bluuebunny/crossref_metadata_2025 huggingface dataset:
P13.13 Clinical factors involved in brain metastasis edema: results of a retrospective cohort and evaluation of the best edema descriptor
Authors: Pin Y , Loo M , Waissi W , Paix A , Todeschi J , Antoni D , Proust F , Ahle G , Noël G
Published: September 2019

BACKGROUND

Brain metastasis (BM) are frequently surrounded by brain edema with a variable extension. This pathological increase in the water mass from the interstitial or intracellular space is the source of neurological symptoms but some studies also showed a prognosis impact of this edema. Nevertheless, the current edema evaluation methods are poorly reproducible and were not extensively evaluated. From a series of patients with brain metastasis, we analyzed factors influencing perilesional edema extension in function of three edema descriptors which were qualitatively evaluated: the absolute cumulative intracranial edema volume (CIEV, in mL), the edema on tumor volume ratio (ER), and the Edema Theoretical Thickness (ETT, in mm), new factor designed to be more independent from geometrical considerations.

MATERIAL AND METHODS

Clinical, biological and imaging factors were retrospectively recorded from patients referred for upfront stereotactic radiotherapy of one to three BMs. CIEV, ER and ETT were calculated for each patient. Non-colinear factors were selected using the Farrar-Glauber test. Impact of these factors on edema was tested with an univariate then a multivariate linear regression for each edema descriptor. Each resulting regression model was qualitatively evaluated using the F-test, R square value and residuals calculation.

RESULTS

Between January 2012 to December 2017, 182 patients were included. Upon 20 potentially prognostic factors recorded, 10 were kept, including clinical, biological and imaging factors. In the multivariate analysis, the CIEV was influenced by the cumulative intracranial tumor volume (CITV) (coefficient of 1.95, p<.001). The CIEV F-statistic p-value and R square were <10–15 and 0.30, respectively. The ETT was significantly influenced by the CITV (0.31, p<.001) and the extracerebral disease control (-1.58, p=.049). The F-test p-value and R square were <10-10 and 0.25, respectively. No significant linear regression was found for the ER. Residuals were more clinically relevant for the ETT compared to the CIEV.

CONCLUSION

Being significantly influenced by the cumulative brain tumor volume and the extracerebral disease control, the ETT might be a factor to include in future BM works because its strong relationships with confounding factors and its ability to provide robust intra and inter subjects comparisons.
P14.07 Complete response under treatment with proton therapy followed by chemotherapy together with Tumor Treating Fields in a biopsied IDH wildtype glioblastoma patient
Authors: Stein M , Dohmen H , Woelk B , Uhl E , Kolodziej M , Jensen A
Published: September 2019

BACKGROUND

Proton therapy is able to apply high radiation doses to the tumor while sparing healthy tissues by reducing integral dose. Tumor Treating Fields (TTFields) are low intensity (1–3 V/cm) and intermediate frequency (100–300 kHz) alternating electric fields that demonstrated significantly increased survival rates in combination with adjuvant temozolomide (TMZ) in patients with newly diagnosed glioblastoma (ndGBM). Especially in ndGBM IDH wildtype with unmethylated MGMT promotor therapeutic options are restricted. Here, we report on a patient with biopsied ndGBM IDH wildtype with complete radiological response.

MATERIAL AND METHODS

Brain MRI demonstrated an occlusive hydrocephalus and a ring enhancing lesion in the right posterior thalamus in a 42 year old male. Endoscopic third ventriculostomy and stereotactic biopsy of the lesion were performed. Histopathological examination resulted in the diagnosis of a glioblastoma (WHO grade IV), IDH 1 wildtype (R132), IDH 2 wildtype (R172), HIST1H3B/C wildtype, TERT wildtype (C228 and C250), BRAF wildtype, and unmethylated MGMT promotor. In view of the tumor site, resection was not feasible. Consequently, the patient received definitive chemoradiation with TMZ to a total dose of 60Gy incl. proton boost of 5x2 GyRBE. TTFields therapy in combination with TMZ was initiated 4 weeks after completion of chemoradiation, TMZ maintenance was completed per protocol after 6 cycles. TTFields therapy was continued for more than 13 month and to-date the patient is still on therapy.

RESULTS

Current follow up time is 20 months after initial diagnosis with the patient showing a radiological complete response. The first MRI following chemoradiation with TMZ and protons (showed pseudoprogression. After 3 months, the MRI again showed slightly increasing contrast enhancement. However, no clinical symptoms of tumor progression were present. The TTFields usage (compliance) rate, i.e. the rate per time the patient is applying the therapy, of the patient was 86 %. This was well above the independent prognostic threshold of 75 % and supports the feasibility of this approach. A further MRI after 8 weeks showed a stable disease. In a MRI 4 months later, partial response with decreased contrast enhancement plus perfusion restriction in the tumor area was observed. Another MRI after 3 months showed a complete response without perfusion signal in the tumor area. In the clinical examination the patient had no neurological deficits and to-date the patient is still stable

CONCLUSION

Complete response was observed following combination treatment of chemoradiation with TMZ including proton boost, TMZ maintenance and TTFields in a patient with pathologically confirmed GBM IDH wildtype. To our knowledge, this is the first report on a ndGBM patient receiving proton therapy followed by TTFields therapy.
P14.12 The cost-effectiveness of tumor-treating fields in patients with newly diagnosed glioblastoma
Authors: Armoiry X , Auguste P , Dussart C , Guyotat J , Connock M
Published: September 2019

BACKGROUND

The addition of novel therapy “Tumor-Treating fields” (TTF) to standard radio-chemotherapy with Temozolomide (TMZ) has recently shown superiority over conventional TMZ regimen in patients with glioblastoma. Despite the clinical benefit of TTF, there is a strong concern regarding the cost of this new treatment. A first cost-effectiveness analysis, which was published in 2016, was based on effectiveness outcomes from an interim analysis of the pivotal trial and used a “standard” Markov model. Here, we aimed to update the cost-effectiveness evaluation using a partitioned survival model design and using the latest effectiveness data.

MATERIAL AND METHODS

A partitioned survival model was developed with three mutually exclusive health states: stable disease, progressive disease, and dead. Parametric models were fitted to the Kaplan-Meier data for overall and progression-free survival. These generated clinically plausible extrapolations beyond the observed data. The perspective of the French national health insurance was adopted and the time horizon was 20 years. Base case results were expressed as cost/life-years (LY) gained (LYG). Secondary analyses were undertaken, with the results presented as cost/per quality adjusted life years (QALY) gained. Last, we undertook deterministic and probabilistic sensitivity analyses.

RESULTS

After applying 4% annual discounting of benefits and costs, the base case model generated incremental benefit of 0.507 LY at a incremental cost of €258,695 yielding an incremental cost effectiveness ratio (ICER) of €510,273 / LYG. Secondary analyses yielded an ICER of €667,173/QALY. Sensitivity analyses and bootstrapping methods showed the model was relatively robust. The model was sensitive to TTF device costs and the parametric model fitted to the Kaplan-Meier data for overall survival. The cost-effectiveness acceptability curve showed TTF has 0% of being cost-effective under conventional thresholds.

CONCLUSION

Using a partitioned survival model, uprated costs and more mature survival outcomes, TTF when compared to standard radio-chemotherapy with TMZ is not likely to be cost-effective. This has major implications in terms of access of newly eligible patients
P14.14 Scalp invasion of diffuse large b-cell lymphoma without systemic involvement
Authors: Hasturk A E , Eyupoglu E E , Gel G , Gokce C
Published: September 2019

Diffuse large B-cell lymphoma of the scalp with extra and intracranial extension without systemic invasion in a non-immune compromised patient is extremely rare. It should be considered in the differential diagnosis of scalp masses and meningeal lesions. Early diagnosis and surgical treatment is associated with a good outcome. 74 years old male patient with no known history of malignancy came to our clinic for left frontal swelling. He had no systemic cancer involvement. Contrast-enhanced cranial MRI showed a mass lesion invading left frontal skin, subcutaneous tissue, temporal muscle, bone and the underlying dural layer (Figure 1). Surgical excision was decided and after planning with the plastic surgery consultation, the patient was taken into surgery. Skin was lifted with a left frontal flap and the invasion was observed. Skin flap was placed down and the tumoral tissue was totally excised with a margin of normal bone tissue. The pathology assessment of the frozen specimen was found concordant with lymphoma. No injury or invasion of the dura was seen macroscopically. After dural closure, metacrilate cranioplasty was performed in order to replace the removed bone flap. Afterwards patient was handed over to the plastic surgeon. To ensure tumor resection with a safe margin, a transposition scalp flap was designed in the parieto-occipital region. The flap was raised in the supraperiosteal plane with preservation of the pericranium and it was transferred to the defect site. In addition, the flap donor area was reconstructed with a split-thickness skin graft taken from the right thigh region. Then, a wound dressing was applied to the surgical area and opened on postoperative 4th day. No complications such as necrosis, hematoma, infection or wound dehiscence occurred postoperatively. Both the graft and the flap completely healed (Figure 2). The patient showed no new neurological deficits or wound problems postoperatively and did not experience any problems both in plastic surgical and neurosurgical follow-up period (Figure 3). The final pathology result reported as diffuse large B cell lymphoma with invasion of the skin, subcutaneous tissue, temporal muscle and bone. Afterwards, medical treatment was planned with consultation to the hematology and radiotherapy clinics. Primary Non-Hodgkin’s lymphoma (NHL) extending extra cranially and intra cranially without any systemic or skeletal findings is extremely rare. These lesions usually get misdiagnosed as they mimic other conditions such as meningiomas. Both radiological and histopathological diagnoses are very important. Radical surgical resection and reconstruction must be contemplated in treatment and also chemotherapy and radiotherapy alternatives should be considered. Malignant NHL should be taken into account for differential diagnosis in the mass lesions of the scalp.
P14.15 Benefit of Bevacizumab for recurrent glioblastoma. Results of 81 patients from a single institution
Authors: Absalyamova O , Kobiakov G , Agabekyan G , Poddubsky A , Belyashova A , Lodygina K , Absalyamov A , Kobiakov N
Published: September 2019

BACKGROUND

No standard of care has been established for patients with progressive glioblastoma (rGBM). Previous studies suggested that bevacizumab (BEV) is safe and produces responses that result in a decreased use of glucocorticoids and increased progression-free survival (PFS) with an unclear effect on overall survival (OS). Crossover to BEV in the control arm is the possible reason why the advantage of BEV has not been proven in Phase III trials. We retrospectively analyzed own results of BEV treatment in rGBM.

MATERIAL AND METHODS

81 patients progressed after radiotherapy plus concomitant and maintenance temozolomide (TMZ) and undergo BEV as monotherapy (BevMo, 11 patients) or in combinations (Irinotecan (BevI) - 53, lomustine (BevL)- 11, TMZ (BevT) - 6. Median age 54 years. Among them 33 patients were re-irradiated: 11 - radiosurgery (RS), 20 fractionated irradiation (RT), 2 - RS+RT. 33 patients continued BEV after progression with changing or adding cytostatic. PFS was calculated from the date of verification, PFS1 - from the date of 1-st progression, PFS2 - from the date of 2-nd progression.

RESULTS

Median PFS was 9.0 ([CI] 7.0–10.9) months. Median PFS1 was 10.5 ([CI] 8.1–12.9) months. In the BevMo, BevI, BevL, BevT group PFS1 was 15.7, 10.1, 10.5, 13.2 months, respectively, p=0.7. Objective response (OR) was reached in 34%, stable disease (SD) in 28%, progression (PD) in 37% patients. 16 patients stopped BEV without progression (4-patient`s decision, 7- doctor`s decision, 2 - adverse event, 3 - concomitant disease). Median time of BEV treatment was 11.6 months. Median BEV-free interval till progression was 3.7 months. 33 patients continued or restarted BEV after progression. Median PFS2 was 8.0 ([CI] 4.9–11.1) months. The median OS from the date of 1-st progression was 23.5 months ([CI] 18.7–27.4). In groups with RT, RS, RS+RT and no re-irradiarion OS was 24.6 ([CI] 17.6–31.5), 35.4 ([CI] 35.0–35.8), 17.8, 20.6 ([CI] 15.2–26.0), respectively, p=0.2.

CONCLUSION

OS in our group is outrageously high. Maintaining BEV after progression was effective. In our group BEV discontinuation led to rapid progression. The resumption of Bev with progression was effective, which indicates the advisability of its continuous application.
P14.19 The inverse paradigm of IDH-wildtype glioblastoma is fundamental to overcome the two causes of resistance and develop novel effective therapies
Authors: Brognaro E
Published: September 2019

BACKGROUND

IDH-wildtype glioblastoma behaves differently from all other solid tumors. This is the reason why after decades of praiseworthy therapeutic efforts, the prognosis remains very poor. Many clues (radiological, clinical, surgical) and recent indirect experimental evidence converge to indicate that the entire brain parenchyma is micro-infiltrated from the very beginning by the founding clone before the primary bulk has started its growth. Therefore, only in IDH-wildtype glioblastoma the malignant (i.e. distantly infiltrating the organ of origin) and deadly (leading cause to patient’s death) phases coincide and overlap in one single phase.

MATERIALS AND METHODS

Appropriate sampling procedures must absolutely take into consideration both the tumor bulk and the micro-infiltrated brain parenchyma. They can be performed (with full respect for ethical issues) analyzing neoplastic and “healthy” material obtained from living patients (a), using animal models (b), studying post-mortem samples from rapid autopsies (c), comparing local and distant recurrences with the primary bulk (d). The study and analysis of the bulk tumor must be carried out by collecting multiple multiregional spatially separated samples throughout the whole tumor mass. The analysis of the micro-infiltrated brain parenchyma in living patients can be performed appropriately and ethically also from surgical patient tissue.

RESULTS

The phylogenetic tree of the tumor bulk must be inferred and reconstructed by the collection and analysis of multiple regionally separated samples. Additionally, driver and passenger events will be identified as well as the CSCs of samples. The procedures to ethically sample the micro-infiltrated brain parenchyma enable us to collect and identify the founder CSCs which lie quiescent in the perivascular parenchymal niches across the whole brain. Indeed, distant recurrences are due to their activation.

CONCLUSION

IDH-wildtype glioblastoma is the only brain tumor which arises from astrocyte-like cells of the SVZ ribbon layer and it is able to micro-infiltrate the whole supratentorial brain parenchyma before starting its growth. Its unique inverse paradigm explains the emergence of distant recurrences (sharing only truncal mutations with the primary bulk) and adds, in addition to the heterogeneity of the primary bulk and its residues, a second crucial cause of resistance to take into account (i.e. the founder CSCs which reside quiescent, in G0 state, in the perivascular parenchymal niches). Therefore, innovative therapies must identify and selectively target either CSCs unique properties related to their impaired asymmetrical division or stable driver lesions of the founder CSC (without alternative mutations and pathways) or exclusive markers used by the founder CSCs to settle dormant (involving mechanisms of adhesion, anchorage and cell cycle arrest) in their niches.
P14.29 Prediction of overall survival in patients with malignant glioma using dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET
Authors: Bauer E K , Stoffels G , Blau T , Reifenberger G , Werner J M , Lohmann P , Rapp M , Fink G R , Langen K , Galldiks N
Published: September 2019

BACKGROUND

Characterization of gliomas according to the revised World Health Organization (WHO) classification of 2016 has gained major importance regarding prognostication. The present study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in newly diagnosed and molecularly defined astrocytic high-grade glioma (HGG) of the WHO grades III or IV.

MATERIAL AND METHODS

Before initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumor/brain ratios (TBRmax/mean), as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated with regard to the overall survival (OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess their predictive power for OS.

RESULTS

Sixty patients (45 GBM, 15 AA) of two university centers were retrospectively identified. Patients with a methylated MGMT promoter as well as with an IDH mutation had a significantly longer OS (both P<0.001). Furthermore, ROC analysis revealed in IDH-wildtype HGG (n=45) that a TTP>25 minutes (AUC, 0.90; sensitivity, 90%; specificity, 87%; P<0.001) was highly prognostic for a longer OS (29 vs. 12 months; P<0.001). Besides a complete resection and a methylated MGMT promoter, TTP remained significant in the multivariate survival analysis (P=0.002, P=0.016, and P=0.003, respectively), indicating an independent predictor for OS. In contrast, both TBRmax and TBRmean were not prognostic (AUC, 0.37 and 0.32, respectively).

CONCLUSION

Data suggest that within the subgroup of patients with newly diagnosed and untreated IDH-wildtype GBM and AA, dynamic FET PET additionally allows the identification of patients with an improved OS.
P14.31 CMV reactivation in a cohort of newly-diagnosed glioblastoma patients treated with temozolomide chemoradiotherapy. A single center analysis
Authors: URSU R , Doridam J , Chaugne E , Zannou H , Belin C , Cuzzubbo S , Sirven-Villaros L , Brichler S , Levy-Piedbois C , Carpentier A
Published: September 2019

BACKGROUND

The Cytomegalovirus (CMV) is a ubiquitous herpes virus which infects 60–80 % of the population in Europe. Although the CMV usually remains latent, reactivation can occur in the context of an immunodepression, such as low CD4-lymphocyte levels in HIV patients. Glioblastoma (GBM) patients frequently show lymphopenia, which is related to both the immunosuppressive nature of the tumor and to the treatment with concomitant temozolomide (TMZ) and radiotherapy (RT). Surprisingly, the incidence of CMV reactivation in GBM patients has not been clearly studied so far. We report here our experience on CMV reactivation in a cohort of newly-diagnosed GBM patients, treated with RT and TMZ. We assessed the incidence of CMV reactivation in these patients and tried to identify risk factors for such reactivation.

MATERIAL AND METHODS

All consecutive patients with histologically confirmed malignant GBM recommended for temozolomide chemoradiotherapy in our institution from October 2013 to December 2015 were reviewed. In all patients, sex, age, Karnofsky performance status (KPS), lymphocyte level, serological CMV status and steroid dosages were recorded at the onset, and one month after completion of the concomitant radio-chemotherapy regimen. A CMV reactivation was defined by a detection of CMV DNA > 1000 copies/ml in the patient’s serum.

RESULTS

103 patients meeting the analysis criteria were reviewed. Within these 103 patients, 34 patients (33%) had initial negative serology for CMV, and none of them developed a seroconversion after treatment with concomitant RT + TMZ. Among patients with positive IgG (n=69), 16 patients (23%) developed a positive viremia at one point during treatment with concomitant RT + TMZ. Age (>60 years), lymphocyte count before RT (<1500/mm3) and use of steroids were correlated with CMV reactivation (p<0.05 in univariate analysis). A positive CMV viremia during RT+TMZ did not impact the progression free survival (PFS) but was associated with a shorter overall survival (OS) when compared to the others patients (median: 12 months vs 15 months; p=0.04). No clinical symptoms suggestive of CMV infection were reported.

CONCLUSION

In this single center series, we showed that CMV reactivation occurs in 23% of the GBM patients having a positive serology for CMV. Reactivation was more frequent in older patients, with low lymphocyte counts and treated with steroids. A positive viremia was not associated with poor PFS, a fact that does not support a promoting role of CMV in glioma oncogenesis, which has been sometimes suggested. Yet, the group of patients with CMV reactivation showed a shorter OS, which might be related to an older age and /or poorer clinical conditions in this group.
P14.35 The modern management of brain metastases
Authors: Wallace N D , Kelly P J
Published: September 2019

BACKGROUND

Technological and clinical advances have improved outcomes for patients with brain metastases. They have also added significantly to the complexity of decision-making in such cases. We set out to review the roles of different treatment options to guide management for patients with newly-diagnosed brain metastases.

MATERIAL AND METHODS

We undertook a comprehensive literature review to examine all treatment options for brain metastases. We particularly focused on recent advances and where these can be applied to clinical practice.We examined the impact of the improvement of SRS technology from older frame-based setups to modern linear accelerator based treatment with the capacity for fractionated stereotactic radiotherapy (SRT). We identified clinical situations where either SRS or WBRT, or a combination of the two, should be most strongly considered. Several novel targeted systemic therapies cross the blood-brain-barrier so we have explored their outcomes for patients with brain metastases from BRAF-mutated melanoma and EGFR or ALK/ROS1 mutated NSCLC. By examining these techniques in detail, we have formulated an algorithm-based approach which can inform management.

RESULTS

Surgery is most beneficial in patients with a reasonable prognosis and where other treatment options are unlikely to provide equivalent control. SRS to the surgical cavity can frequently be used alone for post-operative consolidation. SRS and fractionated SRT are valuable treatment options for increasingly large lesions and for increasing numbers of lesions. The choice between SRS and WBRT is, in many cases, a trade-off between the improved intracranial control of WBRT and the more favourable side effect profile of SRS. Upfront therapy with some systemic agents with CNS penetration is an acceptable approach in carefully-selected patients whose outcome is felt to be more related to their extracranial disease. Best supportive care is preferable for many patients with poor performance status and/or short prognosis, although more aggressive measures have a role in the case of symptomatic lesions.

CONCLUSION

A multidisciplinary approach involving Neurosurgeons, and both Radiation and Medical Oncologists is needed to fully evaluate the options for individual patients. As many of the treatment decisions are a trade-off between quality of life and outcome metrics, shared decision-making with patients is also critical to ensure that patients receive the best treatment for them.
P14.45 Primary diffuse large B-cell CNS lymphoma over 80 years: an analysis of 110 patients from the french Oculo-Cerebral Lymphoma (LOC) network
Authors: MAAREK A , Maucort-Boulch D , Houillier C , Hoang-Xuan K , Soussain C , Ghesquières H
Published: September 2019

BACKGROUND

in large unselected series, the median age of Primary CNS Lymphoma (PCNSL) patients (pts) is about 70 years. In one USA cancer registry study for PCNSL patients older than 65 years, 14% of them are older than 80 years. Data on clinical characteristics, therapeutical management, toxicity of treatment and outcome of these very elderly pts are limited.

MATERIAL AND METHODS

we reviewed PCNSL pts aged of 80 years or older included in the database of the French Oculo-Cerebral lymphoma (LOC) network. From January 2011, this network prospectively recorded all newly diagnosed PCNSL from 22 regional expert centers in France.

RESULTS

110 pts with a DLBCL PCNSL aged of 80 years or older were diagnosed between January 2011 and January 2018 representing 8% of pts available in the LOC database. The clinical characteristics were as follows: 63% of females; median age: 83y (80–92); performance status (PS) ≥3, 55% of pts. Median creatinine clearance (CKD.EPI) was 70ml/min. Treatment was initiated either by a neuro-oncology or a hematology team in 35% and 65% of cases, respectively. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) in 85 pts (77%), other chemotherapy regimen in 13 pts (12%) and palliative care in 12 pts (11%). Interestingly, no difference of distribution for the main clinical and biological characteristics was observed between these three groups. After first-line induction chemotherapy, response rate for evaluable patients (n=85) were as follows: 37% of complete response, 9% of partial response, 54% of stable or progressive disease. Rituximab was used in combination with CT in 53/98 treated pts (54%). For toxicity, among the 351 infusions performed for the 85 pts who received MTX-based CT, grade 3–4 toxicities were: 46% of any events, 15% of infection, 13% of cytopenia, 11% of acute renal failure and 8% of elevated liver enzymes. 13% of pts presented toxic death. Median progression free survival (PFS) and overall survival (OS) were 5 months and 8 months, respectively. Pts treated with MTX-based CT had a significantly prolonged PFS and OS. In the univariate analysis performed for the 85 pts treated with MTX-based CT, no initial clinical and biological influenced PFS or OS. Intravenous rituximab used in first line therapy significantly improved PFS and OS.

CONCLUSION

in this large series of consecutive PCNSL pts aged of 80y or over prospectively recorded in a national database, we showed that the prognosis remains poor with major toxicity under conventional treatment. No clinical predictor of survival was highlighted in our series. Patients initially treated with MTX-based CT in combination with rituximab had an improved outcome. The development of target and innovative therapies is needed for this category of patients representing 8% of all PCNSL in the database of the LOC network.​
P14.52 Differential methylation of a single CpG site in the CD95 ligand promoter affects gene activity and correlates with invasiveness of glioma cells
Authors: Merz C , Sykora J , Krendyukov A , Wiestler B , Gieffers C , Wick W
Published: September 2019

BACKGROUND

CD95 ligand (TNFSF6/APO-1L/FASLG) is a member of the Tumour Necrosis Factor Super Family (TNF-SF). Binding of the CD95 ligand (CD95L) to CD95 expressed on intrinsically apoptosis-resistant cancer cells like glioblastoma, triggers intracellular signal transduction resulting in increased tumour growth and invasiveness. A phase II clinical trial in patients with recurrent glioblastoma (NCT01071837) treated by Asunercept (a recombinant glycosylated fusion protein, which selectively binds and inhibits CD95L activity) was followed by a genome-wide assessment of DNA methylation. Here, a CpG-site (designated CpG2) within the CD95L-promotor was identified, exhibiting differential methylation between Asunercept responders (PFS>5 months) and non-responders (PFS < 2 months) with a significant survival benefit achieved in Asunercept treated patients with low CpG2 methylation (HR 0.34, p = 0.025).

METHODS AND RESULTS

We have performed in vitro studies to establish a link between the CpG2 methylation status and cellular characteristics of glioblastoma cell lines. A 3-dimensional spheroid invasion assay showed that highly methylated glioma cells like T98G did not grow and invade the surrounding matrix as aggressively compared to spheroids formed from low methylated glioma cells, e.g. U87-MG. Invasive growth of U87-MG spheroids in these assays was suppressed in the presence of Asunercept. A 1 kb fragment of the T98G CD95L promoter was subsequently cloned into a CpG-free reporter gene plasmid. Luciferase-based reporter gene assays of in vitro methylated and unmethylated plasmids in transfected HEK cells indicate that the CD95L promoter, despite the observed sparseness of CpG sites, is at least partially regulated by its methylation level. Furthermore, mutational disruption of the CpG2 site completely silenced reporter gene activity in vitro, which insinuates that both methylation level and gene promoter sequence are involved in regulation of the CD95L gene.

CONCLUSION

In essence, the level of CpG2 methylation correlates to aggressiveness of glioma derived cancer spheroids in vitro, and methylation of the CD95L promoter in glioblastoma tissue from patients might warrant use as a potential biomarker predicting response to therapy with Asunercept. We are currently developing a specific and sensitive assay to quantify CpG2 methylation considered as a companion diagnostic for further clinical studies.
P14.56 Recurrent Glioblastomas: Should we operate a second and even a third time
Authors: Yahia-Cherif M , De Witte O , Mélot C , Lefranc F
Published: September 2019

BACKGROUND

The aim of this study was i) to analyse the effect of repeat surgeries on the survival of patients with focally recurrent glioblastoma who have benefited from temozolomide treatment and ii) to identify potential prognostic factors for survival.

MATERIAL AND METHODS

Cases from 2005 to 2014 in the glioblastoma database of our department were retrospectively reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) as a function of time after one, two and three surgical resections. All patients received the standard of care after the first surgery (temozolomide during and after radiotherapy) and adjuvant treatment after repeat surgeries.

RESULTS

One hundred-thirty-two glioblastoma patients (median age: 57 years) were included in the study. Among them, 68, 53 and 11 patients underwent one, two and three surgical resections, respectively. The median OS was 11, 16 and 18 months, respectively, for patients who underwent one, two and three surgical resections. Patients who underwent two (p<0.001) or three (p<0.01) surgeries survived significantly longer than patients who underwent only one. No significant difference was observed between patients who underwent two versus three surgeries (p=0.76). A second resection performed more than 6 months after the initial resection was the only factor associated with prolonged survival (p=0.008).

CONCLUSION

Glioblastoma patients who benefited from temozolomide treatment and underwent surgery for recurrent glioblastoma exhibited a significant increase in survival compared with patients who did not undergo a second surgery. By contrast, a third surgery for a second recurrence did not contribute to any significant survival benefit.
P14.57 Association of tryptophan metabolism and depression in patients with primary brain tumors
Authors: Juhasz C , John F , Michelhaugh S K , Muzik O , Barger G R , Mittal S
Published: September 2019

BACKGROUND

Patients with brain tumor have an increased risk for depressive disorder, whose underlying pathomechanism may involve dysregulated tryptophan/kynurenine metabolism. In this study, we analyzed the relation of depression to cerebral and systemic tryptophan metabolism in patients with primary brain tumors.

MATERIAL AND METHODS

Thirty-four patients with newly-diagnosed (n=19) or recurrent (n=15) primary brain tumors (25 gliomas, 8 meningiomas, 1 dysembryoplastic neuroepithelial tumor) underwent pre-treatment alpha-[11C]methyl-L-tryptophan (AMT)-PET and completed the Beck Depression Inventory-II (BDI-II) questionnaire. MRI and AMT-PET images were co-registered, and AMT K values (estimate of unidirectional tryptophan uptake, related to tryptophan metabolism) were measured in contralateral non-tumoral cortical and subcortical regions and correlated with BDI-II total and subscale (cognitive, affective, and somatic) scores. In a subset of 28 patients, plasma tryptophan metabolite levels were also measured and correlated with BDI-II scores.

RESULTS

In the whole group (n=34), 35% of the patients (n=12) had BDI-II scores indicating depression, while only a minority of them (n=5) were treated with selective serotonin reuptake inhibitors (SSRI). No difference was observed in AMT K values between gliomas vs. non-gliomas or between newly-diagnosed vs. recurrent tumors. Frontal cortical and thalamic AMT K values positively correlated with BDI-II total and somatic subscale scores (r=0.49, p=0.004 and r=0.53, p=0.001, respectively), and these correlations became stronger when patients with SSRI treatment were excluded. Levels of plasma tryptophan and its metabolites were not different between gliomas vs. non-gliomas, newly-diagnosed vs. recurrent tumor nor depressed vs. non-depressed patients. SSRI treatment showed no effect on plasma tryptophan metabolite levels. No correlation was found between depression and plasma tryptophan and its metabolite levels.

CONCLUSION

While plasma levels of tryptophan metabolites are not associated with depressive symptoms, higher tryptophan metabolism in the frontal cortex and thalamus, measured by PET, may serve as an imaging biomarker of brain tumor-associated depression and supports the role of dysregulated tryptophan/kynurenine metabolism in this condition.
P14.63 The use of TTFields for newly diagnosed GBM patients in Germany in routine clinical care (TIGER: TTFields in Germany in routine clinical care)
Authors: Bähr O , Tabatabai G , Fietkau R , Goldbrunner R , Glas M G
Published: September 2019

BACKGROUND

Despite various clinical phase 3 trials, survival for the most common brain tumour, glioblastoma (GBM), has not improved since 2005. Alternating electric fields with low-intensity and intermediate frequency, known as tumor treating fields (TTFields) were shown to inhibit cancer cell division. In the EF-14 phase 3 trial, the addition of TTFields to adjuvant temozolomide (TMZ) chemotherapy demonstrated significant extension of median overall, progression-free and long-term survival in newly diagnosed GBM (ndGBM) patients. As there is very high interest among prescribing physicians from all disciplines in Germany to further evaluate these effects in routine clinical care, the aim of the TIGER study is to assess safety and efficacy of TTFields in routine clinical care as well as reasons for patients refusing TTFields treatment, changes in quality of life within 4 months after start of therapy, treatment duration and compliance.

METHODS

The TIGER study is a multi-centre, prospective, non-interventional study in Germany (NCT03258021). All ndGBM patients who are eligible for TTFields therapy are asked for consent for study participation and comprehensively introduced to the therapy to allow them to make a conscious positive or negative therapy decision. At baseline and 2–4 months after treatment start, demographic data as well as the QoL and reasons for therapy decision are evaluated applying the EORTC-QLQ-C30/BN-20 and TTFields questionnaire, respectively. A number of about 1000 patient is planned (500 in each arm with positive and negative treatment decision, respectively) with a follow-up period of 18 months.

RESULTS

At the time point of the last data cut-off (March 2019), more than 460 patients in the trial have made a decision for or against treatment with TTFields. Within this population, more than 80% of patients agreed to undergo TTFields therapy. The median age of patients included in the trial is actually 58.4 years (range 19–85). In this population 47 % received complete resection, 32 % partial resection and 22 % biopsy.

CONCLUSION

Systematic and prospective data analysis for the use of TTFields in routine clinical care including patient’s therapy decision can be assessed in the TIGER trial. Additionally, the study supports the evaluation of treatment duration and usage rate, which could drive future analysis of TTFields treatment duration. Most recent data will be presented at the EANO annual meeting.
P14.80 Advances in radiotherapy for brain tumors (benign, malignant and pediatrics tumors)
Authors: Theodorou M
Published: September 2019

BACKGROUND

New techniques in radiation oncology such as VMAT (volumetric modulated arc therapy), IGRT (image guidance radiotherapy) compare 3D-conformal technique offering better coverage of the target and more safety for the organs at risk for brain tumors such as Glioblastomas, low grade gliomas, pediatric tumors, meningiomas, pituitary adenomas, brain metastasis.

MATERIAL AND METHODS

Compare 3D-conformal treatment plans with VMAT -IGRT plan for Glioblastoma, pituitary adenoma, pediatric tumors, low grade gliomas, brain metastasis. Clinical target definition occur with Fusion of planing-MRI with Planing-CT inclusive preoperative and postoperative MRI to exact delineation of GTV (gross tumor volume), CTV (clinical target definition, PTV (planing tumor volume). contouring of organs at risk such as brainstemm, chiasm, N. opticus right and left, eye right and left, lens right and left, brain, cerebellum, internal ears.

RESULTS

VMAT treatment plans offer higher coverage of the target, higher homogenize radiation index and less radiation for the organs at risk. Due to the good safety of the organs at risk less toxicity during radiation was mentioned specially for neuroaxisradiation for medulloblastoma in children. The toleration during radiotherapy with VMAT technique is is much better than 3D conformal technique

CONCLUSION

VMAT technique offers higher radiation dose to the target and less radiation to the organs at risk with better toleration of treatment and less toxicity inclusive late side effects such as radionecrosis.
P14.84 Intraarterial chemotherapy and osmotic blood-brain barrier modification in the treatment of primary CNS lymphoma
Authors: Fortin D , Gahide G , Iorio-Morin C
Published: September 2019

BACKGROUND

Primary central nervous system lymphomas (PCNSL) are considered a rare and aggressive form of central nervous system (CNS) tumors. High-dose methotrexate has become the backbone of PCNSL treatment, and is recommended by the EANO guidelines. In most recent protocols, investigators tend to postpone or even avoid the use of radiotherapy; indeed, its use has become controversial with findings of associated severe neuro-toxicity, especially in elderly patients. To maximize delivery across the BBB, we use cerebral intra-arterial chemotherapy (CIAC) coupled with osmotic blood-brain barrier disruption (OBBBD). We hereby report our single-center experience over 18 years with the CIAC + BBBD technique using 2 different HD-MTX protocols.

MATERIAL AND METHODS

This phase II study was conducted at the Centre hospitalier Universitaire de Sherbrooke (CHUS) from November 1999 to May 2018. The protocol was approved by the institutional review board, and informed consent was obtained in accordance to institutional regulation in every patient After enrollment and initial evaluation, patients were treated every four weeks (1 cycle) for 12 cycles, unless progression. After general anesthesia, a transfemoral approach was used to catheterize either the right or left internal carotid artery or the dominant vertebral artery, depending on tumor(s) location. OBBBD was performed by infusing 20% mannitol in the selected vascular distribution for 30 seconds at a rate that fills the vascular distribution so as to maximize the contact of the mannitol with the endothelial cells.Two different chemotherapy regimens were sequentially used in this study. High-dose MTX (5 g IV) was the cornerstone of both regimens: the first regimen (1999 to 2007) also included etoposide phosphate IV (400 mg/m²) and cyclophosphamide IV (660 mg/m²), whereas the 2nd regimen (1998 to 2018) also included carboplatin IA (400 mg/m²).

RESULTS

The present analysis therefore concerns a cohort of 44 naive patients recruited over 18 years in a single center. Median follow-up was 38 months. Overall, a CR was induced in 34 patients (79%). Themedian time to CR was 7.3 months (IQR: 7.8). Of these 34 patients, 11 (25.6%) are still alive, and 9 of these are disease-free after treatment discontinuation. The actuarial median survival (MS) was 46.5 months (95% CI: 30.9–62.2) for the cohort. Survival was 88%, 64%, 54%, 39% and 18% at 1, 2, 3,5 and 10 years (Figure 1 and Table 2).The progression-free survival was 43.4 months (95% CI: 17.9–68.9). Five occurrences of vascular complications related to the treatment were observed (11.6%).

Conclusion: CIAC HD-MTX-based protocols with OBBBD is a safe and well-tolerated procedure for the management of primary CNS lymphoma. Our single center data suggests better PFS and survival outcomes compared to IV protocols with less hematologic toxicity and good tolerability, especially in the elderly.
P14.86 Bevacizumab-associated intracerebral hemorrhage in patients with CNS malignancy: A single-center retrospective cohort study
Authors: Clarke N , Ruff M
Published: September 2019

BACKGROUND

Gliomas are a known risk factor for the development of spontaneous intracranial hemorrhage (ICH) independent of therapies directed against them, with studies reporting an incidence of 1.9–3.8%. Bevacizumab (BEV) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) FDA approved for recurrent glioblastoma. ICH is commonly considered to be a potential adverse effect of BEV use in patients with glioma, with previous retrospective studies describing incidence of intracerebral hemorrhage ranging from 1.9–3.3%.

Material and METHODS

We performed a single center (Mayo Clinic, Rochester, MN) retrospective chart review of all patients who received BEV therapy at our institution for a diagnosis of primary CNS malignancy. We used ICD-9 and ICD-10 codes to identify adult patients with primary CNS neoplasms that subsequently developed ICH.

RESULTS

We screened 10,507 adult patients with a diagnosis of primary CNS neoplasm treated at our center from 01/31/2008 to 12/31/2018 and found 644 patients treated with bevacizumab. Of these, 23 (3.6%) suffered an ICH within 12 weeks of a BEV infusion (median 9 days post infusion, 1–24 IQR). The dose of BEV in all hemorrhages was either 10 mg/kg every two weeks (n = 21) or 15 mg/kg every three weeks (n = 2). No patients treated with infusions at 7.5 mg/kg every three weeks (n = 79) or 5 mg/kg every two weeks (n = 17) suffered ICH events, however this did not meet significance (P = 0.06) when compared to patients on 10 mg/kg or above. The median ICH score was 1 (0–2 IQR). There was an increase in ECOG scores documented at clinical follow up following the hemorrhage compared to the pre-hemorrhage functional status (ECOG 3.28 versus 1.2, p = < 0.0001), with 13 patients (56%) having developed severe debility or death (ECOG 4 n = 3, ECOG 5 n = 10).

CONCLUSION

In our single-center cohort of patients with a primary diagnosis of CNS neoplasms treated with BEV, ICH occurred in 3.6% of patients. Those who experienced an ICH in proximity to BEV infusion had significant morbidity and mortality with a clear decline in functional status. There was a signal of dose response as far as ICH incidence in our cohort with dosages 10 mg/kg per infusion or above.
P14.87 Leptomeningeal dissemination in high grade glioma: Correlation of MRI, cytology and standard CSF indices
Authors: Durand H , Lamy F , Parratte T , Brinet A , Blain A , Lamy F , Gaultier C , Droy-Dupré L , Leblanc S , Oesterlé H , Olteanu S , Atlani D , Voirin J , Mokhtari K , Ahle G
Published: September 2019

BACKGROUND

Only few studies report the incidence of leptomeningeal dissemination (LMD) in patients with high grade glioma (HGG), although LMD is not a rare condition of recurrence. We aimed to describe the diagnostic features and treatment modalities in a series of patients treated for HGG in our institution.

METHODS

Review of clinical presentation, radiological features and CSF analysis in a case series.

RESULTS

17 patients from our institution were diagnosed with LMD. The diagnosis of LMD was based on magnetic resonance image and/or cerebrospinal fluid (CSF) analysis. The spectrum of clinical presentation was broad, mainly intracranial hypertension, impaired general condition, pain, worsening of pre-existing symptoms, and epileptic seizures. Median time from onset of clinical deterioration to diagnosis of LMD was 3 weeks (0–16). Leptomeningial involvement was reported in 6/17 at initial MRI reading, whereas reassessment with careful comparison to previous MRI showed signs of LMD in all patients. CSF analysis revealed pleocytosis (11/17), high proteinorrachia (13/17), elevated lactate levels (15/16), low glucose levels (5/17), and increased CSF pressure (5/9). Nevertheless, diagnostic accuracy of initial CSF cytological analysis was low (2/17). A reassessment of the specimen by an experienced neuropathologist disclosed 1 additional positive and 1 additional suspect cytology. After diagnosis of LMD, salvage treatments comprised Bevacizumab, Lomustine, Fotemustine, liposomal cytarabine and best supportive care. The median overall survival after the diagnosis was 3 months.

DISCUSSION AND CONCLUSIONS

LMD in HGG is not a rare condition of recurrence, and its outcome is poor. It remains a diagnostic challenge, as it may be overlooked on MRI follow-up at its early stage. In case of clinical progression with no overt cause reported on MRI, we recommend careful second MRI reading. In case of doubt lumbar puncture should be performed in order to prove LMD and eliminate infection (i.e. HSV). Upon standard CSF indices, elevated lactate levels should give rise to the suspicion of LMD. Cytological CSF analysis seems to be of low diagnostic yield: This may be improved by faster processing after sampling and by standardized workup including staining with IDH, GFAP and Olig2.