bluuebunny/crossref_metadata_2025 huggingface dataset:
P14.51 Brain mapping for mentalizing in GBM patient
Authors: Chung D , Yoon W
Published: September 2019

BACKGROUND

Glioblastoma is a disease with very poor outcome. Most patients underwent maximal safe resection, especially focusing in the preservation of motor and language function. However, many caregivers were suffered from the blockage of emotion communication with patients. So the definition of maximal safe resection must include the preservation of cognition and mentalizing of patients. Here we present the experience of brain mapping in awake surgery to preserve mentalizing.

MATERIAL AND METHODS

A 61-year-old male patient with headache was transferred to our hospital because of brain tumor on CT scan checked in another hospital. On the initial MRI, multi-septate cystic tumor was shown on left medial prefrontal area. The patient was recommended the surgical resection, but patient discharged with the denial of the operation. Ten days later, patient visited our hospital again with slowness of response by the enlargement of tumor size. The tumor extensively involved left cingulum and corpus callosum at anterior part. On diffusion tensor image, tumor located at mediosuperior part of inferior fronto-occipital fasciculus (IFOF). The patient showed deficit of visual and verbal memory, generative naming ability, and phonemic generative naming ability on preoperative neuropsychological test (SNSB-II). Pyramid and palm tree test (PPTT) and ‘Reading the Mind in the Eyes’ test (RMET) were also performed to evaluate the semantic association function and mentalizing preoperatively.

RESULTS

The patient underwent awake surgery with asleep-awake-asleep technique. The tumor was resected until identification of incorrect response to PPTT or RMET on subcortical stimulation (Ojeman stimulator, 1.5mA, 60Hz, biphasic). The histopathologic diagnosis was glioblastoma. Small part of tumor was remained on cingulum, but patient was discharged without change of mentalizing.

CONCLUSION

Although the patients with glioblastomas show poor outcome, we think that it is important to consider the cognition and mentalizing of patients for emotion communication with caregivers. With awake surgery, mentalizing can be preserved in selective patients.
P14.67 Somatostatin receptor targeted radioligand therapyin head and neck paraganglioma
Authors: Müther M , Roll W , Stegger L , Zinnhardt B , Schäfers M , Weckesser M , Rahbar K , Stummer W
Published: September 2019

BACKGROUND

Surgical resection is the therapy of choice in head and neck paraganglioma. However, surgery is associated with significant morbidity depending on tumor size and localization. In case of progressive residual or recurrent disease, new and less aggressive therapeutic options are warranted. Somatostatin receptor (SSTR) targeted therapies pose a promising alternative, as SSTRs are upregulated in paragangliomas. Only few studies provide evidence on efficacy of 177Lu-DOTATATE therapy in these patients. The aim of this study was to evaluate the efficacy of peptide receptor radiotherapy (PPRT) with 177Lu-DOTATATE for head and neck paragangliomas.

METHODS

A total of seven consecutive patients (mean age: 60 years, range: 14–84) with progressive head and neck paragangliomas (3 carotid body tumors, 4 jugulotympanic paragangliomas), treated with PRRT using 177Lu-DOTATATE, were included in this retrospective analysis. Therapy response was assessed by interim and post-therapy 68Ga-DOTATATE-PET-CT and MRI according to morphological and SSTR imaging parameters. Therapeutic uptake was classified on177Lu-DOTATATE scintigraphies 48h p.i. according to the Krenning scale. Longer-term clinical and imaging-based outcome were evaluated.

RESULTS

Patients received a median of 4 cycles (range: 3 to 5) of PRRT with 177Lu-DOTATATE (mean injected dose 7.3 GBq). Interim and post-therapy staging showed at least stable disease in all patients. Tumor uptake in 48h p.i. 177Lu-scintigraphies was moderate to high in all patients (Krenning scale; median: 3; range: 2–4). Furthermore, none of the patients showed progressive disease during the median follow-up time of 28 months (range: 6–37 months).

CONCLUSION

SSTR targeted therapy using 177Lu-DOTATATE shows promising efficacy and may lead to long lasting stable disease.
P14.68 Life expectancy in biopsied GBM patients: a single-centre experience
Authors: Kalita O , Sporikova Z , Halaj M , Cwiertka K , Vaverka M , Hrabalek L , Trojanec R , Hajduch M , Drabek J , Vrbkova J
Published: September 2019

BACKGROUND

The prognosis for patients with GBM remains dismal. The most aggressive multimodal therapy (maximally radical and safe tumour resection, followed by the Stupp protocol oncotherapy) has yielded the best treatment outcomes. Only a small proportion of patients initially undergo brain tumour biopsy. Our aim is to evaluate therapy results of biopsied GBM patients.

MATERIAL AND METHODS

We followed all glioma patients from June 1, 2006. Information on surgeries, patient clinical condition, imagings, and results of histological, immunohistochemical, molecular genetic, and cytogenetic investigations was gathered. For this study, we selected a group of biopsied GBM patients in a period from June 1, 2006 to December 31, 2016. Needle biopsy (stereotactic, or navigated) was advised for unresectable tumours, for patients with unfavourable clinical conditions (KS<60), and for older patients (with age being the only surrogate criterion). Whenever possible, the patients were recommended Stupp protocol oncotherapy. Clinical and MRI follow-up after surgery was carried out (OS, PFS) until the patient’s demise.

RESULTS

Sixty adult GBM patients (27 females and 33 males) with their age ranging from 30 to 85 years old and with a mean age of 66.8 years were enrolled in this study. The diagnosis of GBM was established by biopsy. Fourteen of them (23%) had radiotherapy only. Five patients (8%) were able to receive the Stupp protocol oncotherapy. Forty-one patients (69%) had an unfavourable physical condition which was a contraindication to radiotherapy or chemotherapy, respectively. The average OS was 3.8 months. A limited number of samples were available for IDH status investigation. All of the seventeen GBMs were IDH wild-type.

CONCLUSION

The initial surgical treatment strategy in GBM patients must be in the hands of an experienced neurosurgeon. Biopsy is required even when no further tumour-specific therapy is recommended. Regardless of the treatment strategy (resection or biopsy), multisite tumour sampling should be acquired. In our opinion, a decision to perform needle biopsy should be restricted to patients with unfavourable clinical conditions (age, KS, comorbidities, etc.), to large and deep-located brain tumours very often involving midline structures (corpus callosum, thalamus, basal ganglia), and to older patients. In accordance with these principles, we selected a small GBM patient group (12% of all GBM patients) with very limited life expectancy. The rationale for brain tumour biopsy is prevention of histological misdiagnosis and collection of biomarker data. But only the limited size of the tissue samples obtained was a significant obstacle to comprehensive cytogenetic investigation. We also recommend not to include biopsied GBM patients in studies with patients who had a radical resection. Supported by Ministry of Health of the Czech Republic, grant nr. NV19-04-00281.
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

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

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

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

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

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

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

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

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

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.
Nonepileptic, Stereotypical, and Intermittent Symptoms (NESIS) in Patients With Subdural Hematoma: Proposal for a New Clinical Entity With Therapeutic and Prognostic Implications
Authors: Levesque Mathieu , Iorio-Morin Christian , Bocti Christian , Vézina Caroline , Deacon Charles
Published: September 2019

BACKGROUND

Transient neurological symptoms (TNS) are frequent in patients with subdural hematomas (SDH) and many will receive a diagnosis of epilepsy despite a negative workup.

OBJECTIVE

To explore if patients with TNS and a negative epilepsy workup (cases) evolved differently than those with a positive EEG (controls), which would suggest the existence of alternative etiologies for TNS.

METHODS

We performed a single-center, retrospective, case-control study of patients with TNS post-SDH. The demographics and clinical and semiological features of cases and controls were compared. The outcome and response to antiepileptic drugs were also assessed and a scoring system developed to predict negative EEG.

RESULTS

Fifty-nine patients with SDH-associated TNS were included (39 cases and 20 controls). Demographic characteristics were comparable in both groups. Dysphasia and prolonged episodes were associated with a negative EEG. Clonic movements, impaired awareness, positive symptomatology, complete response to antiepileptic drugs, and mortality were associated with a positive EEG. Using semiological variables, we created a scoring system with a 96.6% sensitivity and 100% specificity in predicting case group patients. The differences observed between both groups support the existence of an alternative etiology to seizures in our case group. We propose the term NESIS (NonEpileptic, Stereotypical, and Intermittent Symptoms) to refer to this subgroup and hypothesize that TNS in these patients might result from cortical spreading depolarization.

CONCLUSION

We describe NESIS as a syndrome experienced by SDH patients with specific prognostic and therapeutic implications. Independent validation of this new entity is now required.
Predictors of Local Control of Brain Metastasis Treated With Laser Interstitial Thermal Therapy
Authors: Bastos Dhiego Chaves de Almeida , Rao Ganesh , Oliva Isabella Claudia Glitza , Loree Jonathan M , Fuentes David T , Stafford R Jason , Beechar Vivek B , Weinberg Jeffrey S , Shah Komal , Kumar Vinodh A , Prabhu Sujit S
Published: September 2019

BACKGROUND

Laser Interstitial Thermal Therapy (LITT) has been used to treat recurrent brain metastasis after stereotactic radiosurgery (SRS). Little is known about how best to assess the efficacy of treatment, specifically the ability of LITT to control local tumor progression post-SRS.

OBJECTIVE

To evaluate the predictive factors associated with local recurrence after LITT.

METHODS

Retrospective study with consecutive patients with brain metastases treated with LITT. Based on radiological aspects, lesions were divided into progressive disease after SRS (recurrence or radiation necrosis) and new lesions. Primary endpoint was time to local recurrence.

RESULTS

A total of 61 consecutive patients with 82 lesions (5 newly diagnosed, 46 recurrence, and 31 radiation necrosis). Freedom from local recurrence at 6 mo was 69.6%, 59.4% at 12, and 54.7% at 18 and 24 mo. Incompletely ablated lesions had a shorter median time for local recurrence (P < .001). Larger lesions (>6 cc) had shorter time for local recurrence (P = .03). Dural-based lesions showed a shorter time to local recurrence (P = .01). Tumor recurrence/newly diagnosed had shorter time to local recurrence when compared to RN lesions (P = .01). Patients receiving systemic therapy after LITT had longer time to local recurrence (P = .01). In multivariate Cox-regression model, the HR for incomplete ablated lesions was 4.88 (P < .001), 3.12 (P = .03) for recurrent tumors, and 2.56 (P = .02) for patients not receiving systemic therapy after LITT. Complication rate was 26.2%.

CONCLUSION

Incompletely ablated and recurrent tumoral lesions were associated with higher risk of treatment failure and were the major predicting factors for local recurrence. Systemic therapy after LITT was a protective factor regarding local recurrence.
Reducing Nicotine Without Misleading the Public: Descriptions of Cigarette Nicotine Level and Accuracy of Perceptions About Nicotine Content, Addictiveness, and Risk
Authors: Byron M Justin , Hall Marissa G , King Jessica L , Ribisl Kurt M , Brewer Noel T
Published: September 2019

Significance

The public incorrectly believes very low nicotine content (VLNC) cigarettes are less carcinogenic than current cigarettes, a belief associated with lower motivation to quit under a VLNC standard. We examined how different descriptions of the nicotine level in VLNC cigarettes affect the accuracy of the public’s perceptions about nicotine content, addictiveness, and cancer risk.

Methods

Participants were a national convenience sample of 1353 US adults (22% smokers). In an online experiment, we randomized participants to a VLNC description using (1) concise language; (2) a percentage; (3) an interpretation; (4) a percentage and interpretation; (5) a percentage and a pictograph; or (6) a percentage, interpretation, and pictograph; or to a control description using (7) FDA's “minimally or nonaddictive” phrasing. We assessed accuracy of perceived nicotine content, addictiveness, and cancer risk compared to current cigarettes.

Results

Compared to control, the percentage description resulted in more accurate perceptions about nicotine content (76% vs. 49% accuracy) and addictiveness (44% vs. 34%), but less accurate perceptions about cancer risk (56% vs. 68%; all ps < .05). Adding interpretation or pictographs to the percentage description did not increase accuracy. The concise language description reduced accuracy of perceived nicotine content and addictiveness but increased accuracy of cancer risk (all ps < .05).

Conclusions

Stating that 95% of nicotine would be removed more accurately conveyed the nicotine content and addictiveness of VLNC cigarettes. However, descriptions that better conveyed nicotine content and addictiveness misled people about cancer risk.

Implications

Implementation of a VLNC standard should include plans for a communication campaign that conveys that VLNC cigarettes will be less addictive but equally toxic to smoke. Stating the percent reduction in nicotine is likely to more clearly communicate reduced addictiveness but may also exacerbate risk misperceptions. VLNC communication requires further study to ensure the public accurately understands a VLNC standard.
Using mixed methods to map vaguely defined research areas
Authors: Degn Lise , Mejlgaard Niels , Schneider Jesper Wiborg
Published: September 2019

The aim of this article is to present an alternative method for science mapping, which remedies some of the classic limitations to e.g. using co-citation analysis as a mapping tool. With the emergence of new, more complex and interdisciplinary areas of research it becomes important to adjust our understandings of how to study these areas, and the argument of the present paper is that in order to provide high-resolution maps of emerging scientific areas, we need to start in the ‘cognitive colleges’ of the research areas themselves. To do so, a mixed methods design with co-nomination as its backbone is proposed. The potential and limitations of the alternative approach to science mapping are discussed based on an empirical example of mapping an vaguely defined research area in Denmark.
Cerebellar contribution to emotional body language perception: a TMS study
Authors: Ferrari Chiara , Ciricugno Andrea , Urgesi Cosimo , Cattaneo Zaira
Published: September 2019

Consistent evidence suggests that the cerebellum contributes to the processing of emotional facial expressions. However, it is not yet known whether the cerebellum is recruited when emotions are expressed by body postures or movements, or whether it is recruited differently for positive and negative emotions. In this study, we asked healthy participants to discriminate between body postures (with masked face) expressing emotions of opposite valence (happiness vs anger, Experiment 1), or of the same valence (negative: anger vs sadness; positive: happiness vs surprise, Experiment 2). While performing the task, participants received online transcranial magnetic stimulation (TMS) over a region of the posterior left cerebellum and over two control sites (early visual cortex and vertex). We found that TMS over the cerebellum affected participants’ ability to discriminate emotional body postures, but only when one of the emotions was negatively valenced (i.e. anger). These findings suggest that the cerebellar region we stimulated is involved in processing the emotional content conveyed by body postures and gestures. Our findings complement prior evidence on the role of the cerebellum in emotional face processing and have important implications from a clinical perspective, where non-invasive cerebellar stimulation is a promising tool for the treatment of motor, cognitive and affective deficits.
Retinal Changes in Schizophrenia: A Systematic Review and Meta-analysis Based on Individual Participant Data
Authors: Kazakos Charalampos T , Karageorgiou Vasilios
Published: September 2019

Background

Retinal assessment has indicated the presence of neuronal loss in neurodegenerative disorders, but its role in schizophrenia remains unclear. We sought to synthesize the available evidence considering 3 noninvasive modalities: optical coherence tomography, electroretinography, and fundus photography, and examine their diagnostic accuracy based on unpublished individual participant data, when provided by the primary study authors.

Methods

We searched MEDLINE, SCOPUS, clinicaltrials.gov, PSYNDEX, Cochrane Controlled Register of Trials (CENTRAL), WHO International Clinical Trials Registry Platform, and Google Scholar, up to October 30, 2018. Authors were contacted and invited to share anonymized participant-level data. Aggregate data were pooled using random effects models. Diagnostic accuracy meta-analysis was based on multiple cutoffs logistic generalized linear mixed modeling. This study was registered with PROSPERO, number CRD42018109344.

Results

Pooled mean differences of peripapillary retinal nerve fiber layer thickness in micrometer between 694 eyes of 432 schizophrenia patients and 609 eyes of 358 controls, from 11 case-control studies, with corresponding 95% confidence intervals (CIs) by quadrant were the following: −4.55, 95% CI: −8.28, −0.82 (superior); −6.25, 95% CI: −9.46, −3.04 (inferior); −3.18, 95% CI: −5.04, −1.31 (nasal); and −2.7, 95% CI: −4.35, −1.04 (temporal). Diagnostic accuracy, based on 4 studies, was fair to poor, unaffected by age and sex; macular area measurements performed slightly better.

Conclusion

The notion of structural and functional changes in retinal integrity of patients with schizophrenia is supported with current evidence, but diagnostic accuracy is limited. The potential prognostic, theranostic, and preventive role of retinal evaluation remains to be examined.
Bone marrow osteoprogenitors are depleted whereas osteoblasts are expanded independent of the osteogenic vasculature in response to zoledronic acid
Authors: Hughes Russell , Chen Xinyue , Hunter Keith D. , Hobbs Jamie K. , Holen Ingunn , Brown Nicola J.
Published: September 2019

Zoledronic acid (ZOL) is an antiresorptive drug used to prevent bone loss in a variety of conditions, acting mainly through suppression of osteoclast activity. There is growing evidence that ZOL can also affect cells of the mesenchymal lineage in bone. We present novel data revealing significant changes in the abundance of perivascular mesenchymal stromal cells (MSCs)/osteoprogenitors and osteoblasts following the injection of ZOL, in vivo. In young mice with high bone turnover and an abundance of perivascular osteoprogenitors, ZOL significantly (P < 0.0001) increased new bone formation. This was accompanied by a decline in osterix‐positive osteoprogenitors and a corresponding increase in osteoblasts. However, these effects were not observed in mature mice with low bone turnover. Interestingly, the ZOL‐induced changes in cells of the mesenchymal lineage occurred independently of effects on the osteogenic vasculature. Thus, we demonstrate that a single, clinically relevant dose of ZOL can induce new bone formation in microenvironments enriched for perivascular MSC/osteoprogenitors and high osteogenic potential. This arises from the differentiation of perivascular osterix‐positive MSC/osteoprogenitors into osteoblasts at sites that are innately osteogenic. Collectively, our data demonstrate that ZOL affects multiple cell types in bone and has differential effects depending on the level of bone turnover.—Hughes, R., Chen, X., Hunter, K. D., Hobbs, J. K., Holen, I., Brown, N. J. Bone marrow osteoprogenitors are depleted whereas osteoblasts are expanded independent of the osteogenic vasculature in response to zoledronic acid. FASEB J. 33, 12768–12779 (2019). www.fasebj.org
Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling
Authors: Sun Xuewu , Zhang Boya , Pan Xin , Huang Hai , Xie Ziang , Ma Yan , Hu Bin , Wang Jiying , Chen Zhijun , Shi Peihua
Published: September 2019

The endogenous metabolite itaconate has emerged as a regulator of macrophage function that limits inflammation. However, its effect on cell differentiation and osteoclast‐related diseases is unclear. Here, for the first time, we explored the effect of itaconate and its cell‐permeable itaconate derivative, 4‐octyl itaconate (OI) on osteoclast differentiation in vitro and in vivo. Firstly, we demonstrated that itaconate concentration was lower in estrogen‐deficient mice. OI released itaconate and induced the expression of nuclear factor–erythroid 2–related factor 2 (Nrf2) in bone marrow–derived macrophages during osteoclastogenesis. Furthermore, OI significantly suppressed the early, middle, and late stages of osteoclastogenesis induced by receptor activator of NF‐αB ligand in vitro, as confirmed by tartrate‐resistant acid phosphatase staining. Moreover, it significantly inhibited fibrous actin ring formation and bone resorption in vitro. Mechanistically, we observed that OI enhanced Nrf2 expression by suppressing its association with ubiquitin via inhibition of the E3 ubiquitin ligase (Hrd1). OI also inhibited LPS‐induced the reactive oxygen species and inflammatory responses via Hrd1. An estrogen deficiency (via ovariectomy)–induced osteoporosis model was also established. Here, on micro‐computed tomography and histologic analysis showed that OI effectively suppressed ovariectomy‐induced bone loss. In summary, OI, an itaconate derivative, can inhibit osteoclastogenesis in vitro and in vivo, indicating that OI could be a potential drug to treat osteoclast‐related diseases; our results also link itaconate to the development of osteoporosis.—Sun, X., Zhang, B., Pan, X., Huang, H., Xie, Z., Ma, Y., Hu, B., Wang, J., Chen, Z., Shi, P. Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling. FASEB J. 33, 12929–12940 (2019). www.fasebj.org