Felix Bokstein

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.

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 (95u2009%) at least one therapeutically-actionable GA was detected, most commonly in EGFR [17 (40u2009%)]. Genotype-directed treatments were prescribed in 13 patients, representing a 30u2009% 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 30u2009% 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.

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 (70.2xa0%) patients were diagnosed with glioblastoma and 14 (29.8xa0%) with grade III glioma. The indications for SRS were small (up to 30xa0mm in diameter) locally progressing lesions in 32/47 (68xa0%) or new distant lesions in 15/47 (32xa0%) patients. The median target volume was 2.2xa0cc (0.2–9.5xa0cc) and the median prescription dose was 18xa0Gy (14–24xa0Gy). Three patients (5.5xa0% incidence in 55 treatments) developed radiation necrosis. In eight cases (17xa0%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0xa0%) 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 5.0xa0months (1.0–96.4). Median survival time after SRS was 15.9xa0months (2.3–109.3) overall median survival (since diagnosis) was 37.4xa0months (9.6–193.6xa0months). Long-lasting responses (>12xa0months) after SRS were observed in 25/46 (54.3xa0%) 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. 7.3xa0months, pxa0=xa00.0102). 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 50xa0% of the patients.

Optic pathway gliomas in adults.

BACKGROUNDnOptic pathway gliomas (OPGs) are considered relatively benign pediatric tumors. Adult patients with OPG can be divided into 2 groups: adult patients with tumors diagnosed in childhood and adult patients diagnosed during adulthood.nnnOBJECTIVEnTo characterize the clinical course of adult patients with OPG.nnnMETHODSnWe retrospectively collected clinical and imaging data of all adult OPG patients monitored in our medical center between 1990 and 2012.nnnRESULTSnTwenty-two adult patients were included. Age at diagnosis varied widely (6 months-66 years), as did age at last follow-up (18-74 years). Ten patients were diagnosed at adulthood and 12 in childhood. Of the patients diagnosed at childhood, 6 had radiological progression during childhood, and 3 of those patients suffered visual impairment. From this group, 1 patient had further progression during adulthood accompanied by additional visual decline, and 2 patients had additional visual decline during adulthood despite no signs of progression. Of the 6 patients whose tumors were stable during childhood, all 6 remained stable during adulthood. Of 10 patients diagnosed at adulthood, 6 patients suffered visual deterioration; in 5 of them, a concomitant progression was noted. Two patients were diagnosed with high-grade gliomas.nnnCONCLUSIONnOPGs may be active during childhood or adulthood. Those patients who experienced anatomic activity during childhood are prone to continue experiencing active disease during adulthood. A significant percentage of patients diagnosed with low-grade OPG at adulthood may suffer progression, visual decline, or both.nnnABBREVIATIONSnNF1, neurofibromatosis 1OPG, optic pathway gliomas.

Classification of High-Grade Glioma into Tumor and Nontumor Components Using Support Vector Machine

BACKGROUND AND PURPOSE: Current imaging assessment of high-grade brain tumors relies on the Response Assessment in Neuro-Oncology criteria, which measure gross volume of enhancing and nonenhancing lesions from conventional MRI sequences. These assessments may fail to reliably distinguish tumor and nontumor. This study aimed to classify enhancing and nonenhancing lesion areas into tumor-versus-nontumor components. MATERIALS AND METHODS: A total of 140 MRI scans obtained from 32 patients with high-grade gliomas and 6 patients with brain metastases were included. Classification of lesion areas was performed using a support vector machine classifier trained on 4 components: enhancing and nonenhancing, tumor and nontumor, based on T1-weighted, FLAIR, and dynamic-contrast-enhancing MRI parameters. Classification results were evaluated by 2-fold cross-validation analysis of the training set and MR spectroscopy. Longitudinal changes of the component volumes were compared with Response Assessment in Neuro-Oncology criteria. RESULTS: Normalized T1-weighted values, FLAIR, plasma volume, volume transfer constant, and bolus-arrival-time parameters differentiated components. High sensitivity and specificity (100%) were obtained within the enhancing and nonenhancing areas. Longitudinal changes in component volumes correlated with the Response Assessment in Neuro-Oncology criteria in 27 patients; 5 patients (16%) demonstrated an increase in tumor component volumes indicating tumor progression. These changes preceded Response Assessment in Neuro-Oncology assessments by several months. Seven patients treated with bevacizumab showed a shift to an infiltrative pattern of progression. CONCLUSIONS: This study proposes an automatic classification method: segmented Response Assessment in Neuro-Oncology criteria based on advanced imaging that reliably differentiates tumor and nontumor components in high-grade gliomas. The segmented Response Assessment in Neuro-Oncology criteria may improve therapy-response assessment and provide earlier indication of progression.

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.

The effect of parental age on the presence of de novo mutations - Lessons from neurofibromatosis type I.

Neurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous disease with a prevalence of 1:2500. Approximately, 50% of the cases are sporadic. Advanced paternal age is associated with germline mutations and autosomal diseases. We aimed to use NF1 as a paradigm to study the effect of parental age on sporadic mutation rates for both advanced and younger parental ages.

Surgery for Recurrent High-Grade Glioma After Treatment with Bevacizumab

BACKGROUNDnBevacizumab (BVZ) is an antiangiogenic agent approved by the Food and Drug Administration that is used for the treatment of recurrent glioblastoma. Complications related to impaired healing may adversely affect patients resected for recurrent high-grade glioma (HGG) after treatment with BVZ.nnnOBJECTIVEnTo examine the complication rate, outcome, and tumor vasculature in patients resected for recurrent HGG after treatment with BVZ.nnnMETHODSnData were reviewed retrospectively from patients undergoing surgery for recurrent HGG after treatment with BVZ. Results were compared with a control group of recurrently operated BVZ-naïve HGG. Tumor samples and magnetic resonance imaging scans were analyzed.nnnRESULTSnFifteen patients underwent HGG resection after progression after BVZ. Forty-four BVZ-naïve patients who underwent surgeries for tumor recurrence were included as controls. Median time from BVZ treatment to surgery was 30 days (2-107). Median overall survival from time of tumor diagnosis was 21.0 months (12-83.0), and median survival from post-BVZ surgery was 5.0 months (2.0-19.0), compared with 8.1 months in BVZ-naïve controls measured from time of their last reoperation. Five of the 15 patients survived 6 or more months after post-BVZ surgery. Nine patients developed postsurgical complications requiring intervention. Complication rates for surgery after BVZ treatment were 66.7% compared with 38.6% in the control group (Pxa0= 0.077). We did not see overt changes in histopathology or immunohistochemistry staining; however, tumor vasculature in tumors resected after treatment with BVZ showed a significant decrease in mean vessel density.nnnCONCLUSIONSnSurgery for recurrent HGG may be feasible in a select group of patients. Mean tumor vessel density may be decreased after treatment with BVZ.

MRI radiomics analysis of molecular alterations in low-grade gliomas

PurposeLow-grade gliomas (LGG) are classified into three distinct groups based on their IDH1 mutation and 1p/19q codeletion status, each of which is associated with a different clinical expression. The genomic sub-classification of LGG requires tumor sampling via neurosurgical procedures. The aim of this study was to evaluate the radiomics approach for noninvasive classification of patients with LGG and IDH mutation, based on their 1p/19q codeletion status, by testing different classifiers and assessing the contribution of the different MR contrasts.MethodsPreoperative MRI scans of 47 patients diagnosed with LGG with IDH1-mutated tumors and a genetic analysis for 1p/19q deletion status were included in this study. A total of 152 features, including size, location and texture, were extracted from fluid-attenuated inversion recovery images,