanized monoclonal antibody against VEGF-A. This study was designed to determine the efficacy and safety of these regimens in the cooperative group setting. Eligibility included age ≥18, recurrent or progressive GBM after standard chemoradiation. Treatment was intravenous bevacizumab 10 mg/kg and either irinotecan (CPT) 125 mg/m2 every 2 weeks or temozolomide (TMZ) 75-100 mg/m2 day 1-21 of 28 day cycle. Accrual goal was 57 eligible patients per arm. Primary endpoint was 6 month progression-free survival (6-m PFS); a predetermined rate of ≥35 % to declare efficacy. 60 eligible patients were enrolled on TMZ arm and 57 patients on CPT arm. Median age was 56, median KPS was 80. For TMZ arm, the 6-m-PFS rate was 39 % (23/59); for the CPT arm, the 6-m-PFS rate was 38.6 % (22/57). Objective responses: TMZ arm had 2 (3 %) CR, 9 (16 %) PR; CPT arm had 2 (4 %) CR, 13 (24 %) PR. Overall there was moderate toxicity: TMZ arm with 33 (55 %) grade 3, 11 (18 %) grade 4, and 1 (2 %) grade 5 (fatal) toxicities; CPT arm had 22 (39 %) grade 3, 7 (12 %) grade 4, and 3 (5 %) grade 5 toxicities. The 6-m-PFS surpassed the predetermined efficacy threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide exposure. Toxicities were within anticipated frequencies with a moderately high rate of venous thrombosis, moderate hypertension and one intracranial hemorrhage.

Stereotactic radiosurgery (SRS) in high-grade glioma: judicious selection of small target volumes improves results.

We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3-109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients.

Differentiation between treatment-related changes and progressive disease in patients with high grade brain tumors using support vector machine classification based on DCE MRI.

Differentiation between treatment-related changes and progressive disease (PD) remains a major clinical challenge in the follow-up of patients with high grade brain tumors. The aim of this study was to differentiate between treatment-related changes and PD using dynamic contrast enhanced (DCE) MRI. Twenty patients were scanned using conventional, DCE-MRI and MR spectroscopy (total of 44 MR scans). The enhanced lesion area was extracted using independent components analysis of the DCE data. Pharmacokinetic parameters were estimated from the DCE data based on the Extended-Tofts-Model. Voxel based classification for treatment-related changes versus PD was performed in a patient-wise leave-one-out manner, using a support vector machine classifier. DCE parameters, K (trans), v e, k ep and v p, significantly differentiated between the tissue types. Classification results were validated using spectroscopy data showing significantly higher choline/creatine values in the extracted PD component compared to areas with treatment-related changes and normal appearing white matter, and high correlation between choline/creatine values and the percentage of the identified PD component within the lesion area (r = 0.77, p < 0.001). On the training data the sensitivity and specificity were 98 and 97 %, respectively, for the treatment-related changes component and 97 and 98 % for the PD component. This study proposes a methodology based on DCE-MRI to differentiate lesion areas into treatment-related changes versus PD, prospectively in each scan. Results may have major clinical importance for pre-operative planning, guidance for targeting biopsy, and early prediction of radiological outcomes in patients with high grade brain tumors.

Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors.

Patients with progressive primary brain tumors (PBT) are attracted to promising new treatments, even prior to convincing data. Anti-PD1 immunotherapies have been in the spotlight since publication of groundbreaking results for metastatic melanoma with pembrolizumab (PBL). Our objective was to report on the response and toxicity of PBL in patients with advanced PBT. We retrospectively reviewed the charts of 22 patients (17 adults and 5 children) with recurrent central nervous system tumors treated with PBL. We analyzed prior antineoplastic therapies, steroid usage, and outcomes. Patients received a median of two neoplastic therapies prior to PBL, and a median of three infusions of PBL in adults and four in children. Twelve patients (9 adults and 3 children) started PBL on steroids (median dose in adults 4 mg; range 2-8, and in children 1.5 mg, range 0.5-4) and five patients received steroids later during PBL treatment. Twelve patients (10 adults and 2 children) received concomitant bevacizumab with PBL. Side effects were minimal. All patients showed progressive tumor growth during therapy. Median OS from the start of PBL was 2.6 months in adults and 3.2 months in children. Two GB patients underwent tumor resection following treatment with PBL. Tumor-lymphocytic response in these cases was unremarkable, and PD-L1 immuno-staining was negative. In this series of 22 patients with recurrent primary brain tumors, PBL showed no clinical or histologic efficacy. We do not recommend further use of PBL for recurrent PBT unless convincing prospective clinical trial data are published.

Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients.

Genomic research of high grade glioma (HGG) has revealed complex biology with potential for therapeutic impact. However, the utilization of this information and impact upon patient outcome has yet to be assessed. We performed capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 cancer-associated genes, with average depth of over 1000 fold, to guide treatment in HGG patients. We reviewed clinical utility and response rates in correlation to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8 anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma. Twenty-five patients were profiled with the 315 gene panel. The median number of identified genomic alterations (GAs) per patient was 4.5 (range 1-23). In 41 patients (95 %) at least one therapeutically-actionable GA was detected, most commonly in EGFR [17 (40 %)]. Genotype-directed treatments were prescribed in 13 patients, representing a 30 % treatment decision impact. Treatment with targeted agents included everolimus as a single agent and in combination with erlotinib; erlotinib; afatinib; palbociclib; trametinib and BGJ398. Treatments targeted various genomic findings including EGFR alterations, mTOR activation, cell cycle targets and FGFR1 mutations. None of the patients showed response to respective biologic treatments. In this group of patients with HGG, NGS revealed a high frequency of GAs that lead to targeted treatment in 30 % of the patients. The lack of response suggests that further study of mechanisms of resistance in HGG is warranted before routine use of biologically-targeted agents based on NGS results.

Classification of tumor area using combined DCE and DSC MRI in patients with glioblastoma.

This study proposes an automatic method for identification and quantification of different tissue components: the non-enhanced infiltrative tumor, vasogenic edema and enhanced tumor areas, at the subject level, in patients with glioblastoma (GB) based on dynamic contrast enhancement (DCE) and dynamic susceptibility contrast (DSC) MRI. Nineteen MR data sets, obtained from 12 patients with GB, were included. Seven patients were scanned before and 8 weeks following bevacizumab initiation. Segmentation of the tumor area was performed based on the temporal data of DCE and DSC at the group-level using k-means algorithm, and further at the subject-level using support vector machines algorithm. The obtained components were associated to different tissues types based on their temporal characteristics, calculated perfusion and permeability values and MR-spectroscopy. The method enabled the segmentation of the tumor area into the enhancing permeable component; the non-enhancing hypoperfused component, associated with vasogenic edema; and the non-enhancing hyperperfused component, associated with infiltrative tumor. Good agreement was obtained between the group-level, unsupervised and subject-level, supervised classification results, with significant correlation (r = 0.93, p < 0.001) and average symmetric root-mean-square surface distance of 2.5 ± 5.1 mm. Longitudinal changes in the volumes of the three components were assessed alongside therapy. Tumor area segmentation using DCE and DSC can be used to differentiate between vasogenic edema and infiltrative tumors in patients with GB, which is of major clinical importance in therapy response assessment.

Calcification in high grade gliomas treated with bevacizumab.

Calcification is a rare phenomenon in high grade glioma (HGG). CT scans are sensitive to mineralization but used infrequently for tumor assessment in the MRI era. The presence of calcification can be overlooked on routine MRI. Calcification may reflect chronicity and natural changes in the tumor or its milieu over time and may be accelerated by certain treatments. Calcification may have clinical significance which could signal potential risk for stroke or hemorrhage related to particular therapies; or it may be a positive prognostic factor for treatment response. The true incidence and relevance of calcification in HGG and relation to therapy is unclear. During treatment of HGG patients with bevacizumab (BVZ) we observed significant tumor calcification on brain CT. We performed a retrospective review of HGG patients treated with BVZ to quantitate the incidence of calcification in this group compared to those treated with cytotoxic therapy alone. Sixty-two patients with progressive HGG were treated with BVZ and a cytotoxic agent. Among 19 patients treated for 6+ months, 12 had a CT scan performed. We observed an unexpected phenomenon of calcification in the CT scans of several patients. We were also able to comparatively quantitate the incidence of calcification in a control group of primary glioblastoma (GB) patients not exposed to BVZ therapy. The incidence of calcification in the general GB population is increased with longer survival. The phenomenon is increased with anti-angiogenic therapy for brain tumors. Calcification may have significance as a predictor for treatment response.

Human cerebral blood volume measurements using dynamic contrast enhancement in comparison to dynamic susceptibility contrast MRI.

INTRODUCTION: Cerebral blood volume (CBV) is an important parameter for the assessment of brain tumors, usually obtained using dynamic susceptibility contrast (DSC) MRI. However, this method often suffers from low spatial resolution and high sensitivity to susceptibility artifacts and usually does not take into account the effect of tissue permeability. The plasma volume (vp) can also be extracted from dynamic contrast enhancement (DCE) MRI. The aim of this study was to investigate whether DCE can be used for the measurement of cerebral blood volume in place of DSC for the assessment of patients with brain tumors. METHODS: Twenty-eight subjects (17 healthy subjects and 11 patients with glioblastoma) were scanned using DCE and DSC. vp and CBV values were measured and compared in different brain components in healthy subjects and in the tumor area in patients. RESULTS: Significant high correlations were detected between vp and CBV in healthy subjects in the different brain components; white matter, gray matter, and arteries, correlating with the known increased tissue vascularity, and within the tumor area in patients. CONCLUSION: This work proposes the use of DCE as an alternative method to DSC for the assessment of blood volume, given the advantages of its higher spatial resolution, its lower sensitivity to susceptibility artifacts, and its ability to provide additional information regarding tissue permeability.

Gliomas of the posterior fossa in adults.

Infratentorial gliomas are relatively rare tumors compared to their supratentorial counterparts. As such they have not been extensively characterized as a group and are usually excluded from clinical studies. Using our database we aimed to characterize adult gliomas involving the posterior fossa with respect to their clinical behavior and prognostic factors. We reviewed our neurosurgical and neuro-oncological data bases for adult patients diagnosed with gliomas involving the posterior fossa between 1996 and 2010. Of 1,283 glioma patients, 57 patients with gliomas involving the posterior fossa were identified (4.4 %). Tumors were further classified by location as primary brainstem (n = 21) and primary cerebellar (n = 18) tumors. On univariate analysis survival was correlated to tumor grade and KPS. In addition we have identified a unique group of patients (n = 18) with previously diagnosed supratentorial gliomas who subsequently developed noncontiguous secondary infratentorial extension of their tumors with subsequent rapid clinical deterioration. Gliomas of the posterior fossa comprise a heterogeneous group of tumors. Histological grade of the tumor was found to be the main prognostic factor. Survival of primary cerebellar gliomas is comparable to supra-tentorial gliomas, while brainstem gliomas in adults fare better than in the pediatric population. Secondary extension of supratentorial gliomas to the posterior fossa signifies a grave prognosis.

Neurolymphomatosis: an International Primary CNS Lymphoma Collaborative Group report.

Neurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%. It occurred as the initial manifestation of malignancy in 26% of cases. The affected neural structures included peripheral nerves (60%), spinal nerve roots (48%), cranial nerves (46%), and plexus (40%) with multiple site involvement in 58%. Imaging studies often suggested the diagnosis with 77% positive magnetic resonance imaging, and 84% (16 of 19) positive computed tomography-positron emission tomography studies. Cerebrospinal fluid cytology was positive in 40%, and nerve biopsy confirmed the diagnosis in 23 of 26 (88%). Treatment in 47 patients included systemic chemotherapy (70%), intra-cerebrospinal fluid chemotherapy (49%), and radiotherapy (34%). Response to treatment was observed in 46%. The median overall survival was 10 months, with 12- and 36-month survival proportions of 46% and 24%, respectively. NL is a challenging diagnosis, but contemporary imaging techniques frequently detect the relevant neural invasion. An aggressive multimodality therapy can prevent neurologic deterioration and is associated with a prolonged survival in a subset of patients.

Delayed initiation of radiotherapy for glioblastoma: how important is it to push to the front (or the back) of the line?

Glioblastoma is a malignant tumor characterized by a rapid proliferation rate. Contemporary multi-modality treatment consists of maximal surgical resection followed by radiation therapy (RT) combined with cytotoxic chemotherapy. The optimal timing of these different steps is not known. Four studies from the pre-temozolomide era, encompassing a total of 4,584 subjects, have examined the consequences of a delay between resection and starting RT. Whereas the two small single-institution studies found this delay to be detrimental, two large multi-institutional studies found delay to be either slightly beneficial or at least not harmful. Here, we critically compare the methodologies and results presented in these studies, and include a novel analysis of the combined datasets. We conclude that moderate wait periods (up to 4-6 weeks post-operatively) are safe and may be modestly beneficial. Conversely, there is no evidence to justify waiting longer than 6 weeks. Underlying radiobiological principles are discussed.

Concurrent Tumor Treating Fields (TTFields) and Radiation Therapy for Newly Diagnosed Glioblastoma: A Prospective Safety and Feasibility Study.

Background: TTFields are a loco-regional, anti-mitotic treatment comprising low-intensity alternating electric fields. In the EF-14 study of newly diagnosed glioblastoma (ndGBM), TTFields in combination with temozolomide (TMZ) significantly improved survival vs. TMZ alone. In preclinical studies TTFields had a radiosensitizing effect and increased the efficacy of radiation therapy (RT). This study prospectively evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for ≥18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) combined with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150-200 mg/m2 for 5 days) plus TTFields. Patients were followed for 24 months or until second disease progression. The primary outcome was safety of the combined therapies; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were graded per CTCAE v4.0. Results: Ten patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median Karnofsky Performance Score was 90.0, and 80% patients were male. Five (50%) patients had undergone tumor resection while the remainder had biopsy only. Eight patients experienced ≥1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced ≥1 AE. Three patients suffered from serious AEs (urinary tract infection, confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in eight (80%) patients; all were of low severity (CTCAE grade 1-2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. Conclusions: Eighty percent of patients experienced grade 1-2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed without an increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. Preliminary efficacy results are promising and warrant further investigation of concurrent TTFields/RT/TMZ treatment in ndGBM patients.

Surgical Management of "Kissing" Spinal Plexiform Neurofibromas in Neurofibromatosis Type 1 Patients.

BACKGROUND: "Kissing" neurofibromas (KNs) are a unique group of spinal tumors found in neurofibromatosis type 1 (NF1) patients. These are bilateral neurofibromas that approximate each other at the same level, with significant impingement compression of the cord or thecal sac. The best management options and surgical strategies for NF1 patients with KN have not been standardized. METHODS: We conducted a retrospective study evaluating adult NF1 patients with KN. All patients are followed routinely at the Gilbert Israeli NF Center. Patients' files were reviewed for natural history, imaging features, surgical technique, and surgical outcome. RESULTS: Twelve patients with at least 1 pair of KN were identified (6 females). Median age at spinal presentation was 24 (range 17-48). KNSs were located at the cervical (n = 8) and lumbar (n = 8) region, with no thoracic involvement. Seven of the 12 patients were operated; all underwent surgery due to cervical compression with progressive myelopathy. Four patients remained asymptomatic during the follow-up period. Three patients underwent multiple operations. Operative outcome was favorable in 71% of patients, with marked overall motor improvement or stabilization of neurologic deterioration. Two patients who entered surgery with a low functional reserve deteriorated after surgery. CONCLUSIONS: In our series, KN caused progressive cord compression in 7 of the 8 patients with cervical tumors. No intervention was needed for lumbar tumors. Cervical tumors should be followed closely, with a low threshold for intervention. NF1 patients harboring KN should be followed both clinically and radiologically for life.