bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of machine learning techniques to electron microscopic/spectroscopic image data analysis
Authors: Muto Shunsuke , Shiga Motoki
Published: September 2019

The combination of scanning transmission electron microscopy (STEM) with analytical instruments has become one of the most indispensable analytical tools in materials science. A set of microscopic image/spectral intensities collected from many sampling points in a region of interest, in which multiple physical/chemical components may be spatially and spectrally entangled, could be expected to be a rich source of information about a material. To unfold such an entangled image comprising information and spectral features into its individual pure components would necessitate the use of statistical treatment based on informatics and statistics. These computer-aided schemes or techniques are referred to as multivariate curve resolution, blind source separation or hyperspectral image analysis, depending on their application fields, and are classified as a subset of machine learning. In this review, we introduce non-negative matrix factorization, one of these unfolding techniques, to solve a wide variety of problems associated with the analysis of materials, particularly those related to STEM, electron energy-loss spectroscopy and energy-dispersive X-ray spectroscopy. This review, which commences with the description of the basic concept, the advantages and drawbacks of the technique, presents several additional strategies to overcome existing problems and their extensions to more general tensor decomposition schemes for further flexible applications are described.
Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
Authors: Andreou Tereza , Rippaus Nora , Wronski Krzysztof , Williams Jennifer , Taggart David , Cherqui Stephanie , Sunderland Ashley , Kartika Yolanda D , Egnuni Teklu , Brownlie Rebecca J , Mathew Ryan K , Holmen Sheri L , Fife Christopher , Droop Alastair , Lorger Mihaela
Published: September 2019

Background

Brain metastases (BrM) develop in 20–40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems.

Methods

Green fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene-expression analysis and subsequent validation of a series of promoter-green fluorescent protein-reporter constructs in mice (n = 5). One of the promoters was used to deliver tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL vs control group).

Results

HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (mean [SD] = 37.6% [7.2%] of all infiltrating cells for murine HSC progeny; 27.9% mean [SD] = 27.9% [4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3–53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (mean [SD] = 8.8% [7.8%]). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice. TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (mean [SD] = 19.0 [3.4] vs mean [SD] = 15.0 [2.0] days for TRAIL vs control group; two-sided P = .006), demonstrating therapeutic and translational potential of our approach.

Conclusions

Our study establishes HSC gene therapy using a myeloid cell–specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions.
Arabidopsis GAAPs interacting with MAPR3 modulate the IRE1-dependent pathway upon endoplasmic reticulum stress
Authors: Zhu Manli , Tang Xiaohan , Wang Zhiying , Xu Wenqi , Zhou Yan , Wang Wei , Li Xin , Li Rui , Guo Kun , Sun Yue , Zhang Wei , Xu Ling , Li Xiaofang
Published: September 2019

Arabidopsis GAAP1 and GAAP3 interacted with MAPR3. MAPR3 and the interaction between GAAPs and MAPR3 mitigated ER stress through modulation of RIDD and the autophagy pathway dependent on association with IRE1B.
Comparative genomics can provide new insights into the evolutionary mechanisms and gene function in CAM plants
Authors: Yang Xiaohan , Liu Degao , Tschaplinski Timothy J , Tuskan Gerald A
Published: September 2019

Crassulacean acid metabolism (CAM) photosynthesis is an important biological innovation enabling plant adaptation to hot and dry environments. CAM plants feature high water-use efficiency, with potential for sustainable crop production under water-limited conditions. A deep understanding of CAM-related gene function and molecular evolution of CAM plants is critical for exploiting the potential of engineering CAM into C3 crops to enhance crop production on semi-arid or marginal agricultural lands. With the newly emerging genomics resources for multiple CAM species, progress has been made in comparative genomics studies on the molecular basis and subsequently on the evolution of CAM. Here, recent advances in CAM comparative genomics research in constitutive and facultative CAM plants are reviewed, with a focus on the analyses of DNA/protein sequences and gene expression to provide new insights into the path and driving force of CAM evolution and to identify candidate genes involved in CAM-related biological processes. Potential applications of new computational and experimental technologies (e.g. CRISPR/Cas-mediated genome-editing technology) to the comparative and evolutionary genomics research on CAM plants are offered.
When leaving is normal and staying is novel: Men’s labor migration and women’s employment in rural Mozambique
Authors: Agadjanian Victor , Hayford Sarah R. , Oh ByeongDon
Published: September 2019

Considerable cross-national research has examined the impact of international labor migration on livelihoods in sending households and communities. Although findings vary across contexts, the general underlying assumption of this research is that migration represents a novel income-generating alternative to local employment. While engaging with this assumption, we also argue that in many sending communities where labor migration has been going on for generations, it is the decision not to migrate and instead to pursue local livelihood opportunities that might constitute a true departure from the expected behavior. Importantly, both the decisions to migrate and not to migrate are part of a household strategy shaped by gendered negotiation and bargaining. Building on these propositions, we use rich survey data from rural Mozambique, a typical setting of long-established large-scale international male labor out-migration, to examine married women’s gainful employment outside subsistence agriculture as it relates to their husbands’ migration or local work. We find a somewhat lower likelihood of employment among migrants’ wives, compared with nonmigrants’ wives, and this pattern strengthens with increased duration of migration. However, we also find substantial differences among nonmigrants’ wives: women married to locally employed men have themselves by far the highest probability of employment, while wives of nonemployed men are no different from migrants’ wives, net of other factors. These findings are discussed in light of interconnected gendered complexities of both migration-related and local labor market constraints and choices.
Histopathological study on the prevalence of trichosporonosis in formalin-fixed and paraffin-embedded tissue autopsy sections by in situ hybridization with peptide nucleic acid probe
Authors: Sadamoto Sota , Shinozaki Minoru , Nagi Minoru , Nihonyanagi Yasuhiro , Ejima Kozue , Mitsuda Aki , Wakayama Megumi , Tochigi Naobumi , Murakami Yoshitaka , Hishima Tsunekazu , Nemoto Tetsuo , Nakamura Shigeki , Miyazaki Yoshitsugu , Shibuya Kazutoshi
Published: September 2019

Trichosporon species are some of the most common pathogenic yeasts in Asia, and many are resistant to echinocandin antifungal drugs. Effective treatment of fungal infections requires the selection of appropriate antifungals and the accurate identification of the causal organism. However, in histopathological specimens Trichosporon spp. are often misidentified as Candida species due to morphological similarities. In situ hybridization (ISH) is a useful technique for identifying fungal species in formalin-fixed and paraffin-embedded (FFPE) tissue sections. Although many novel probes for ISH are available, the practical use of ISH for identification of fungi remains limited, in part due to the lack of adequate verifications. We conducted a two-center retrospective observational study in which the ISH technique was used to differentiate Trichosporon spp. and C. albicans in FFPE tissue from autopsy specimens. The study included 88 cases with blood stream yeast infection without Cryptococci extracted from 459 autopsy files of cases with proven invasive fungal infection (IFI). Positive signals for the Trichosporon spp. protein nucleic acid (PNA) probe and C. albicans PNA probe were seen for 7 and 35 cases, respectively, whereas the remaining 46 were negative for both. For the Trichosporon spp.- positive specimens, 5/7 were reported as candidiasis in autopsy records. Our results suggested that accurate histological identification of fungal infections remains challenging, but ISH may be a suitable approach to support histological findings. In addition, this retrospective study suggested that trichosporonosis may have high prevalence among cases of bloodstream yeast infections in Japan.
Origin of the galaxy H i size–mass relation
Authors: Stevens Adam R H , Diemer Benedikt , Lagos Claudia del P , Nelson Dylan , Obreschkow Danail , Wang Jing , Marinacci Federico
Published: September 2019

We analytically derive the observed size–mass relation of galaxies’ atomic hydrogen (H i), including limits on its scatter, based on simple assumptions about the structure of H i discs. We trial three generic profiles for H i surface density as a function of radius. First, we assert that H i surface densities saturate at a variable threshold, and otherwise fall off exponentially with radius or, secondly, radius squared. Our third model assumes the total gas surface density is exponential, with the H i fraction at each radius depending on local pressure. These are tested against a compilation of 110 galaxies from the THINGS, LITTLE THINGS, LVHIS, and Bluedisk surveys, whose H i surface density profiles are well resolved. All models fit the observations well and predict consistent size–mass relations. Using an analytical argument, we explain why processes that cause gas disc truncation – such as ram-pressure stripping – scarcely affect the H i size–mass relation. This is tested with the IllustrisTNG(100) cosmological, hydrodynamic simulation and the Dark Sage semi-analytic model of galaxy formation, both of which capture radially resolved disc structure. For galaxies with $m_* \ge 10^9\, {\rm M}_{\odot }$ and $m_{\rm H\, {\small {I}}} \ge 10^8\, {\rm M}_{\odot }$, both simulations predict H i size–mass relations that align with observations, show no difference between central and satellite galaxies, and show only a minor, second-order dependence on host halo mass for satellites. Ultimately, the universally tight H i size–mass relation is mathematically inevitable and robust. Only by completely disrupting the structure of H i discs, e.g. through overly powerful feedback, could a simulation predict the relation poorly.
The nature of faint radio galaxies at high redshifts
Authors: Saxena A , Röttgering H J A , Duncan K J , Hill G J , Best P N , Indahl B L , Marinello M , Overzier R A , Pentericci L , Prandoni I , Dannerbauer H , Barrena R
Published: September 2019

We present spectra and near-infrared images of a sample of faint radio sources initially selected as promising high-redshift radio galaxy (HzRG) candidates. We have determined redshifts for a total of 13 radio galaxies with redshifts ranging from 0.52 ≤ $z$ ≤ 5.72. Our sample probes radio luminosities that are almost an order of magnitude fainter than previous large samples at the highest redshifts. We use near-infrared photometry for a subsample of these galaxies to calculate stellar masses using simple stellar population models, and find stellar masses to be in the range $10^{10.8} {--}10^{11.7} \, \mathrm{M}_\odot$. We then compare our faint radio galaxies with brighter radio galaxies at $z$ ≥ 2 from the literature. We find that fainter radio galaxies have lower Ly α luminosities and narrower line widths compared to the bright ones, implying photoionization by a weaker active galactic nucleus (AGN). We also rule out the presence of strong shocks in faint HzRGs. The stellar masses determined for faint HzRGs are lower than those observed for brighter ones. We find that faint HzRG population in the redshift range 2–4 forms a bridge between star-forming and narrow-line AGNs, whereas the ones at $z$ > 4 are likely to be dominated by star formation, and may be building up their stellar mass through cold accretion of gas. Finally, we show that the overall redshift evolution of radio sizes at $z$ > 2 is fully compatible with increased inverse Compton scattering losses at high redshifts.
Dynamical friction in slab geometries and accretion discs
Authors: Vicente Rodrigo , Cardoso Vitor , Zilhão Miguel
Published: September 2019

The evolution of planets, stars, and even galaxies is driven, to a large extent, by dynamical friction of gravitational origin. There is now a good understanding of the friction produced by extended media, either collisionless or fluid-like. However, the physics of accretion or protoplanetary discs, for instance, is described by slab-like geometries instead, compact in one spatial direction. Here, we find, for the first time, the gravitational wake due to a massive perturber moving through a slab-like medium, describing e.g. accretion discs with sharp transitions. We show that dynamical friction in such environments can be substantially reduced relatively to spatially extended profiles. Finally, we provide simple and accurate expressions for the gravitational drag force felt by the perturber, in both the subsonic and supersonic regime.
PL3.2 Trabectedin for recurrent WHO grade II or III meningioma: a randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)
Authors: Preusser M , Silvani A , Le Rhun E , Soffietti R , Lombardi G , Sepulveda J , Brandal P , Beaney R , Bonneville-Levard A , Lorgis V , Bromberg J , Erridge S , Cameron A , Marosi C , Golfinopoulos V , Gorlia T , Weller M , Wick W
Published: September 2019

BACKGROUND

EORTC-1320-BTG investigated the activity, safety and quality of life of therapy with the tetrahydroisoquinoline alkaloid trabectedin (Yondelis®) in patients with recurrent higher-grade meningiomas. Trabectedin was originally derived from the Caribbean sea squirt, Ecteinascidia turbinata, and currently is manufactured by total synthesis.

METHODS

Adult patients with histological diagnosis of WHO grade II or III meningioma and radiologically documented progression after maximal feasible surgery and radiotherapy were randomly assigned in a 2:1 ratio to receive intravenous trabectedin (1.5 mg/m2every three weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS).

RESULTS

Within 22.1 months, we randomized a total of 90 patients (n=29 in LOC arm, n=61 in trabectedin arm) in 35 institutions and nine countries. In the LOC arm, the following treatments were administered: hydroxyurea (n=11), bevacizumab (n=9), none (n=4), chemotherapy (n=3), somatostatin analogue (n=1), combined chemotherapy and somatostatin analogue (n=1). With 71 PFS events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00–2.03; p=0.204) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) in the LOC and 21.1% (95% CI, 11.3%-32.9%) in the trabectedin arm. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR for death, 0.98; 95% CI, 0.54–1.76; p=0.94).Grade 3 to 5 adverse events occurred in 44.4% (18.5% related, 4 serious adverse events, 0 lethal events) of the patients in the LOC and 59% (32.8% related, 57 serious adverse events and 2 toxic deaths) of patient in the trabectedin arm.

CONCLUSIONS

In this first prospective randomized trial performed in recurrent grade II or III meningioma, trabectedin did not improve PFS and OS and was associated with significantly higher toxicity as compared to LOC treatment. The data collected in this study may serve as benchmark for future clinical trials in this setting.
PL3.5 Efficacy and safety of selinexor in recurrent glioblastoma
Authors: Lassman A B , Wen P Y , van den Bent M , Plotkin S R , Walenkamp A , Green A , Huang X , Karla Rodriguez-Lopez K , Kauffman M G , Shacham S , Mau-Soerensen M
Published: September 2019

BACKGROUND

New treatment modalities are needed for recurrent glioblastoma (rGBM). Selinexor is a novel, oral selective inhibitor of nuclear export which forces nuclear retention of tumor suppressor proteins including p53 and p27, leading to apoptosis. We previously reported interim results showing tolerability, preliminary efficacy, and blood-brain barrier penetration in a surgical cohort (N=8). We now report updated results following completion of accrual to non-surgical cohorts (N=68).

MATERIALS AND METHODS

This is an open-label, multicenter, phase 2 study of selinexor monotherapy. Patients (pts) not undergoing surgery for measurable rGBM per response assessment neuro-oncology criteria (RANO) were enrolled in one of 3 arms encompassing different dosing schedules of selinexor (50 mg/m2 [~ 85 mg] BIW, 60 mg BIW, and 80 mg QW). Treatment was continuous, although cycles were defined as 28 days and response was assessed every other cycle by MRI. Prior treatment with radiotherapy and temozolomide was required and prior bevacizumab was exclusionary. The primary endpoint was 6-month progression free survival (6mPFS) rate, calculated by the Kaplan-Meier method.

RESULTS

76 pts were enrolled; 24, 14 and 30 pts on doses of ~85 mg BIW, 60 mg BIW, and 80 mg QW, respectively. Median age was 56 years (range 21–78). Median number of prior treatments was 2 (range 1–7)

At the end of the 6 cycles, 30.2% pts on 80 mg QW were free from progression. The 6mPFS rate on 80 mg QW was 18.9%. Best RANO-defined responses (assessed locally) among 26 evaluable pts on 80 mg QW included 1 complete response, 2 partial responses, 7 stable disease, and 16 with progressive disease. Complete and partial responses were durable: the complete and a partial responder remain on selinexor for 393 and 1093 days respectively, as of the cut-off date. Median duration of response was 10.8 months. The most common related adverse events (all grades) in pts on ~85 mg BIW/60 mg BIW/80 mg QW were nausea (42%/64%/63%), leukopenia (38%/7%/43%), fatigue (71%/71%/47%), neutropenia (29%/14%/33%), decreased appetite (46%/71%/27%), and thrombocytopenia (67%/29%/23%).

CONCLUSION

Selinexor demonstrated efficacy, with durable responses and disease stabilization in rGBM. Based on the favorable efficacy and safety profile, selinexor at a dose of 80 mg QW is recommended for further development in rGBM.
JS1.3 Autoimmune encephalitis as immune related adverse event (irAE) of check point inhibitors (CPI) not so rare as we thought
Authors: Taliansky A , Gadot M , Urban D , Bar J , Shapira-Frumer R , Kaufman B , Asher N , Leibowitz-Amit R , Itay A
Published: September 2019

INTRODUCTION

CPI has significant efficacy and toxicities. We describe our experience with CPI treated patients diagnosed with irAE encephalitis.

METHODS

Patients treated with CPI during 2017–2018 were identified from institute’s EMR. Patients treated for irAE encephalitis were identified from the database of the Neuro-Oncology Unit of the Institute. Results: Eleven patients were diagnosed with irAE encephalitis out of 1500 treated with CPI at the Institute (0.73%). Four patients had NSCLC, 3 had melanoma, the one patient had each of SCLC, uterine carcinoma, RCC and breast cancer. Median age was 69 years (49–87). Four of 11 were treated with chemo-CPI, 3-with CPI combinations. Median onset of symptoms was at 19 days (5–180) following initial treatment. All events were high grade severity. Eight patients fully recovered after immunotherapy discontinuation and steroid treatment, of these, 2 melanoma patients underwent uncomplicated CPI re-challenge. Three patients, all non-melanoma, had severe neurological sequelae. Two of them were treated with steroids, PLEX and cyclophosphamide: one improved neurologically although died 6 months later from cancer. One patient was oncologically stable but died from neurological deterioration 7 months later. The additional patient was treated with steroids only because his advanced age and decease in hospice 2 months later.

CONCLUSION

Encephalitis, as an irAE of CPI, seems to be more common and severe than previously thought, predominantly in non melanoma patients. Nevertheless, in the majority of cases it is reversible and in some melanoma patients immunotherapy re-challenge is safe. Future studies will have to define risk factors and severity prediction.
OS1.6 Peripheral blood immune profiles at first recurrence of IDH wild type glioblastoma after standard chemoradiotherapy predict overall survival: secondary analyses of the phase II DIRECTOR trial
Authors: Wirsching H , Terksikh E , Manuela S , Carsten K , Patrick R , Becher B , Weller M
Published: September 2019

BACKGROUND

Isocitrate dehydrogenase (IDH) wildtype glioblastoma is associated with distinctive peripheral blood immune cell profiles that evolve under first line chemoirradiation with temozolomide. Whether peripheral blood immune cell profiles at recurrence are associated with survival of IDH wildtype glioblastoma has not been studied in detail.

PATIENTS AND METHODS

Peripheral blood mononuclear cells (PBMC) of 21 healthy donors and of 52 clinically well-annotated patients with IDH wildtype glioblastoma were analyzed by 11-color flow cytometry at 1st recurrence after standard chemoirradiation with temozolomide and at 2nd recurrence after dose-intensified temozolomide re-challenge. Patients were treated within the randomized phase II trial DIRECTOR, which explored the efficacy of dose-intensified temozolomide at first recurrence of glioblastoma. Patients were classified based on unsupervised analyses of PBMC profiles at 1stand 2ndrecurrence. Associations with survival were explored in multivariate Cox models controlling for established prognostic and predictive factors.

RESULTS

At 1strecurrence, two patient clusters were identified which differed in CD4+ T-cell fractions, but not with respect to CD8+ T-cells, CD4+;CD25+;FoxP3+ regulatory T-cells, B-cells or monocytes. The composition of CD4+, CD8+ or regulatory T-cell fractions was similar in both clusters. All control samples clustered with the CD4high cluster. Patients in both clusters did not differ by established prognostic factors, including age, O6-methylguanine-DNA-methyl-transferase (MGMT) gene promoter methylation, tumor volume, Karfnosky performance score or steroid use. Progression-free survival was similar (CD4high vsCD4low 2.1 vs 2.4 months, p=0.19), whereas post-recurrence overall survival was longer among the CD4highcluster (12.7 vs 8.7 months, p= 0.004). At 2nd recurrence, monocyte fractions increased, whereas memory CD4+ T-cell fractions decreased. Unsupervised segregation of patients by CD4+ subpopulations yielded two clusters characterized by the abundance of memory T-cell fractions and higher memory CD4+ fractions were associated with longer overall survival at 2nd recurrence (p=0.004). The reported prognostic associations were retained in multivariate Cox models controlling for established prognostic factors.

CONCLUSION

We conclude that temozolomide-associated memory CD4+ T-cell depletion may have deteriorating effects on the survival of glioblastoma patients.
OS3.1 Antiepileptic drugs and their association with depression, anxiety and subjective cognitive impairment in glioma patients
Authors: van der Meer P B , Taphoorn M J B , van den Bent M J , Dirven L , Koekkoek J A F
Published: September 2019

BACKGROUND

Epileptic seizures are a common symptom in glioma patients and generally treated with antiepileptic drugs (AEDs), which are considered to have the potential of mood-modulating and neurocognitive adverse effects. This observational study aimed to assess the independent association between AEDs and depression, anxiety and subjective cognitive impairment in glioma patients.

MATERIAL AND METHODS

Use of AEDs was defined as a categorical variable (none or at least one). Depression and anxiety were measured with the Hospital Anxiety and Depression Scale, while subjective cognitive impairment was measured with the Medical Outcomes Study-Cognitive Functioning Scale. Hierarchical multivariable logistic regression analyses were performed for each outcome separately. Besides use of AEDs, other confounding variables such as seizure severity and Karnofsky Performance Status score were included. Analyses were repeated for the two most commonly prescribed AEDs separately, levetiracetam or valproic acid, with the same confounding variables.

RESULTS

A total of 272 grade II-IV glioma patients were included in the study, of which 68% used at least one AED. Prevalence of depression was 10% for patients taking 0 AEDs and increased significantly to 21% (adjusted Odds Ratio [aOR]=2.4 [95%Confidence Interval {CI}=1.0–5.8]) for those taking ≥1. Prevalence was not significantly different between patients using 0 and using ≥1 AEDs for both anxiety (19% versus 26%, aOR=1.1 [95%CI=0.6–2.2]) and subjective cognitive impairment (16% versus 21%, aOR=1.2 [95%CI=0.6–2.5]). Although prevalences of depression (13% versus 23%, aOR=1.6 [95%CI=0.8–3.2]) and anxiety (17% versus 31%, aOR=1.8 [95%CI=0.9–3.3]), but not subjective cognitive impairment (20% versus 18%, aOR=1.7 [95%=0.4–1.4]), differed significantly between patients not using and using levetiracetam, these associations were not independent. No significant differences were found between patients not using and using valproic acid on the three outcome measures.

CONCLUSION

After adjustment of confounders, only depression was associated with the use of AED’s. No such relation was found for anxiety or subjective cognitive impairment. Use of levetiracetam or valproic acid were not independently related to depression, anxiety or subjective cognitive impairment.
OS6.1 Targeting Purine Metabolism to Overcome Therapeutic Resistance in Glioblastoma
Authors: Ahmed A U , Shireman J , Atashi F , Saathoff M , Ali E , Lee G , Park C , Savchuk S , Rayyan J , James C , Ben-Sahra I
Published: September 2019

BACKGROUND

A distinguishing characteristic of all cancers is uncontrolled cell division, and they require additional nucleotide bases such as purines, the building blocks of DNA and RNA, to sustain their uncontrolled growth. Purines can be synthesized from scratch by de novo pathway or salvaged by recycling surrounding nucleotides that are released by hydrolytic degradation. Even though the central nervous system (CNS), as well as CNS associated malignancies like glioblastoma (GBM), rely more heavily on the salvage pathway due to its energy efficiency, its precious role in promoting chemoresistance and GBM recurrence is yet to be elucidated.

MATERIAL AND METHODS

We have examined the role of purine biosynthesis in GBM by using stable isotope tracing analysis as well as utilizing a knockdown (KD) system to investigate its effect on i) DNA damage response during temozolomide (TMZ) therapy, ii) tumor engraftment and iii) therapeutic responses in vivo.

RESULTS

Through gene expression and protein-protein interaction analysis, we have identified ARL13B, member of ADP-ribosylation factor-like protein family, as a novel regulator of the purine biosynthesis pathway in GBM. ARL13B can physically interacting with the inosine monophosphate dehydrogenase 2 (IMPDH2), a key rate-limiting enzyme for purine biogenesis. Isotope tracer analysis under normal physiological conditions revealed that during TMZ treatment, salvage recycling activity was decreased by 50% while de novo pathway activity remains unchanged. In contrast, TMZ treatment of ARL13B knock-out cells results in a ~50% decrease in de novo pathway activity (p-value=0.004), whereas purine salvage pathway activity is upregulated ~6-fold (p-value <0.0001). ARL13B knockdown cells treated with TMZ show a robust increase in DNA double-strand breaks compared to control cells exposed to TMZ, as demonstrated by gH2X staining. Mice orthotopically engrafted with KD cells experience prolonged survival relative to mice engrafted with unmodified cells.

CONCLUSION

We propose that ARL13B-IMPDH2 interaction has two consequences: i) augmentation of de novo purine biosynthesis activity, and ii) inhibition of nucleotide recycling. The increasing de novo purine biosynthesis during TMZ therapy helps GBM cells reduce the recycling of nucleotides via the salvage pathway that have been modified as a result of TMZ alkylation. This, in turn, protects the cells from deleterious effects of incorporating modified nucleotides into newly-synthesized DNA while maintaining a supply of purine building blocks to support uncontrolled proliferation. Our results indicate that the interaction of ARL13B-IMPDH2 functions as a purine biosynthesis regulator that could be targeted for increasing efficacy of TMZ treatment of GBM. ​
OS6.5 ERGO2: A prospective randomized trial of a 9-day schedule of calorically restricted ketogenic diet and fasting or standard diet in addition to re-irradiation for malignant glioma
Authors: Voss M , Wagner M , von Mettenheim N , Harter P N , Wenger K , Franz K , Bojunga J , Gerlach R , Glatzel M , Paulsen F , Hattingen E , Baehr O , Ronellenfitsch M W , Fokas E , Imhoff D , Steinbach J P , Rödel C , Rieger J
Published: September 2019

BACKGROUND

Ketogenic diet (KD) and fasting have anticancer effects in tumor models, possibly due to a differential stress response with sensitization of tumor cells and protection of normal tissue. We therefore set up ERGO2 (NCT01754350), the first randomized clinical trial of calorically-restricted KD and intermittent fasting (KD-IF) in addition to re-irradiation for recurrent malignant gliomas.

MATERIAL AND METHODS

Patients were randomized 1:1 to re-irradiation combined with either calorically unrestricted diet (standard diet, SD) or KD-IF. The KD-IF schedule included 3 days of KD (21–23 kcal/kg/d), followed by 3 days of fasting and again 3 days of KD. The primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6). Secondary endpoints were PFS, local control, overall survival (OS), frequency of epileptic seizures, rate of ketosis and quality of life.

RESULTS

50 patients were included. Four patients quit the trial before treatment and three patients stopped KD-IF prematurely. Of the 20 patients who completed KD-IF, 17 patients developed ketosis at day 6, and glucose levels declined significantly. KD-IF was well-tolerated with a modest weight loss of -2.1±1.8 kg. No severe adverse events attributable to the diet occurred. There was no difference in PFS6 between the two groups (KD-IF: 20%, SD: 16%). Similarly, no difference in PFS, local PFS6 and OS were observable. Explorative analysis revealed that among patients of the KD-IF group, those who achieved ketosis of at least 1.5 mmol/l had significantly longer PFS compared to those with lesser or no ketosis.

CONCLUSION

KD-IF is feasible and effective in inducing ketosis in heavily pretreated patients with recurrent glioblastoma. However, the short schedule reported here failed to increase the efficacy of re-irradiation.
OS7.3 Health-related quality of life (HRQoL) evaluation in the REGOMA trial: a randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients
Authors: Lombardi G , Del Bianco P , Brandes A , Eoli M , Rudà R , Ibrahim T , Lolli I , Pace A , Daniele B , Pasqualetti F , Rizzato S , Bergo E , Caccese M , Padovan M , Soffietti R , De Salvo G , Zagonel V
Published: September 2019

BACKGROUND

REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point.

MATERIAL AND METHODS

HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P=0.01 (2-sided).

RESULTS

Of 119 randomized pts, 117 partecipated in the HRQoL evaluation, and 114 had a baseline assessment (n=56 REG; n=58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD=28.6) vs 7.6 (SD=16.0); p=0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively;p=0.02).

CONCLUSION

In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.
OS7.5 Healthcare utilization, medication use, and productivity loss in glioma patients with depressive symptoms and their family caregivers
Authors: Boele F W , Jansen F , Meads D , Verdonck-de Leeuw I M , Heimans J J , Reijneveld J C , Short S C , Klein M
Published: September 2019

BACKGROUND

Gliomas are associated with great societal burden through both direct (health and social care) and indirect (e.g., productivity loss) costs, but socioeconomic reports are scarce. We describe costs in a sample of glioma patients at high risk for depression and their family caregivers, and explore relationships between costs and treatable symptoms (depression; fatigue; cognitive complaints).

MATERIAL AND METHODS

Data from a nationwide randomised trial comparing internet-based therapy for depressive symptoms with waitlist controls were used.

Healthcare utilization, medication use, and productivity loss based on the

Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TIC-P) were described and costs in the past 4 weeks were calculated. Caregivers reported on their own costs and wellbeing

We used generalized linear regression models to predict costs using multiple observations per participant and robust standard errors. We included depressive symptoms (CES-D), fatigue (CIS), cognitive complaints (MOS), tumour grade (low-/high-grade), and disease status (stable/progression/active treatment).

RESULTS

Data from 91 glioma patients and 46 caregivers were used with multiple assessments from baseline through 12 months follow-up. Baseline data showed that over a 4 week period, 64.8% of patients (M=€394.99, sd=856.83) and 41.3% of caregivers (M=€131.11, sd=392.89) had used healthcare services. Medication was used by 90.1% of patients (M=€100.83, sd=191.07) and 43.5% of caregivers (M=€13.19, sd=21.03). Productivity loss resulted in M=€1231.19, sd=2185.35 for patients and M=€310.92, sd=841.36 for caregivers. In total, mean direct and indirect costs were €1632.22 (sd=2314.25) for patients and €447.85 (sd=1002.94) for caregivers. In patients, more depressive symptoms and cognitive complaints were associated with increased healthcare use costs; higher tumour grade and active disease were linked with higher medication costs (all p<.05). Active treatment was related to higher overall costs (p<.05). In caregivers, increased caregiver fatigue was associated with higher productivity loss and overall costs; more caregiver cognitive complaints were associated with higher total costs; higher tumour grade was associated with higher healthcare use and total costs; and patient active treatment was linked with higher healthcare use costs (all p<.05).

CONCLUSION

Direct and indirect costs are substantial in glioma patients and caregivers. This indicates that the true cost of brain tumours is a burden shared between patients, caregivers, the healthcare system, and society more widely. Tentative links between costs and symptoms of depression, fatigue, and cognitive complaints indicate that adequate support may lead to cost reductions. Multivariable regression models are currently being prepared.
OS7.6 Socioeconomic burden and associations with quality of life in meningioma patients
Authors: Wirsching H , Morel C , Roth P , Weller M
Published: September 2019

BACKGROUND

Socioeconomics affect the outcome of neurological patients, but the socioeconomic burden of brain tumors has not been studied in detail.

PATIENTS AND METHODS

This survey study in a clinically well-annotated cohort of meningioma patients was designed to explore socioeconomic status parameters at diagnosis and one year thereafter. The survey comprised level of education, profession, employment status, subjective work ability, monthly income and the EPICES social deprivation score. Quality of life (QoL) and symptom burden were queried utilizing the EORTC-QLQ-C30/BN20 and MDASI-BT. A multivariate binary regression model was applied to explore associations of socioeconomics with QoL.

RESULTS

Completed surveys were obtained from 249 of 410 patients (61%) who were invited to participate. The level of education was an apprenticeship or higher in 214 patients (86%). One year after diagnosis, there was a 20% decline in the fraction of employed patients and a more than twofold increase in unemployment and disability (p<0.001). There was a decrease in monthly income among patients with a baseline income below national average (p=0.008). On multivariate analyses, there was an association of inferior QoL with pre-operative unemployment or retirement (OR 2.43, 95% CI 1.02–5.88), whereas a subjective work ability of >70% was associated with better QoL (OR 0.37, 95% CI 0.15–0.92).

CONCLUSION

Socioeconomics assessments should be incorporated in prospective neuro-oncology clinical trials. A more detailed knowledge of the effects of socioeconomics on patient outcome will aid in identifying patients at risk for deterioration and allow to implement improved preventive and supportive strategies.
OS8.6 Sensitivity of human meningioma cells to the cyclin-dependent kinase inhibitor, TG02
Authors: Le Rhun E , von Achenbach C , Sahm F , Wang S S , Neidert M C , Rushing E , Lawhon T , Schneider H , von Deimling A , Weller M
Published: September 2019

BACKGROUND

Standards of care for meningioma include surgical resection, which may be curative, and radiotherapy as required. Pharmacotherapy plays only a minor role in this disease; however, novel systemic approaches are urgently needed for patients who are no longer candidates for local therapy.

MATERIAL AND METHODS

We generated primary cultures from surgically removed meningiomas to explore the activity of a novel cyclin-dependent kinase inhibitor, TG02, in meningioma cell cultures. Tumor and cell cultures were characterized by mutation profiling and DNA methylation profiling. DNA methylation data were used to allot each sample to one out of six previously established meningioma methylation classes: benign (ben)-1, 2, 3, intermediate (int)-A, B, and malignant (mal). The activity of TG02 was assessed by standard cell culture assays.

RESULTS

Cell cultures were derived from nine meningiomas. Four tumors assigned to the methylation class ben-2 showed the same class in the cell culture whereas cell cultures from five non-ben-2 tumors showed a different class, a more malignant class in four of five patients. Cell cultures were uniformly sensitive to the growth inhibitory effects of TG02 in the nanomolar range. Assignment of the cell cultures to a more malignant methylation classifier appeared to be more closely associated with TG02 sensitivity than assignment to a higher WHO grade of the primary tumors.

CONCLUSION

Primary cell cultures from meningioma facilitate the investigation of the anti-meningioma activity of novel agents. TG02, an orally available cyclin-dependent kinase inhibitor, warrants further exploration in this disease.
OS9.3 Clinical, molecular and radiomic profile of gliomas with FGFR3-TACC3 fusion
Authors: Picca A , Alentorn A , Saragoussi E , Bielle F , Ducray F , Villa C , Schmitt Y , Lerond J , Leclerc J , Lasorella A , Iavarone A , Mokhtari K , Savatovsky J , Sanson M , Di Stefano A
Published: September 2019

PURPOSE

Actionable oncogenic fusion FGFR3-TACC3 (F3T3) is found in 3% of gliomas. Our goal was to characterize the clinical, radiological and molecular features of patients with F3T3-positive glioma.

PATIENTS AND METHODS

Overall, we screened 1112 gliomas by RT-PCR (861 WHO grade IV, 140 grade III and 111 grade II) and identified 50 F3T3-positive cases. We performed a radiological and radiomic case control study.

RESULTS

F3T3 fusion was exclusively found in IDH wild-type gliomas. F3T3 was mutually exclusive with the EGFR amplification (0/38 versus 143/336 of F3T3-negative cases, P=0.01), whereas it was associated with CDK4 amplification (7/33 versus 22/321 of F3T3-negative cases, P=0.04) and MDM2 amplification (6/33 versus 15/354 of F3T3-negative cases, P=0.03). F3T3-positive gliomas showed a longer overall survival than F3T3-negative gliomas (median OS 40.1 and 20.0 months, P=0.02), particularly in the grade IV subgroup (40.1 versus 19.0 months, P=0.006). Multivariate analysis showed that F3T3 fusion is an independent predictor of favorable outcome for glioblastoma patients. F3T-positive gliomas were associated with involvement in non-eloquent areas (r=0.31 P=0.007), cortico-subcortical regions and insula involvement (adjusted p<0.001), poorly defined enhancing margins (r=0.48 P<0.001), poorly defined non-enhancing margins (r=0.61 P<0.001), and higher proportion of edema (r=0.43 P<0.001). Radiomics analysis correctly classified F3T3-positive glioma with an AUC of 0.82. We compared different Cox proportional hazards models using Harrel’s C-Index. Although radiomics alone obtained a high C-Index (0.75, SD 0.04), the model combining clinical, genetic and radiomic data showed the highest C-index (0.81, SD 0.04).

CONCLUSION

Gliomas harboring F3T3 gene fusions show specific molecular features, distinct radiological and radiomic features and a less aggressive clinical evolution.
OS12.3 L3MBTL3 is a novel suppressor of medulloblastoma tumorigenesis
Authors: Rual J
Published: September 2019

BACKGROUND

Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements but are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed and molecular stratification of patients with medulloblastoma has yet to be routinely implemented in the clinic. TheNotchpathway governs cell proliferation in many biological contexts, including SHHand Group#3medulloblastoma tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of Notch for the modulation of Notch signals, and L3MBTL3, a methyllysine reader.L3MBTL3 is recruited by RBPJ on chromatin at the enhancers of Notch/RBPJ target genes to repress their expression.Deletions ofthe L3MBTL3locus are observed in patientswith WNTand Group#3medulloblastomaand expression of L3MBTL3 in the SHHmedulloblastoma-derived cell DAOY inhibits cell growth, suggesting a putative tumor suppressor role for L3MBTL3 in medulloblastoma.

METHODS

To further investigate the putative role of L3MBTL3 as a suppressor of medulloblastoma tumorigenesis, we used our novel L3mbtl3KO mouse in combination with a genetically engineered ND2:SmoA1mouse model of SHHmedulloblastoma in a survival analysis.

RESULTS

Our survival analysis validated in vivoour hypothesis that L3mbtl3is a tumor suppressor in this disease context. Indeed, our data show that [ND2:SmoA1; L3mbtl3+/-] mice have a significantly lower survival rate than ND2:SmoA1 mice (P= 0.0322; Log-rank test). Hence, the RBPJ-L3MBTL3 interaction is at the heart of a molecular mechanism governing the repression of Notch/RBPJ target genes and malfunction of this molecular mechanism contributes to L3MBTL3’s tumor suppressor role in medulloblastomathrough aberrant “de-repression” of Notch/RBPJ target genes.

CONCLUSION

L3MBTL3 is a novel suppressor of medulloblastoma tumorigenesis. Our discovery providesinsights into the role of the L3MBTL3 inmedulloblastomathat could be harnessed in the future for the therapeutic benefit of patientswith medulloblastoma.
P03.03 Dynamics of brain metastasis cavities between resection and adjuvant stereotactic radiotherapy and impact of the delay on local control
Authors: Mousli A , Bihin B , Gustin T , Koerts G , Mouchamps M , Daisne J F
Published: September 2019

BACKGROUND

Adjuvant stereotactic radiotherapy (SRT) to the surgical cavity of brain metastases (BM) improves the local control. An early post-operative irradiation is desirable to limit the risk of recurrence while delaying it might reduce the risk of radionecrosis by reducing the size of the target volume (TV) thanks to the cavity constriction. The purpose of our study was to examine cavity dynamics after resection to determine if delaying SRT influences cavity size as well as local progression (LP).

MATERIAL AND METHODS

We reviewed 70 BM resection cavities treated with adjuvant SRT. A preoperative, immediate postoperative and at the time of SRT, 3D T1-weigthed MRI, were available for all patients. The volumes were retrospectively calculated with the PACS software Telemis® version 4 and the iPlan RT image software. For all cavities, the TV was obtained by expanding the cavity by a median margin of 2mm to account for microscopic spread. The surgical track and edema areas were not included in the TV. The dynamic evolution of cavities and LP according to the delay of SRT were analyzed.

RESULTS

The median time from surgery to SRT was 27 days (3–99). The median preoperative and SRT cavity volumes were 7.2 cc (ranges: 0.5–29.5) and 8 cc (ranges: 0.8–31), respectively. After margin expansion, the TV was increased to a median of 14.8 cc. The volumetric cavity changes were an increase by 2 cc in 35 %, whereas only 22.5 % decreased by 2 cc and 42.5% cavities were stable (defined as a change ≤2 cc). We noted that 11% of volume change were attributable to the delay (r2 = 0.11). forty-seven patients were treated within a delay of 30 days and experienced early LP in 10.6 % against 20 % beyond 30 days (p= 0.6).

CONCLUSION

In the interval between surgery and SRT, BM cavities dynamics are inconstant and unpredictable in function of time. Furthermore, delaying SRT may compromise local control, though the difference was not statistically significant due to the small size of our population. A preoperative SRT strategy looks more promising by alleviating the problem of time and reducing the volume of irradiated brain.