bluuebunny/crossref_metadata_2025_split huggingface dataset:
OS10.3 Primary therapy and survival in over 70-year-old patients with primary central nervous system lymphoma: a contemporary, nationwide, population-based study in the Netherlands
Authors: van der Meulen M , Bromberg J E C , Visser O , Doorduijn J K , Dinmohamed A G 
Published: September 2019

Abstract

BACKGROUND
Elderly patients with primary central nervous system lymphoma (PCNSL) have a poor prognosis. In this contemporary, nationwide, population-based study, we assessed the contribution of primary therapy on overall survival (OS) among elderly PCNSL patients in the Netherlands.

METHODS
All patients aged ≥ 70 years with cytologically and/or histologically proven PCNSL diagnosed between 2014–2016 were selected from the nationwide Netherlands Cancer Registry. Univariable analysis of OS was performed with the log-rank test. Multivariable Cox regression was applied to assess factors associated with OS, with adjustment for age (71–74, 75–79 and ≥80 years), sex, prior malignancy, primary therapy (no therapy, radiotherapy [RT] only, chemotherapy [CT]), and rituximab treatment.

RESULTS
Overall, 109 patients were registered; 39%, 39%, and 22% were aged 71–74, 75–79 and ≥80 years, respectively. Most patients received CT (45%), followed by no therapy (33%) and RT only (22%). With increasing age, the application of CT decreased (60%, 43%, and 24%), and RT only increased (10%, 26%, 26%) in the three age groups. CT consisted of methotrexate (MTX)-based or MTX only regimens in 98%. In patients treated with CT, Rituximab was added in 31%. During follow-up, 89 patients (82%) died. Median OS was 5.3 months (95% confidence interval [CI], 3.3–7.8), no difference was observed in median OS across the three age groups (6.8, 4.4, and 4.6 months, respectively; P=0.348). However, in the groups no therapy, RT only, and CT, median OS (95% CI) was 1.3 (1.0–2.0), 6.5 (4.4–12.5), and 20.3 (8.6–41.4) months (P<0.001), respectively. Moreover, 2 year OS (95%CI) was 49% (34–62) in patients treated with chemotherapy compared with 17% (5–34) in patients treated with RT. Median OS (95% CI) was 20.3 (8.6–41.4) in recipients of MTX-based regimens and 5.0 (2.4-not reached) months in recipients MTX only (P=0.185). In multivariable analysis, treatment with CT or RT was the only factor associated with OS: age group and the addition of Rituximab were not associated with OS.

CONCLUSION
In this contemporary population-based study, OS remained poor among patients with PCNSL aged over 70 years, irrespective of age group. Clinical condition likely influenced therapy choices but in those judged fit enough to receive CT, almost 50% survived 2 years. Therefore, future prospective intervention studies are warranted to assess which group of elderly patients benefit from CT or less intensive approaches.
OS12.6 Intracranial GBM PDX Mutations Induced by Temozolomide Treatment
Authors: James C , Horbinski C , Bartom E , Burdett K , Scholtens D , Ahmed A 
Published: September 2019

Abstract

BACKGROUND
Temozolomide (TMZ) is routinely used in the post-surgical treatment of patients with newly diagnosed glioblastoma (GBM). Nearly all GBM recur following TMZ treatment, and there is an increasing body of data that detail TMZ-associated mutations in recurrent GBM. In vivo models of recurrent GBM are scarce in comparison to models of treatment-naïve GBM.

MATERIAL AND METHODS
Mice with intracranial treatment naïve GBM patient derived xenograft (PDX) were treated with radiotherapy (RT) only, TMZ only, or RT + TMZ. Tumors were monitored for recovery from treatment by bioluminescence imaging (BLI), and upon animal subject decline due to growing tumor, subjects were euthanized, with viable intracranial tumor dissected and used to establish subcutaneous tumor in new animal hosts that received no treatment. Subcutaneous tumors were sequentially passaged through two additional animal hosts. DNA was extracted from third passage subcutaneous tumors and subjected to full exome sequencing. PDX exome sequence data were examined for genes with nonsynonymous frameshift and nonsense variants (mutations).

RESULTS
Exome sequence analysis showed striking differences between PDX receiving RT only vs. TMZ with or without RT. Most notable is the substantially greater incidence of G-C to A-T transition mutations in TMZ-treated PDX, which are a signature of TMZ treatment. All TMZ-treated PDX also showed substantially more genes being mutated than PDX receiving RT only: one cycle RT only = 88; one cycle TMZ only = 339; one cycle of concurrent RT + TMZ = 531; one cycle of concurrent RT + TMZ followed by two additional cycles of TMZ only = 1502. The PDX subjected to multiple cycles of TMZ treatment prior to establishment as a subcutaneous tumor has shown stable resistance to TMZ treatment in subsequent experiments. Importantly, TMZ-treated PDX had mutations in LTBP4, MSH6, and PREX1 genes that are enriched in patient GBM following recurrence after initial TMZ treatment (Nat Genet 2016;48:768–76); these genes were not mutated in PDX receiving RT only.

CONCLUSION
Our study results support the following: 1) Intracranial GBM PDX treated with TMZ develop a global genomic treatment signature, as well as specific mutations that are observed in recurrent patient GBMs; 2) Mutations detected in TMZ-treated intracranial tumors are stable, persisting after repeated subcutaneous passages without further treatment; 3) Paired naïve and TMZ-treated GBM PDX will facilitate studies aimed at increasing our understanding of TMZ resistance, and help identify new therapies for more effective treatment of recurrent GBM.
P01.01 The role of exosome miRNA between tumor cells and microglias during the progression of medulloblastoma
Authors: Chang Q , Zhu L , Li N 
Published: September 2019

Abstract

BACKGROUND
Medulloblastoma (MB) is the most common malignant paediatric brain tumor. Recent studies show that M2 cells were relative more abundant in Shh subtype of MBs compared with other three subtypes. It’s known that M2 cells have close relationship with many tumors’ progression. But if they play any role in the progression of Shh subtype of MB is not yet clear. Many studies demonstrate that exosomes carring miRNAs have close relationship with tumor invasion. The aim of present study is to clarify the role of exosome miRNA between tumor cells and microglias during the progression of Shh subtype of medulloblastoma.

MATERIAL AND METHODS
Immunofluerescence staining using iNOS and Arg1, which is M1 and M2 specific marker, respectively, was performed in four subtypes of MBs. After coculture of exosomes extracted from Shh subtype of MB cell (DAOY) with microglia cell (BV2), Q-PCR and ELISA assay were done to evaluate the polarization status of the microglia. Transwell and scratch assay were then performed to detect the migration ability of DAOY cell after treatment of exosomes from polirized M2 cells. MiRNA sequencing by Ion Proton technology was then done to analyze the miRNAs expression level between Shh subtype and other subtype of MBs. Transformation assay was used to overexpress and inhibit the expression of these miRNAs respectively to further clarify the role of exosome miRNA in the polarization of BV2 cells.

RESULTS
M2 cells were observed more abundant than other three subtypes of tumors, supporting that M2 cells play some role in this subtype of MBs. Exosomes of DAOY cells can induce the polarization of M2 cells. The polarized M2 cells can improved the migration and invasion ability of DAOY cell. Dozens of miRNAs were identified with different expression level between Shh subtype of MBs and other subtype of MB cells. Among them, 4 miRNAs were reported to be related with polariztion of M2 in many other lesions. Three of the 4 miRNAs can induce the polarization of M2 in present study.

CONCLUSION
Our study demonstrated exosome miRNA play a critical role between tumor cells and microglias during the progression of Shh subtype of medulloblastoma.
P02.01 Analysis of Multimodal Intraoperative Monitoring During Intramedullary Spinal Ependymoma Surgery
Authors: Park J , Kim J , Shin M , Choi D 
Published: September 2019

Abstract

BACKGROUND
To evaluate the validity of intraoperative somatosensory-evoked potential (SSEP) and motor-evoked potential (MEP) monitoring according to two different warning criteria for 6 months after intramedullary spinal ependymoma (IMSE) surgery.

MATERIAL AND METHODS
To evaluate the validity of intraoperative somatosensory-evoked potential (SSEP) and motor-evoked potential (MEP) monitoring according to two different warning criteria for 6 months after intramedullary spinal ependymoma (IMSE) surgery.

RESULTS
The success rates of SSEP and MEP monitoring were 84.9% and 83.7%, respectively. There was one indeterminate case in SSEP and six in MEP. All-or-none criterion in SSEP and MEP monitoring showed higher specificity, PPV, and DOR than 50% decline criterion during 6 months. During the follow up, 37 of 38 extremities (97.4%) and 21 of 29 extremities (72.4%) were observed the improvement of sensory and motor deficit, respectively. Seven indeterminate cases also showed good clinical outcomes. However, most patients remained some degree of neurologic deficit.

CONCLUSION
Many false positive and false negative results of SSEP and MEP monitoring occurred immediately postoperative period. All-or-none criterion was more beneficial for IMSE surgery than 50% decline criterion. This trend was maintained until 6 months after surgery.
P03.12 Complete versus incomplete resection in newly diagnosed Glioblastoma: Impact on functional Outcome
Authors: Proescholdt M A , Haj A , Doenitz C , Schebesch K , Brawanski A 
Published: September 2019

Abstract

BACKGROUND
Surgical resection of (GBM) has three goals: Tissue acquision to establish a histological and molecular diagnosis, prolongation of survival and improvement of neurological impairment. Regarding survival gain, complete resection is superior to incomplete resection. However, no data are available, whether complete resection also has a higher impact on neurological improvement rates compared to incomplete resection. The goal of our study was to compare the reduction of focal neurological deficits and improvement of functional independency in newly diagnosed GBM patients receiving a complete vs. incomplete resection.

MATERIAL AND METHODS
A cohort of 299 patients (mean age 60.6 year; female/male ratio 124/175) were included. Neurological and functional independence status was measured by the medical research neurological performance status (NPS), the Karnofsky performance score (KPS) and the presence of seizures. Focal neurological impairment regarding hemiparesis, aphasia visual field (VFD) and cranial nerve deficits (CND) was recorded and semi - quantitatively rated pre- and postoperatively as well as at follow up. The extent of resection (EOR) was analyzed using early postoperative MRI scanning and was classified in either complete (CR), incomplete (IR) resection.

RESULTS
The complete and incomplete resection groups were balanced regarding gender, age, preoperative KPS, MGMT and IDH1 status. Median overall survival (OS) was 14.5 months, showing a significant benefit of complete resection (17.9 vs. 11.5; p = 0.0001). Impaired KPS was detected in 87.9%, epileptic seizures were displayed by 31.4% of all patients, the most frequent focal deficit was aphasia with 25.1%, followed by CND (20.1%) and hemiparesis (17.1%). KPS was improved in 45.6%, seizures were reduced in 91.5%, the highest improvement of focal deficit was achieved in CND (71.7%) the lowest in VFD (44.8%). Complete resection did achieve a higher improvement rate in hemiparesis (79.1% vs. 49.8%; p = 0.03) and seizure activity (97.7% vs. 86.3%; p = 0.04). In all other domains the improvement rates after complete resection were not significantly different to incomplete resection. Finally, complete resection did not show a higher rate of postsurgical worsening rate in any of the domains.

CONCLUSION
Complete resection is safe and does convey superior improvement rates of epileptic seizures and hemiparesis.
P03.13 Evaluation of PIK3CA mutational status in glioma molecular subgroups
Authors: Brito C , Azevedo A , Esteves S , Martins C , Mafra M , Roque L , Pojo M 
Published: September 2019

Abstract

BACKGROUND
Gliomas are the most common and lethal malignant tumors of central nervous system. In 2016, World Health Organization (WHO) classification included IDH mutations and 1p/19q codeletion as diagnostic criteria to define glioma entities. However, new biomarkers for diagnosis, prognosis and response to therapy are needed. In this context, PIK3CA mutations have been described as constitutive mutations, which highlights their relevance in gliomas. Here we clarified the clinical relevance of PIK3CA mutations according to the 2016 WHO classification, the potential impact on diagnosis, prognosis, response to therapy, as well as their correlation with EGFR amplification and PTEN deletion.

MATERIAL AND METHODS
A cohort of 444 adult diffuse glioma samples from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) was classified according to the 2016 WHO Classification. The mutational status of exon 9 and 20 of PIK3CA was evaluated in molecular subgroups of gliomas by Sanger sequencing. PTEN deletion and EGFR amplification were identified by Fluorescent in situ hybridization (FISH).

RESULTS
PIK3CA mutations showed a higher frequency in the subgroup of gliomas with IDH mutations and 1p/19q codeletion - oligodendrogliomas (10%). In Glioblastoma (GBM) IDH-mutant and IDH-wildtype these oncogenic mutations were observed in 9% and 3% of cases, respectively. Similar results were obtained using The Cancer Genome Atlas (TCGA) data, which was 8% and 2%, respectively. H1047R and E542K were the most frequent mutations identified in the glioma molecular subgroups. Importantly, we found 3 unreported pathogenic variants in exon 20 of PIK3CA (c.3112T>C, c.2988T>C, c.3040C>T) and one polymorphic variant (c.3210A>G). In addition, PIK3CA mutations, PTEN deletion and EGFR amplification were not mutually exclusive alterations in glioma molecular subgroups. For the first time in gliomas, it was identified the rs45455192 polymorphism at a frequency of 16% in astrocytomas IDH-mutant, 24% in oligodendrogliomas and 18% in both molecular subgroups of GBM, although this polymorphism did not have prognostic value. The analysis of PIK3CA mutations in glioma recurrences showed that these mutations are maintained during glioma progression.

CONCLUSION
In two independent cohorts (IPOLFG and TCGA), it was obtained similar frequencies of PIK3CA mutations in GBM molecular subgroups. In addition, these mutations are more relevant in less aggressive gliomas (IDH-mutated and 1p/19q codeleted). These alterations seem to be important in tumor maintenance and progression, which makes this gene a potential therapeutic target. In the future, we will investigate the effect of the in vitro pharmacological inhibition of PIK3CA in GBM mutant cell lines.
P04.07 Correlation of 18F-fluorethyl-L-tyrosine (18F-FET) uptake in positron emission tomography (PET) and MRI growth rate in low-grade glioma
Authors: Mueller M , Kamp M , Sabel M , Stoffels G , Galldiks N , Langen K , Rapp M 
Published: September 2019

Abstract

BACKGROUND
Low-grade gliomas (LGGs, WHO grade II) are a heterogeneous group of tumors of the central nervous system with diverse behavior in histopathology, genetics and growth patterns. Therefore, different therapeutic strategies are discussed ranging from watchful waiting to radical resection and adjuvant radio-/chemotherapy. For a better evaluation of tumor progression or malignant transformation, the O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) uptake in PET or the tumor growth rate assessed on MRI are used depending on the neurooncological center. Here, we correlated both methods.

MATERIAL AND METHODS
Inclusion criteria for this retrospective study were (1) newly diagnosed and neuropathologically confirmed low-grade glioma; (2) at least two MRIs at initial diagnosis and follow-up for calculation of the tumor growth rate (using IDS7 by Sectra AB, Sweden, 2018); (3) and an additional preoperative 18F-FET PET scan.

RESULTS
From 2008 to 2018, 34 patients were identified (mean age 39.7 years; 68% diffuse astrocytoma). The mean tumor growth rate on MRI was 0.091 cm3/d. The average mean 18F-FET uptake was 1.42; the average maximum 18F-FET uptake was 2.18. The Pearson correlation coefficient between the tumor growth rate and the mean and maximum 18F-FET uptake was r=0.19, and r=0.10. In the group of diffuse astrocytomas, the mean growth rate in tumors with a mean 18F-FET uptake of >1.5 was significantly higher than the mean growth rate of those with a mean 18F-FET uptake of ≤1.5 (p<0.1).

CONCLUSION
Data suggest that astrocytic LGGs with increased 18F-FET uptake may show a more aggressive behaviour, with a potentially higher risk for an earlier tumor progression or malignant transformation. For further elucidation of a correlation between the tumor growth rate and the 18F-FET uptake, larger prospective studies are needed. In the future, the combination of both methods in the management of low-grade gliomas could help to detect tumor progression as well as tumor malignization more precisely.
P04.19 Analysis of tumor immune microenvironment and immune checkpoint modulators across infantile and pediatric pilocytic astrocytomas to elucidate the role of immunotherapy in these tumors
Authors: Kaur K , Suri V , Sharma M C , Garg A , Suri A , Sarkar C 
Published: September 2019

Abstract

BACKGROUND
Pilocytic astrocytomas are the most common central nervous system tumors in pediatric age-group. Although grade I, some of the cases show recurrence and progression, and few might not be amenable to surgery due to location or size, and hence have a less favorable prognosis. Drugs blocking immune check-point interactions such as those including programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now in clinical use for certain tumors. We performed this study to understand the potential candidature of pilocytic astrocytomas in infants and children for immunotherapy by analyzing the expression of immune checkpoint proteins and immune infiltrate, and correlating with clinical details, wherever possible.

MATERIALS AND METHODS
Cases with adequate tissue (2010–2017) diagnosed in pediatric age-group (<18 years) were retreived from the archives of Department of Pathology, AIIMS, New Delhi. Immunohistochemistry for PD-L1 (SP263, Ventana), CTLA-4, CD3, CD8, CD4 and CD68 was performed. Quantification of cytotoxic lymphocytes was done using digital imaging in the core of the tumor.

RESULTS
A total of 50 pilocytic astrocytomas were included, 14 of them were <3 years (infants), while 36 were of pediatric age-group (3–18 years). Overall, male preponderance was noted. Cerebellum was the most common location, followed by 4th venrticle, optic pathway, hypothalamus, cerebrum and thalamus. Almost all CD3 lymphocytes were cytotoxic T-lymphocyes (CD8 positive, CTLs). Helper T-lymphocyte infiltration was not seen. Median CTL density/mm3 was 13/mm3(Range:1–85/mm3). CTLA-4 was positive in 4 cases, positivity ranged from 1–4 cells/lpf. PD-L1 was found to be positive in 7 cases, and the positivity ranged from 1+ to 2+ in 1 to 5% of tumor cells. A median TAM (tumor associated macrophages) density of 44/hpf (range: 1–98/hpf) was noted. There was no correlation of CTL density with PD-L1 or CTLA-4 expression, and neither with TAM density. On correlation with clinical parameters, a higher density of CTLs and TAMs was noted in infants, and a higher proportion of cases revealed PD-L1 positivity, though not statistically significant. There was no correlation of TILs or TAMs with the tumor location.

CONCLUSION
Immune check point blockade using PD-(L)1 or CTLA4 inhibitors may not be a potential therapeutic option for unresectable or recurrent pilocytic astrocytomas, as low positivity rate as well as extremely low percentage of tumor/ immune cells found to be positive. However, alternate forms of immunotherapy might be helpful as most of the cases showed immune infiltrates and a high density of tumor-associated macrophages (TAMs). Large scale studies with larger numbers and longer follow-up periods including in-vitro and clinical studies are warranted for decoding the tumor immunogram.
P05.04 Phase 2 open-label study of maintenance treatment with ibrutinib following first line methotrexate-based immuno-chemotherapy in elderly patients with primary CNS lymphoma (PCNSL)
Authors: Bairey O , Amiel A , Yust-Katz S , Gurion R , Siegal T 
Published: September 2019

Abstract

BACKGROUND
Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment proved to prolong PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas.

MATERIAL AND METHODS
Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate-based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and maintenance ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months.

RESULTS
Of the 14 patients screened for the study 2 were excluded due to relapse while on screening. 12 patients have been enrolled with a median age of 74 (61–80) years. The median interval between diagnosis of PCNSL and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months and she is still alive after 24 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed.

CONCLUSION
Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-Methotrexate based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.