bluuebunny/crossref_metadata_2025_split huggingface dataset:
P14.69 Evaluation of electric field intensity delivered by Tumor-Treating Fields therapy to PET-defined metabolic volumes in recurrent glioblastomas
Authors: Mittal S , John F , Naveh A , Bomzon Z , Barger G R , Juhasz C 
Published: September 2019

Abstract

BACKGROUND
Tumor-Treating Fields (TTFields) therapy is a clinical treatment option for patients with newly-diagnosed and recurrent glioblastomas. Electric field intensities (EFIs) delivered to the tumor mass may affect treatment responses. In this study, we used the patients’ neuroimaging data to create realistic head models and evaluate: (i) the magnitude of EFIs delivered to the tumor mass; (ii) factors affecting the EFI values; and (iii) factors affecting treatment responses as assessed by amino acid PET.

MATERIAL AND METHODS
Fourteen recurrent glioblastomas in 9 patients were evaluated with α-[11C]-methyl-L-tryptophan (AMT)-PET before and up to 3 months after TTFields therapy (mean follow-up: 2.3 months). Individual MRI and CT scans were used to create patient-specific realistic head models and simulate TTFields delivery to the tumors. For each direction of treatment (antero-posterior, left-right), two 9-disk transducer arrays were simulated using disks placed according to the patients’ NovoTAL System™ based treatment plan. To generate TTFields, an alternating voltage difference (200V peak-to-peak, 200 kHz) was imposed on the outer surfaces of the disks. The simulations were performed using the Sim4Life V3.0 (ZMT-Zurich) quasi-electrostatic solver. The field intensities were normalized to simulate 2A peak-to-peak current supplied by the device. 3D EFI maps were created and fused with the pre- and post-TTFields PET images to measure EFIs delivered to the PET-defined metabolic tumor volume. Interval changes of static AMT uptake and kinetic PET variables were also evaluated.

RESULTS
The mean EFI delivered to the tumors varied between 1.34–2.43 V/cm (mean: 1.86 V/cm). Fronto-parietal tumors received higher mean EFI than temporal lobe tumors (p=0.05). Most tumors showed decreasing (n=9) or stable (n=4) AMT uptake on follow-up PET imaging after TTFields therapy. Higher EFIs delivered to the tumors (r=-0.56, p=0.04) and concomitant bevacizumab treatment (n=7, p=0.01) were associated with a greater PET response. On tracer kinetic analysis, the AMT uptake responses correlated with transport rate changes (p=0.04).

CONCLUSION
TTFields treatment of recurrent glioblastomas delivers variable EFIs to the metabolic tumor volume. Treatment responses on PET are driven by decreased amino acid transport rates, whose magnitude is associated with higher EFIs delivered to the tumor mass and also with concomitant antiangiogenic treatment in those with combined therapy. (The cost of the PET scans was supported by a grant from NovoCure Ltd., Haifa, Israel)
P14.70 Systemic therapy for brain metastases in elderly patients with lung cancer: A systematic review
Authors: Nakasu Y , Mitsuya K , Nakasu S 
Published: September 2019

Abstract

BACKGROUND
Brain metastases (BM) account for the majority of intracranial malignant tumours in the elderly. Almost 50% of BM originate from lung cancer, particularly non-small cell lung cancer (NSCLC). The objective of this review is to summarize the involvement of elderly patients in emerging systemic therapies especially targeted therapies for the treatment of BM from NSCLC.

MATERIAL AND METHODS
PubMed database was searched from 2008 to December 2018. Randomized controlled trials and systematic reviews for BM from NSCLC treated with targeted therapy were included.

RESULTS
A total of 85 studies were evaluated for eligibility, and 23 publications met the eligibility criteria and were screened for inclusion. Of these, only two phase-III studies met all the criteria (Sperduto 2013, Yang 2017), and three other studies of subgroup analysis of trials were focused on BM (Schuler 2016, Gadgeel 2018, Camidge 2018). In the 23 papers, eligibility criteria for age were from 18 years to 75 years old or no upper limits. Actual mean or median ages ranged 51 to 64 years. Population of patients with active BM consisted none to 100% in each study. The two phase-III studies focused on treatment of BM, median ages were 63 and 57 years. The latter reported a TKI showed significantly longer intracranial PFS and no difference in HR was found in age groups older or younger than 60 years. In the three papers of subgroup analysis, response rate of BM or intracranial distant recurrence were examined. Median ages were 51 to 62 years, ranged from 18 to 86 years. However in these analytical efforts, no results were reported about age as an outcome factor.

CONCLUSION
Patients with active or treated BM have become included in randomized controlled trials of systemic pharmacotherapies. Elderly patients also have become included in trials. However, outcomes focused on BM are not clearly understood especially in elderly patients. We need prospective studies and assessment of targeted therapy for elderly patients with BM for better understanding of treatment strategies and options for those patients increasing in number.
P14.79 Randomized phase II trial of Tumor Treating Fields plus radiation therapy plus temozolomide compared to radiation therapy plus temozolomide in patients with newly diagnosed glioblastoma
Authors: Limon D , Bokstein F , Blumenthal D , Ben Harush C , Ram Z , Grossman R 
Published: September 2019

Abstract

BACKGROUND
In last decade, there were numerous attempts to improve the outcome of patients with glioblastoma (GBM), but even after maximal surgical resection, radiation therapy (RT) and temozolomide (TMZ), followed by maintenance TMZ for 6 months the median OS is 14.6 months. In the EF-14 Phase III trial, the addition of Tumor Treating Fields (TTFields) at 200 kHz to maintenance TMZ increased the median OS to 20.9 months, compared with 16.0 months with maintenance TMZ alone (HR, 0.63; 95% CI, 0.53–0.76; p<0.001). Based on these results, the currently accepted standard of care for newly diagnosed GBM (ndGBM) is surgical resection if safely feasible, followed by RT with concomitant TMZ, and then followed by maintenance TMZ in combination with TTFields. Preclinical investigations have shown a radio-sensitizing effect of TTFields on glioma cells, suggesting synergistic effects between TTFields and radiotherapy. In a pilot study of 10 patients with ndGBM, we demonstrated that there was no increased treatment-related toxicity when TTFields were given in combination with RT/TMZ. The only TTFields-related adverse event was skin toxicity below the arrays. Preliminary progression free survival (PFS) data was encouraging. Based on the results of the pilot study, we designed this prospective, randomized Phase II study to further investigate if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression.

MATERIAL AND METHODS
Following debulking surgery or biopsy, 60 adult patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy of at least 3 months will be randomized 1:1 to either a) RT with concomitant TMZ and TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ in combination with TTFields (experimental arm) up to 24 months; or b) RT with concomitant TMZ alone followed by maintenance TMZ in combination with TTFields (control arm). Exclusion criteria: patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or patients with an implanted electronic device. The primary endpoint is progression free survival at 12 months (PFS12). Treatment with TTFields will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. Grading and severity of all adverse events will be recorded using CTCAE V5.0. The sample size of 60 patients provides 80% power with a two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). It is forecasted to take 24 months to fully recruit. Follow-up will continue for >12 months from recruitment of the last patient.
P14.81 Importance of early spectral variations during a longitudinal 60-month follow-up MRI and 1H-MRS in 135 treated glioblastoma patients
Authors: Boussida S , Heintz A , Saidak Z , Lefranc M , Galmiche A , Chombar J , Peltier J , Chauffert B , Boone M , Constans J 
Published: September 2019

Abstract

BACKGROUND
To better understand glioblastomas tumor metabolism and metabolic responses to chemotherapy, radiotherapy and antiangiogenic treatments during a longitudinal 60-month follow-up MRI and 1H-MRS in 135 treated glioblastoma patients.

MATERIAL AND METHODS
135 patients all biopsied and treated by surgery and STUPP protocol underwent MRI (Sagittal T1, FLAIR, T2*, Diffusion, Perfusion, CoronalT2 and 3DT1 post-Gadolinium) and 1H-MRS (PRESS with multiple TEs: 35ms, 144ms and 288ms on a 6 to 12cm3 volume) exams on 1.5T and 3T GEMS. 92/135 patients underwent resection. MRS data were processed under jMRUI yielding amplitudes, areas under curves and ratios of tCho/tCr, tNAA/tCr, Lip+Lact/tCr, Lact/tCr, Glc/tCr, Glx/tCr and Gln/tCr. Statistical analysis of longitudinal MRI perfusion and spectroscopic data (every 2–3 months above 30 months and 6–9 months over).

RESULTS
Spectroscopic proﬁles and ratios improve under STUPP protocol and then worsen depending on the percentage of resection. Biopsied patients: a progressive decrease in ratios of tCho/tCr (0–24 months), Lact/tCr (0–18 months) and Glc/tCr (0–18 months) and Glx/tCr (0–12 months) and then increase at respectively 24, 18, 28 and18 months. Resected patients: a progressive decrease in ratios of tCho/tCr (0–9 months), Lact/tCr (0–15 months) and Glc/tCr (0–15 months) and Glx/tCr (0 and 18 months) and then increase at respectively 32, 20, 18 and 24 months. MRI Gadolinium enhancing tumor and necrosis volumes, Diffusion and FLAIR volumes changed less compared to spectroscopic profiles and ratios which do change more.

CONCLUSION
1H-MRS allows non-invasive follow-up of treated glioblastomas tumors. Despite inter-subjects variability, spectroscopic and metabolic changes often come well before clinical deterioration and sometimes before clinical improvement. Therefore, 1H-MRS could be more sensitive and could detect changes earlier than MRI and sometimes is predictive of survival and response to treatment. The analysis of spectral proﬁles of long survivors is interesting and could help to better understand tumor metabolism and therapeutic responses.
P14.88 Comparison of SNaPshot PCR and digital droplet PCR for the identification of TERT promoter in non-diagnostic biopsies from glioma patients
Authors: Poncet D , Picart T , Guyotat J , Jouanneau E , Joubert B , Vasiljevic A , Honnorat J , Meyronet D , Ducray F , Barritault M 
Published: September 2019

Abstract

BACKGROUND
We previously showed that TERT promotor (pTERT) mutations can be detected in a high proportion of non-diagnostic biopsies from glioma patients using SNaPshot PCR. The aim of the present study was to assess the diagnostic value of digital droplet PCR (ddPCR) in this setting.

MATERIAL AND METHODS
pTERT mutations were retrospectively assessed using SNaPshot PCR and ddPCR in the non-diagnostic biopsies of 14 adult patients who underwent an initial non-diagnostic needle biopsy that led to perform another biopsy that finally demonstrated a pTERT-mutant glioma.

RESULTS
Median age at diagnosis was 69 years and the median interval between the initial and final biopsy was 22 days. The initial biopsy consisted of unspecific infiltrating glial cells (n=10), hemorrhage, necrosis and/or fibrosis (n=4). Using SNaPshot PCR, the final biopsy found an IDH-WT pTERT-mutant glioma in 12 cases (glioblastoma n=12), an IDH-mutant pTERT-mutant oligodendroglioma in one case and an IDH-WT pTERT-WT glioblastoma in one case. Retrospectively, a pTERT mutation was identified by both ddPCR and SNaPshot in the non-diagnostic biopsies in 85% (11 /13) of pTERT mutant-gliomas. No mutation was detected in the non-diagnostic biopsies of IDH-WT pTERT-WT gliomas using either technique. Overall, a pTERT mutation were detected in 79% (11/14) of non-diagnostic biopsies.

CONCLUSION
Digital Droplet PCR, as SNaPshot PCR, enables the identification of pTERT mutations in a high rate of non-diagnostic biopsies from glioma patients. The sensitivity of both techniques seems similar in this setting.
P14.101 Glioblastoma survival outcomes related to cortical/neural stem cells regions
Authors: Kazda T , Jancalek R , Belanova R , Pospisil P , Burkon P , Hynkova L , Slampa P , Lakomy R 
Published: September 2019

Abstract

BACKGROUND
Subventricular brain zone (SVZ) and hippocampal regions are supposed to harbor astrocyte-like neural stem cells. While some tumors may arise from transformed SVZ stem cells, other may be initiated by neo-plastic transformation of non-SVZ progenitor cells or mature glial cells. Lim′s et al classification (Neuro-Oncology 2007) of initial glioblastoma location, related to these neural stem cells regions, was predictive for invasive and multifocal tumor phenotype. The aim of this retrospective single-institutional study is to evaluate the relations of this Lim classification on survival parameters in unselected cohort of glioblastoma patients.

MATERIAL AND METHODS
Patients treated between 2014–2017 were grouped according to initial location of their contrast enhancing lesion as follows: Lim1 (SVZ+⋯SVZ/hippocampal involvement and Cortex+⋯cortex involvement), Lim2 (SVZ+ and Cortex-), Lim3 (SVZ- and Cortex+) and Lim4 (SVZ- and Cortex-). All patients underwent radiotherapy, some patients were indicated to full treatment according to Stupp regimen (at least 3 cycles of adjuvant chemotherapy after postsurgery chemoradiotherapy).

RESULTS
In total, 144 patients were analyzed (94 men, mean age 59 years). 47 patients (30.5%) were treated according to Stupp regimen. Lim1 classification was presented in 74 (48%) patients, Lim2 in 22 (14.3%), Lim3 in 50 (32.5%) and Lim4 in 8 (5.2%) patients. Cortical structures (Lim1 and Lim3) were involved in 124 (80.5%) patients. Median overall survival was significantly better in patients treated according to Stupp regimen (23.3 vs. 8.6 months, p<0.001). Median overall survival differs in respective Lim groups: 12.3, 5.6, 11.8 and 6.6 months (p=0.07). Better survival was in patients with cortical involvement (Lim1+Lim3): 12.3 vs. 6.4 months (p=0.02), especially in subgroup of patients who were not treated according to Stupp regimen (8.9 vs. 4.4 months, p=0.02) vs. those after Stupp regimen (23 vs. 23.4 months, p=0.7).

CONCLUSION
Initial location of enhancing glioblastoma was prognostic for overall survival, with better outcomes in patients presented by involvement of cortical structures comparing to subventricular/hippocampal zones. Molecular patterns may further clarify potential effects of neural stem cells in glioma genesis mirrored in different clinical behavior and location of initial tumor. Supported by Ministry of Health of the Czech Republic, grant No. 18-03-00469
P14.109 Standard error of measurement (SEM) and intraclass coefficient (ICC) in volumetric assessment of postoperative residual tumor volume in glioblastoma
Authors: Hallaert G , Pinson H , Van Roost D , Kalala J , Vandriessche V , Boterberg T 
Published: September 2019

Abstract

BACKGROUND
Residual contrast-enhancing tumor volume (RTV) is an important parameter in glioblastoma (GBM) treatment. MR imaging within 48hrs after surgery is the preferred imaging modality but is prone to variability because of different interpretation by different raters. Variability can be statistically assessed using agreement and reliability parameters. The former are underreported in medical literature and are often mixed up with the latter. But agreement parameters are to be preferred in assessment of the level of agreement between repeated measurements. A typical agreement parameter is the standard error of measurement (SEM), which is expressed in the same unit as the original variable. Reliability parameters on the other hand relate the measurement error to the variability between study objects. A typical and well-known reliability parameter is the intraclass coefficient (ICC), expressed on a scale from 0 to 1. We investigated both SEM and ICC between and within raters concerning RTV in GBM.

MATERIAL AND METHODS
Ten cases were randomly selected from a glioblastoma database. Three observers (a neuroradiologist, NR; a neurosurgeon, NS; a junior neurosurgical trainee, JNT) performed two sessions of volumetric assessment of RTV, blinded for each others results and independently from each other. At least 2 months passed in between sessions. Volumetric assessment was performed using Magnetisation Prepared-Rapid Echo Gradient (MPRAGE) 0.9mm images in standard neuronavigation software (Medtronic Inc, Louisville, CO, USA), in comparison with other images when deemed necessary by the individual rater. Semi-automated segmentation was applied, meaning that the rater used automated segmentation technique on each slice, but adjusted according to his of her own judgement (segmentational growing around the region of interest). Volumes were expressed in mL. Statistical analysis was performed using R software (version 3.4.3 (30-11-2017); Attached packages: psych foreign pander date knitr) to calculate ICCs. SEMs were manually calculated using the formulae by De Vet et al.

RESULTS
Intrarater ICC agreement was 0.96 (0.87–0.99), 1 (0.98–1) and 0.77 (0.34–0.94) for NS, NR and JNT resp. SEM agreement was 0.87mL, 0.25mL and 2.67mL resp. Interrater variability was as follows: NS-NR 0.89 (0.65–0.97) ICC and 1.42mL SEM; NS-JNT 0.93 (0.77–0.98) ICC and 1.52mL SEM; NR-JNT 0.74 (0.28–0.93) ICC and 2.81mL SEM.

CONCLUSION
Agreement on postoperative residual contrast-enchancing tumor volume in GBM was high between neurosurgeon and neuroradiologist, with SEM 1.42mL. SEM probably reflects the differences in interpretation, especially of areas with blood products on postoperative MR imaging. Both intrarater and interrater agreement was highest for more experienced raters.
P14.110 Primary leptomeningeal melanocytic tumors - clinical course and molecular pathological aspects of an underestimated entity
Authors: Dohmen H , Jensen A , Schoeller K , Uhl E , Acker T , Stein M 
Published: September 2019

Abstract

BACKGROUND
Primary leptomeningeal melanocytic tumors (PLMT) of the central nervous system are extremely rare, usually benign pigmented tumors. The aim of our study is to present two complex cases of PLMT with discussion of clinical and molecular aspects.

MATERIAL AND METHODS
Medical charts of two patients from our institution with PLMT were reviewed. Oncogenic common gene mutations in GNAQ (Q209, exon 5), GNA11 (Q209, exon 5), TERT promoter and BRAF (exon 11, 15) were analyzed and a genome-wide DNA methylation array (Infinium Human-MethylationEPIC BeadChip) was performed. Brain tumors were categorized according to their DNA methylation profile using the brain tumor classifier algorithm (https://www.molecularneuropathology.org/mnp).

RESULTS
Case1: A 15 year-old boy presented with a large tumor in the in the cerebellopontine angle with extension to the cavernous sinus and the middle fossa in June 2013. Consequently, partial resection of the PLMT was performed followed by photon radiation therapy. First recurrence developed after 12 months. Despite reradiation with proton therapy, reresection, and several chemotherapies the patient died 4 years and 3 month after initial diagnosis. Histopathological examination of the resected tumor sample revealed a pigmented neoplasm with epithelioid cells with strong expression of melanocytic markers Melan A and HMB 45. In the recurrent biopsy samples, an increase in the Ki-67/MIB index from 2 to 10 % was observed. Molecular analysis showed a characteristic GNA11 Q209L mutation that supports the diagnosis of PLMT.
Case2: In April 2016 the resection of a PLMT in a 42 year-old female in the pinealis region was performed. First recurrence developed after 21 months and reresection followed by proton therapy was performed. A distant tumor developed 7 month later and after resection the patient received local proton therapy. Only 1 month later a new tentorial tumor was detected and treated by proton therapy. Tumor tissue of the local recurrence showed focal epitheloid cell morphology with brain invasion, tumor necrosis and increased mitotic activity. KI-67/MIB1 index was approximately 3% in the first and above 10 % in the second and third operation. The hotspot mutation in GNAQ Q209L was found in all tumor samples. In addition to histological signs of malignancy, an increase in chromosomal aberrations was seen at recurrence as a sign of malignant progression. To-date the patient is alive but new cranial metastases were detected.

CONCLUSION
Though PLMT is defined as benign lesion, the treatment is complicated by early local recurrence as well as intracranial and spinal metastases. For the first time malignant transformation during the clinical course of PLMT was confirmed by histology and DNA methylation array.
P14.112 Long-term application of TTFields in glioblastoma: a multiple-case study
Authors: Lawson McLean A , Kalff R , Walter J 
Published: September 2019

Abstract

BACKGROUND
Tumor treating fields (TTFields) is an antimitotic cancer therapy that utilizes low-intensity, intermediate-frequency alternating electrical fields to treat glioblastoma (GBM). Increased compliance with TTFields is independently prognostic for improved survival and was correlated with significantly improved overall and progression-free survival versus temozolomide (TMZ) alone. We present two exemplary cases of primary GBM treated with TTFields on long-term and adjuvant chemotherapy to explore treatment adherence, feasibility and safety issues.

MATERIAL AND METHODS
We present case details of two patients from our comprehensive cancer center, both of whom have primary GBM and are long-term TTFields users. One patient began TTFields at first diagnosis whilst the other had already survived to two years at the time of TTFields commencement. Their histories and disease status under continuous, ongoing TTFields therapy with concomitant, extended chemotherapy are explored.

RESULTS
Patient A is a 52-year-old male with IDH1-wildtype, MGMT promoter-methylated GBM. He began TTFields 24 months after initial diagnosis. Before starting TTFields, he had two resections, one owing to early locoregional progression, and had underwent standard, dual radiochemotherapy and started adjuvant TMZ. He has now completed 931 days of treatment with an average daily usage of 82% and has survived 55 months from first diagnosis. Since beginning TTFields, he has undergone a further two resections and another radiotherapy course. His chemotherapy regime has been modified several times, from standard-dose to dose-intensified TMZ, then later switched to lomustine and irinotecan-containing protocols. Patient B is a 68-year-old male, also with IDH1-wildtype, MGMT promoter-methylated GBM. He began TTFields six months after first diagnosis and after one tumor resection, concomitant radiochemotherapy and initiation of long-term TMZ therapy. He has now undergone 636 days of TTFields treatment with an average daily usage of 74%. In addition, 28 cycles of TMZ have been completed.

CONCLUSION
During a mean treatment duration of 784 days and alongside extended-course adjuvant chemotherapy, TTFields was well tolerated. Both patients are alive and still receiving treatment. Compliance has remained within the target range. Significant adverse events or treatment interruptions have not occurred. The patients have remained symptomatically stable and their quality of life has been maintained.