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Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.

Background Mesenchymal stemlike cells (MSLCs) have been detected in many types of cancer including brain tumors and have received attention as stromal cells in the tumor microenvironment. However, the cellular mechanisms underlying their participation in cancer progression remain largely unexplored. The aim of this study was to determine whether MSLCs have a tumorigenic role in brain tumors. Methods To figure out molecular and cellular mechanisms in glioma invasion, we have cultured glioma with MSLCs in a co-culture system. Results Here, we show that MSLCs in human glioblastoma (GBM) secrete complement component C5a, which is known for its role as a complement factor. MSLC-secreted C5a increases expression of zinc finger E-box-binding homeobox 1 (ZEB1) via activation of p38 mitogen-activated protein kinase (MAPK) in GBM cells, thereby enhancing the invasion of GBM cells into parenchymal brain tissue. Conclusion Our results reveal a mechanism by which MSLCs undergo crosstalk with GBM cells through the C5a/p38 MAPK/ZEB1 signaling loop and act as a booster in GBM progression. Key Points 1. MSLCs activate p38 MAPK-ZEB1 signaling in GBM cells through C5a in a paracrine manner, thereby boosting the invasiveness of GBM cells in the tumor microenvironment. 2. Neutralizing of C5a could be a potential therapeutic target for GBM by inhibition of mesenchymal phenotype.

Stereotactic radiosurgery(SRS) is one of primary treatment modalities for brain metastases(BM), however local control and radiation necrosis of large BM remain challenging. To overcome these limitations, biweekly 3-stage SRS for LBM was performed in this study. Total 53 patients were treated for 62 LBM. Female was 27(50.9%), and mean age was 63.7±11.8years. The mean KPS was 79.2±9.0 and GPA score was 1.9±0.7. Non-small cell lung cancer(NSCLC) was the most common primary cancer in 31 patients, others include 6 small cell lung cancer(SCLC), 9 gastro-intestinal tract cancer, 5 gynecological cancer, and etc. Epidermal growth factor receptor(EGFR) mutation was identified in 13 patients, and EGFR tyrosine-kinase inhibitor(TKI) was used in 10 patients during and after staged SRS. The mean tumor volume was 19.1cm3. The mean marginal dose of 11.7Gy was delivered to the 50% isodose line based on new treatment planning every two weeks. The mean tumor volume at the second and third stage was 14.8cm3 and 11.0cm3, respectively. The lesions from squamous cell carcinoma of NSCLC decreased most rapidly, and followed by gynecological cancer, SCLC and adenocarcinoma of NSCLC(volume ratio at 3rd stage was 0.39, 0.53, 0.56, and 0.64, respectively). The most significant factor related with tumor volume reduction at 3rd stage was usage of EGFR-TKI(p=0.016; LR analysis). The mean overall survival(OS) was 15.3months, and estimated OS were 62% and 46% at 6 and 12months. In the multivariate analysis, KPS(OR=0.918; 95% CI,0.871-0.968; p=0.002) and usage of EGFR-TKI(OR=0.216; 95% CI,0.059-0.790; p=0.021) were significantly associated with OS. The mean OS of the group of usage of EGFR-TKI was significantly longer than that of the others(20.7months, and 13.1months; p=0.029; log-rank test). The biweekly 3-stage SRS seems to be effective treatment for patients with LBM, especially in patients who were treated with EGFR-TKI during and/or after SRS, also cautiously considering the primary tumor origin.

BACKGROUND Glioblastoma is the most common primary intracranial malignancy in adults. In cases where biopsy is not feasible due to tumors in inoperable locations including the brainstem, biomarkers such as micro RNA-21 (miR-21) extracted from blood samples could be utilized for diagnostic or prognostic purposes. In this study, we examined the role of miR-21 as a diagnostic factor in patients with glioblastoma. METHODS Inclusion criteria included patients with age greater than 20 years and with histologic confirmation of diagnosis. The blood samples were collected prior to surgery, after surgical resection, after concurrent chemoradiotherapy, and after 3 cycles of adjuvant temozolomide therapy. Using TaqMan assay, we extracted miR-21 from blood samples and compared its level with tumor volume on brain magnetic resonance imaging (MRI) scans. miR-21 levels before and after treatments were compared within each subject. RESULTS Eleven newly diagnosed glioblastoma patients were enrolled in this study, and final analyses were performed for eight patients with complete follow up serum samples. Two patients with stable disease after treatment displayed a decrease in miR-21 levels. Three out of four subjects with increase in miR-21 showed progressive disease on MRI scans. One patient with stable disease and an increased miR-21 level experienced postoperative intracranial hemorrhage and ischemic event. The two patients with unchanged miR-21 levels showed stable disease. CONCLUSION miR-21 levels were associated with progressive disease in glioblastoma patients. miR-21 has potential be utilized as a diagnostic marker in patients with glioblastoma, and further studies are needed to elucidate its role as a prognostic marker.

BACKGROUND While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. METHODS Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6). RESULTS One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities. CONCLUSION The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM

BACKGROUND Dendritic cell (DC)-based vaccines have been suggested as one of the promising immunotherapies for treating various cancers, including glioblastoma. We already developed a novel vaccination protocol with peptide-loaded DCs followed by a mixture of synthetic peptides, polyinosine- polycytidylic acid (poly-IC) and anti-CD40 antibodies (Trivax) in a melanoma mouse model. However, in a glioma mouse model, therapeutic efficacy is not as much as enough maybe due to relatively low antigenicity and blood brain barrier. MATERIAL AND METHODS IL-7, which is one of the most important cytokines to expand and develop T cells with anti-tumor immunity, was co-administrated intravenously with Trivax in an orthotopic murine malignant glioma. RESULTS Co-administration of the Trivax and recombinant IL-7 (Trivax7) increased the number of survivin specific T cells measured using ELISPOT assay and the population of central memory T cells, comparing with administration of Trivax. The tumor size of orthotopic mouse model in Trivax 7 group was smaller than those of Trivax only group. Finally, overall survival in Trivax 7 was longer than those of Trivax only. In addition, there was a prolonged survival of antigen-specific T cells in Trivax7 group than Trivax only group. CONCLUSION In summary, our novel combinational immunotherapy may overcome the limitations of current cell-based cancer vaccines and could be applicable for the treatment of glioblastoma patients.

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Phospholipase D (PLD) isozyme is overexpressed in various human tumor tissues and involved in tumorigenesis. However, the molecular mechanisms by which PLD enhances glioma invasion are unknown. In this study, we demonstrate that the increased expression of PLD and its enzymatic activity in the glioma stimulate the secretion and expression of matrix metalloproteinase (MMP)-2 and induce the invasiveness of glioma cells. The upregulation of MMP-2 induced by phosphatidic acid (PA), the product of PLD, was mediated by protein kinase C (PKC), protein kinase A (PKA), nuclear factor-kappaB (NF-kappaB) and Sp1 and it enhanced glioma cell invasion. PA activated PKC and PKA and induced the nuclear translocation and transactivation of NF-kappaB. PA also increased the binding of NF-kappaB and Sp1 to the MMP-2 promoter. Mutation of the NF-kappaB- or Sp1-binding sites significantly attenuated MMP-2 promoter activity. This is the first report to show that NF-kappaB and Sp1 are essential transcriptional factors linking PLD to MMP-2 upregulation, providing evidence that PLD contributes to glioma progression by enhancing MMP-2 expression and tumor cell invasion via PKC/PKA/NF-kappaB/Sp1-mediated signaling pathways.

Although intracranial germ cell tumors are mostly diagnosed in pediatric age group, small proportions of patients are also present in young adults. Here we report our treatment experience in adults of combined neoadjuvant chemotherapy and radiotherapy protocol, originally designed for pediatric patients by the Korean Society for Pediatric Neuro-Oncology (KSPNO). The radiation dosage was stratified by the disease extent and response to the chemotherapy. With retrospective medical chart review from 2006 to 2016, 11 adult patients were identified to be diagnosed as intracranial germ cell tumor and treated in our institution. The patient demographics, tumor location and diagnosis, treatment modality and their prognosis data were gained. All the patients were male with 1 exception, and the median age was 23 (range 20-28). Tumor locations were 4 suprasellar, 5 pineal, and 2 suprasellar, pineal combined. Radiologic evidence of leptomeningeal seeding was present in 4 cases. The diagnosis was germinoma in 8 cases, including 1 case harboring syncytiotrophoblastic giant cells. Remaining 3 cases were diagnosed as yolk sac tumor, choriocarcinoma, and mixed germ cell tumor. Nine patients underwent the aforementioned combined chemotherapy and radiotherapy protocol, and the initial response was CR in 6 patients and PR in 3 patients. Median follow up period was 59.5 months (range 12.3-113.3) and two patients expired due to disease progression at 15.3 months and 19.0 months, whom was initially diagnosed as yolk sac tumor and choriocarcinoma, respectively. No serious treatment-related complications were observed in our patient series. Despite the limited case number of our series, our treatment protocol seems safe and efficient in adult intracranial germ cell tumor patients.

We analyzed clinical data of 376 patients with histologically confirmed anaplastic oligodendroglioma or anaplastic oligoastrocytoma (AOA) from 2000 to 2010. Post-operative therapy was performed in 354 patients (94.1 %), of which 133 received radiotherapy (RT) alone and 189 received both RT and chemotherapy. The use of procarbazine, lomustine, and vincristine (PCV) decreased (57.6 % in 2000-2001 vs. 28.6 %in 2010) and the use of temozolomide (TMZ) increased (0 % in 2000-2001 vs. 61.9 % in 2010) over the study period. A combination of chemotherapy and RT was used more often than RT alone in young patients and patients with a good performance status. The 1p/19q co-deletion status and O-6-methyguanine-DNA methyltransferase methylation were analyzed since 2004. Among the patients who received chemotherapy, TMZ was used more often in patients with AOA and PCV was used more often in patients with the 1p/19q codeletion. Median progression-free survival (PFS) was 2.9 years and overall survival (OS) was 8.7 years. (5-year and 10-year OS rates were 58% and 45%, 5-year and 10-year PFS rates were 38% and 24%). Younger age, frontal lobe location of the tumor, gross total removal, 1p/19q codeletion, and initial RT were associated with longer PFS and OS rates. A clear improvement in progression-free and overall survival was observed for RT and combined CT/RT in compared with CT only. Postoperative RT appears to improve survival for entire group thus total removal and 1p/19q codeletion may not be sufficient criteria to omit RT as a treatment option. These results suggest that RT should continue to be offered as the standard treatment option. Taken together, treatment pattern for oligodendroglial tumors changed significantly across the study period in Korea. In particular, TMZ has replaced PCV, and the use of molecular markers as well as RT alone has increased, but a optimal therapeutic option remains to be defined though the prospective randomized studies.

OBJECTIVES: High-dose methotrexate chemotherapy (HD-MTX) is the mainstay in treatment of primary CNS lymphoma (PCNSL) and has been known to have acute or late toxicity on skin, gastrointestinal mucosa, liver, kidneys, and bone marrow. However, hyperacute adverse events (HADE), which occurred within one hour of HD-MTX administration, are rarely known in PCNSL patients. We report our HADE experiences with 9 consecutive cases. METHODS: Of 51 PCNSL patients, 38 immunocompetent adult PCNSL patients treated with HD-MTX at Seoul St. Mary's Hospital, The Catholic University of Korea between 2004 and 2015 were investigated. Our HD-MTX monotherapy regimen consists of induction period (8 g/m2 on day 1, 10, and 20 for 3 cycles) and maintenance period (3.5 g/m2, every 4 weeks for 3 cycles and then every 3 months for 3 cycles). Medical records were reviewed for each of the HADE events, retrospectively. RESULTS: Of 38 patients who received HD-MTX of 247 cumulative cycles, 9 patients (23.7%; 4 men and 5 women) presented 13 HADE. Median age of the patients was 58 years (range 47 to 64 years) at the time of the event. HADE developed during the maintenance period in 5 patients, at the early induction period in 1 patient and at the rechallenging period for recurrence in 3 patients. HADE symptoms were variable; most commonly skin rashes in 12 events (92.3%), abdominal pain in 2 events (15.4%), and most severely hypotension in 1 event (7.7%). HD-MTX monotherapy was discontinued in 4 patients, continued with corticosteroid premedication and symptomatic application of antihistamine with or without MTX dose modification in 5 patients, and completed in 2 patients. CONCLUSION: Although HD-MTX appears to be a relatively safe medication, greater awareness of possible HADE in HD-MTX chemotherapy is needed for its prevention, early diagnosis and management. Studies to clarify its mechanism should be warranted.