bluuebunny/crossref_metadata_2025 huggingface dataset:
OS3.3 Development of an EORTC questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumours: phase I-III
Authors: Oort Q , Dirven L , Boele F , Grant R , Sato H , Talacchi A , Young T , Reijneveld J C , Taphoorn M J B
Published: September 2019

BACKGROUND

In brain tumour patients, impairments in every day functioning can impact quality of life, and are therefore an important outcome in both clinical trials and practice. One way to measure every day functioning is with an activities of daily living (ADL) questionnaire. Instrumental ADL (IADL) are the cognitively more complex activities, that are essential to function autonomously within society. Cognitive decline may therefore negatively impact IADL, making these activities particularly relevant to brain tumour patients. The aim of this study is to develop a reliable and valid questionnaire to measure IADL in primary malignant and metastatic brain tumour patients.

MATERIAL AND METHODS

The questionnaire development study followed the standard European Organisation for Research and Treatment of Cancer (EORTC) four phase methodology: (I) generation of activities list, (II) construction of item list, (III) pre-testing, and (IV) field testing. This report covers phases I-III. To ensure cross-cultural validity, participants were recruited from different countries (The Netherlands, United Kingdom, Italy, Austria and Japan). In phase I, potential activities were identified based on a literature review and in-depth interviews with patients, proxies and healthcare professionals. In phase II, activities were turned into items, and translated into all required languages by the EORTC Translation Unit. In phase III, the item list was pre-tested in patient-proxy dyads. In accordance with predetermined decision rules to reduce items, final items were selected, and preliminary psychometric properties (i.e. factor structure, validity, reliability) were assessed.

RESULTS

Phase I (N=44 dyads) resulted in 59 IADL activities which were converted into 59 items in phase II. In phase III, N=85 dyads completed and reviewed this item list. The item list was subsequently reduced to 32 items. An exploratory factor analysis indicated several items measuring similar underlying constructs (e.g. domestic life and using computer/smartphone) showing acceptable to good (α≥0.7) internal consistency (range α=0.69–0.89). Seven items were less related to these underlying constructs (e.g. work or managing your own medication), and therefore single items. Construct validity, measured with known-group comparisons analyses between cognitively impaired and unimpaired patients, showed significant differences in scores between the two groups on some scales and several single items.

CONCLUSION

The currently developed EORTC IADL-BN32 questionnaire can be a valuable asset in assessing IADL functioning in brain tumour patients, but further validation in phase IV is required and is planned.
OS3.5 Prescription medications in glioma patients and the prevalence of depression, anxiety and subjective cognitive impairment
Authors: van der Meer P B , Taphoorn M J B , van den Bent M J , Dirven L , Koekkoek J
Published: September 2019

BACKGROUND

Several medications prescribed for the management of symptoms in glioma patients, such as antiepileptic drugs and corticosteroids, have been associated with depression, anxiety and cognitive impairment in glioma patients. However, no previous study has incorporated all prescription medications instead of only one class of medications. The aim of this observational study was to assess the prevalence of depression, anxiety and subjective cognitive impairment associated with prescription medications, that have a potential for such adverse drug effects, in glioma patients.

MATERIAL AND METHODS

Use of prescription medications with a >1% risk of potential depressive, anxiety or cognitive adverse effects was defined as a categorical variable (0, 1 or ≥2), separately for each adverse drug effect. Depression and anxiety were measured with the Hospital Anxiety and Depression Scale, while subjective cognitive impairment was measured with the Medical Outcomes Study-Cognitive Functioning Scale. Hierarchical multivariable logistic regression analyses were performed for each outcome separately. Besides use of medications with a >1% risk of adverse effects (depression, anxiety or cognitive adverse effects, depending on the outcome analysed), other confounding variables such as seizure severity and Karnofsky Performance Status score were included.

RESULTS

A total of 272 grade II-IV glioma patients were included in the study. Prevalence of depression increased significantly from 9% for patients taking 0 medications with >1% risk of depressive adverse effects, to 18% taking 1 medication and 29% (adjusted Odds Ratio [aOR]=3.3 [95% Confidence Interval {CI}=1.3–8.4]) taking ≥2 medications. Prevalence of subjective cognitive impairment also increased significantly, from 14% for patients using 0 medications with a >1% risk of cognitive adverse effects to 25% using 1 and 29% using ≥2 medications, but association was not independent (aOR=2.1 [95%CI=0.8–5.6]). While prevalence of anxiety increased from 18% for patients using 0 medications with >1% risk of anxiety adverse effects to 25% using 1 and 33% (aOR=1.7 [95%CI=0.7–4.1]) using ≥2 medications, this was not significant.

CONCLUSION

Higher number of medications with depressive or cognitive adverse effects used by a glioma patient corresponds with a higher prevalence of depression and subjective cognitive impairment. However, after adjustment of potential confounders the association is only independent for depression.
OS3.6 Prediagnostic symptoms and signs of adult glioma: the patients’ view
Authors: Peeters M C M , Dirven L , Koekkoek J A F , Gortmaker E G , Fritz L , Vos M J , Taphoorn M J B
Published: September 2019

BACKGROUND

Little is known about the symptoms and signs glioma patients experience in the year before diagnosis, either or not resulting in health care usage. The objective of this study was to determine the incidence of several symptoms and signs glioma patients experienced in the year prior to diagnosis, as well as visits to a general practitioner (GP) related to these issues.

MATERIAL AND METHODS

This was a cross-sectional study, including adults diagnosed with a glioma <12 months ago. Patients were asked to complete a 30-item study-specific questionnaire, if possible with input of a proxy, focusing on symptoms and signs they experienced in the 12 months before diagnosis. For each indicated symptom/sign, patients were asked whether they consulted the GP for this issue. In addition, the presence of comorbidity and other chronic complaints were assessed, as well as consulted health care professionals (HCPs) in the year prior to diagnosis. The statistical analyses were corrected for multiple testing.

RESULTS

Between July 2016 and March 2019, 58 patients completed the questionnaires, 54 (93%) with input of a proxy. Forty-one (72%) patients were men, with a median age of 60 years (range 43–78), and the median time since diagnosis was 4 months (range 1–12). Forty (69%) patients had a comorbidity or chronic complaint, and the median number of consulted HCPs was 2 (range 0–8). The median number of symptoms/signs experienced in the year before diagnosis was 8 (range 2–19) in low-grade and 5 (range 0–24) in high-grade glioma (p=0.258). The five most frequently mentioned problems were fatigue (34/58, 59%), mental tiredness (28/58, 48%), sleeping disorder (23/58, 40%), headache (22/58, 38%) and stress (20/58, 34%), with no differences between low- and high grade glioma. Twenty-five (43%) patients had visited the GP with at least one issue. We found that patients who did consult their GP reported significantly more often muscle weakness (11 vs 3, p=0.002), paralysis in for example a hand or leg (10 vs 3, p=0.006), or a change in consciousness (9 vs 3, p=0.013) compared to those that did not consult the GP. However, they did not differ with respect to the number of symptoms (median 7 vs 5), comorbidities and chronic complaints (median 1 vs 1), or overall health care usage (median 3 vs 2).

CONCLUSION

Glioma patients experience a range of problems in the year prior to diagnosis, but patients who consult the GP report significantly more often neurological problems.
OS6.2 Loss of CYP46A1 directs altered cholesterol homeostasis and opens therapeutic opportunities for glioblastoma
Authors: Han M , Wang S , Li X , Wang J , Bjerkvig R
Published: September 2019

BACKGROUND

Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM.

MATERIAL AND METHODS

Molecular and clinical data was obtained from publicly genomic databases. Immunohistochemistry was applied to assess protein levels of CYP46A1 in primary GBM samples. Lentiviral constructs expressing CYP46A1 were transduced into LN229, LN18 and primary GBM GSCs for functional assays carried out in vitro and in vivo in an orthotopic xenograft model. RNA-seq was performed to identify downstream targets of 24OHC.

RESULTS

CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. Reduced CYP46A1 expression was associated with increasing tumour grade and poor prognosis in GBM patients. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. Treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz (EFV), an activator of CYP46A1 with BBB penetration, inhibited GBM growth in vivo.

CONCLUSION

Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.
OS8.3 Gamma knife radiosurgery for large meningiomas: 10 years of experience
Authors: Abdel Karim K , El-Shehaby A , Reda W , Emad Eldin R , Nabeel A , Tawadros S
Published: September 2019

BACKGROUND

The use of gamma knife radiosurgery for the treatment of intracranial meningiomas has been established as an effective and safe treatment modality. Larger meningiomas are typically managed by surgery followed by radiosurgery. For situations where patients are not amenable to surgery fractionated stereotactic radiotherapy is the traditionally suggested treatment. Treatment of large meningiomas (usually defined as >10 cc) by stereotactic radiosurgery has been investigated in some recent reports, either by single-session, volume-staged or hypofractionation technique. However, there are no long-term results. The purpose of this study is to assess the long-term efficacy and safety of gamma knife radiosurgery for large (15 cc or more) intracranial meningiomas.

MATERIAL AND METHODS

In this study we included 80 patients with large meningiomas (³ 15 cc) who were followed up for more than 5 years. Non-benign meningiomas were excluded. Also, meningiomatosis and NF2 patients were not included. There were 18 males (22.5%) and 62 females (77.5%). The mean age was 46 years (20–83 years). Twenty-six patients (32.5%) had previous surgery. Tumor were supratentorial in 14 (17.5%) patients and skull base in 66 (82.5%) patients. The mean tumor volume was 22.3 cc (15–57.3 cc). The mean prescription dose was 11 Gy (9–12 Gy).

RESULTS

The mean follow up period was 8.4 years (5–17 years). The tumor shrank in 43 patients (54%), was stable in 30 patients (37%) and progressed in 7 patients (8%). The tumor control rate was 91%. Adverse radiation effects were observed in 11 patients (14%) but only 5 (6.5%) were symptomatic. These were temporary in all cases.

CONCLUSION

Gamma knife radiosurgery provides an effective and safe treatment option for large meningiomas. Low margin dose appears to be sufficient for tumor control. Surgery remains the first option in these cases.
OS8.4 Impact of brain invasion assessment on outcome in intracranial grade II meningiomas
Authors: Picart T , Dumot C , Ducray F , Durand A , Guyotat J , Berhouma M , Meyronet D
Published: September 2019

BACKGROUND

Brain invasion has already been identified as an independent criterion of meningioma recurrence by Jääskaläinen’s in 1986. While it was only suggested that meningiomas harbouring brain invasion could be staged as grade II in the 2007 WHO Classification of Tumours of the Central Nervous System, brain invasion was clearly listed as a grade II atypical meningioma criterion for the first time in the 2016 version. Since 2007, brain invasion has been carefully screened during the histopathological characterisation of meningiomas in our centre thanks to specific training of the neuropathology department staff. Furthermore, neurosurgeons are asked to provide well-preserved and grossly orientable tumours borders whenever possible. The aim of the present study was to compare the characteristics of patients diagnosed with grade II meningiomas before and after this change of practices.

MATERIAL AND METHODS

We retrospectively reviewed the characteristics of 125 patients with grade II meningiomas diagnosed between 2011 and 2014 (group A) and compared them to those of 166 patients with grade II meningiomas diagnosed between 1998 and 2005 (group B).

RESULTS

Tumour location and socio-demographic parameters were comparable in group A and B with a median age of 62 years in both groups (p=0.18). There were more de novo meningiomas in group A (84% vs 68.7%, p=0.004). Brain invasion was found in 59% in group A and 9% in group B (p=0.00001) while median Ki67 labelling was of 8.4% in group A and 10.5% in group B (p=0.04). Consistently, tumour borders were irregular in 52% in group A and 29% in group B (p=0.0002). Progression free survival was similar in the two groups (65 vs 66 months, p=0.92) but grade progression was more frequently observed in group B (18.9% vs 0%, p=0.006). In group A, meningiomas that were classified as grade II exclusively based on brain infiltration (n=33, group A-bi) had a similar progression rate compared to meningiomas with other criteria of atypia (27% vs 25%, p=0.98) and a similar time to progression (32 vs 32 months, p=0.74). The median time to progression of group A-bi meningiomas was also comparable to that of the other 258 pooled meningiomas (32 vs 40 months, p=0.40).

CONCLUSION

In accordance with the 2016 WHO Classification of Tumours of the Central Nervous System, the outcome of meningiomas defined as atypical solely based on brain infiltration seems to be comparable to that of meningiomas with other criteria of atypia. Appropriate coordination between neurosurgeons and neuropathologists is mandatory to optimally assess this criterion.
OS10.1 Survival analysis of IDH wildtype astrocytomas with molecular features of glioblastoma, WHO grade IV
Authors: Tesileanu C M S , Koekkoek J A F , Dirven L , Dubbink H J , Kros J M , van Duinen S G , Smits M , French P J , Taphoorn M J B , van den Bent M J
Published: September 2019

BACKGROUND

Recently, isocitrate dehydrogenase wildtype (IDHwt) lower grade gliomas (LGGs) that have a telomerase reverse transcriptase (TERT) promoter mutation and/or gain of chromosome 7 combined with loss of chromosome 10 and/or epidermal growth factor receptor amplification have been reclassified as IDHwt astrocytomas with molecular features of glioblastoma, WHO grade IV (‘astrocytomas IDHwt, WHO IV’). Survival of these tumors meeting the criteria of these tumors is less well studied. The objective of this study is to compare the overall survival (OS) between the IDHwt astrocytomas, WHO IV and histological glioblastomas (GBMs).

MATERIAL AND METHODS

In this retrospective multicenter cohort study, all adult patients with a newly diagnosed IDHwt LGG (histologically WHO grade II or III) and with molecular data available were selected from the Erasmus MC and the LUMC from October 2002 to April 2019. LGG patients showing contrast enhancement with necrosis on the MRI at the time of histological diagnosis were excluded. Molecular data were determined using a diagnostic NGS panel. A historical cohort of 195 patients with IDHwt GBMs with molecular data available was used to compare OS. OS was measured from the date of the first diagnostic MR scan.

RESULTS

79 IDHwt LGG patients were identified of which 62 patients had molecular features of glioblastoma (‘astrocytomas IDHwt, WHO IV’), 11 patients did not have these molecular features (‘astrocytomas IDHwt, WHO II & III’). In the remaining 6 patients the molecular data were not conclusive (astrocytomas IDHwt, WHO NOS). Patients with astrocytomas IDHwt, WHO IV were slightly older at diagnosis (median age = 57 years) than patients with GBMs IDHwt in the reference cohort or astrocytomas IDHwt, WHO II & III (respectively: median age 55 years, p=0.032 and 47 years, p=0.035). The relatively young age of our GBM IDHwt cohort reflects more extensive molecular testing in younger patients and histologically lower grade tumors. The median OS of astrocytomas IDHwt, WHO IV (23.8 months) was similar to the median OS of GBMs (19.2 months, log-rank test p=0.37). The median OS in 19 patients with only TERT promoter mutations was 16.8 months, similar to GBMs (p=0.94).

CONCLUSION

There is no statistically significant difference between the OS of IDHwt astrocytomas with molecular features of glioblastoma and the OS of true glioblastomas. Grade II and III IDHwt astrocytoma with molecular features of glioblastoma should be designated WHO grade IV. The presence of TERT promoter mutations alone in this histological context also qualifies for this designation.
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

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

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

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

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

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

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

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

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

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.
P07.02 Enhanced glycolysis in glioblastomas is associated with tumor cells migration
Authors: Ndiaye M , Rébé C , Ilie A , Ménégaut L , Pilot T , Ghiringhelli F
Published: September 2019

BACKGROUND

Glioblastoma is the most common primary brain tumor. Its prognosis remains poor even with the standard treatment - the Stupp protocol.The classic Warburg effect in cancers leads to increased glycolysis which causes acidification of the tumor environment. This phenomenon may favor migration of tumor cells as already reported in pancreatic ductal adenocarcinoma. We therefore hypothesized that enhanced glycolysis in glioblastomas could favor the tumor cell migration.

MATERIAL AND METHODS

We measured glycolysis by the extracellular acidification rate (ECAR) of several human glioblastomas cell lines (LN229, LN18, T98-G, U87-MG, U373-MG, U118-MG) with the Seahorse Analyzer. To confirm these results, we also measured the intracellular cAMP rates using the Cayman’s Elisa kit and we analyzed by RT-PCR the expression of the main genes coding for enzymes involved in glycolysis in these glioblastomas cell lines. Cell migration was measured with a scratch wound healing assay during 24 hours.

RESULTS

U118-MG was the glioblastoma cell line with the highest glycolysis rate, the highest production of cAMP and showed a strong expression of glycolysis-associated genes. LN229 was the glioblastoma cell line with the less important glycolysis rate, the lower production of cAMP and showed a weaker expression of glycolysis-associated genes. According to the scratch wound healing assay, U118-MG cells showed a more important migration than LN229 cells at 24 hours.

CONCLUSION

Glycolysis may be an attractive target to prevent effectively tumor cell migration in glioblastomas. Coupling the evaluation of glycolysis with histomolecular characterization of glioblastomas, could help to identify patients to whom adjuvant therapies that inhibit glycolysis such as fenofibrate could be proposed.
P09.02 Surgical treatment for intracranial meningiomas in elderly patients growing during follow-up study
Authors: Okuma M
Published: September 2019

BACKGROUND

In Japan in which life expectancy exceeds 85 years old, there are many elderly people who have sufficient healthy life even over 75 years of age and maintain social activities. With the increase in life expectancy and widespread use of magnetic resonance imaging (MRI), it is estimated that the number of asymptomatic meningioma diagnosed in elderly patients will increase. They are often followed up for the elderly, but they often become symptomatic as the tumor grows. Considering the inherent complications of the elderly and the patient’s life expectancy, it is often difficult to decide whether to operate. Here, we report the results of surgical treatment for intracranial meningiomas in elderly patients growing during follow-up study.

MATERIAL AND METHODS

Between January 2010 and December 2018, we treated 322 meningioma patients, including 18 patients older than 75 years old who had grown during follow-up. We performed a retrospective analysis of the 18 patients and measured Tumor doubling time (TDT) using CT scan or MRI image. We mainly examined the relationship between TDT and WHO classification, MIB-1 index, edema and calcification, intensity on MRI T2 weighted-imaging.

RESULTS

5 were male and 13 were female. There were 6 cases of skull base meningioma and 13 cases in which the tumor showed high intensity on the MRI T2 weighted-imaging. 4 cases showed intratumoral hemorrhage. 8 cases had edema. 11 cases were symptomatic meningiomas and 7 cases were asymptomatic meningiomas. There were 7 cases of WHO grade I meningioma and 11 cases of WHO grade II or III meningiomas. TDT was an average of 1.82 year (0.37–3.74). 9 patients have taken anticoagulant or antiplatelet medication.

CONCLUSION

In following up elderly meningioma patients, MRI should be performed at periodic intervals if the tumor showed high intensity on the MRI T2 weighted-imaging or had edema. In case of surgical treatment, we should pay attention to taking anticoagulant or antiplatelet medication, and treatment strategy is needed to avoid complications with sufficiently preoperative examination.
P09.03 Array-CGH analysis in meningiomas adds further information of biological behavior
Authors: Calatozzolo C , Rizzo A , Girgenti V , Saladino A , Patanè M , Di Meco F , Pollo B , Sciacca F L
Published: September 2019

BACKGROUND

Meningioma is the most common primary tumor of CNS, usually a benign tumor (grade I) successfully treated by surgical resection, while in the 25–30% of cases is a more aggressive neoplasm with high recurrence rate and poor prognosis (grade II-III). In the last years some studies tried to investigate the genomic profile of meningioma to find additional prognostic factors and potential therapeutic targets. Aim of our study was to use the array-CGH (aCGH) to investigate possible indicators of recurrence risk in meningiomas.

MATERIAL AND METHODS

We retrospectively selected two group of patients: 34 with meningioma WHO grade I (24 F, 10 M, median age at diagnosis 56 yrs) and 19 with meningioma WHO grade II (9 F, 10 M, median age 59 yrs), in order to compare cases recurrent and non-recurrent in each group. We also analyzed 5/18 recurrences WHO grade I and 10/11 WHO grade II. Genomic profiles were investigated by aCGH.

RESULTS

We observed an increase in number of genomic imbalances related to grading and in non-recurrent versus recurrent tumors. 9 WHO I meningiomas were without alterations. The mainly alterations observed were deletions and duplications, moreover we also identified chromothripsis of a single chromosome in 2/18 WHO I recurrent and 2/8 WHO II non recurrent meningiomas, and chromothripsis of multiple chromosomes in 5/11 WHO II recurrent meningiomas. As well we detected the presence of mosaicism, mainly in WHO I recurrent and in grade II meningiomas. In 7/14 WHO I meningiomas we found differences in genomic profile analyzing two samples obtained from two distinct areas. 6/15 recurrences showed the same alterations of the primary tumor. We didn’t detected an association between alteration of 1p and 22q and recurrence risk, as previously suggested, as those were the most diffused imbalances in all meningiomas.

CONCLUSION

In our patients we found a difference in genomic imbalances between grade I and grade II meningiomas, but we also identified additional details of the complexity of alterations in meningioma with the detection of chromothripsis and mosaicism. This latter aspect is a new issue and suggests the presence of more aggressive cell clones that could be predictive of recurrence in grade I meningioma. Moreover, we observed a spatial heterogeneity in half of grade I meningioma analyzed. Our preliminary results suggest that the aCGH, a technique routinely used in many laboratories, could be used to better stratify meningioma patients.