tbuckley/cabot-search huggingface dataset:
P09.18 Location-dependent prognostic factors and recurrence patterns in IDH wildtype glioblastoma
Authors: C. Jungk, R. Warta, A. Mock, B. Hug, M. Bendszus, A. von Deimling, A. Unterberg, C. Herold-Mende
Journal: Neuro-Oncology (2017)

OBJECTIVE: Recent studies suggest that glioblastomas (GBM) contacting the subventricular zone (SVZ) confer a dismal prognosis and may be linked to a distinct cell of origin compared to their cortical counterparts. However, existing analyses have disregarded the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase (IDH) mutant GBM. We therefore sought to examine location-dependent prognostic factors and recurrence patterns exclusively in IDH wildtype GBMs. METHODS: Out of a consecutive cohort of 302 GBM patients treated at our department from 2004 until 2011 for whom clinical, molecular and imaging data were available, 288 patients (95%) did not harbor IDH mutations as ruled out by immunohistochemistry or direct sequencing. Based on preoperative contrast-enhancing MR images, patients were allotted to GBM with (SVZ+) and without (SVZ-) SVZ involvement or with (cortex+) and without (cortex-) cortical involvement, respectively, and compared for demographic, treatment-related, imaging and survival data at first diagnosis and recurrence. Multivariate survival analysis was performed employing a Cox proportional hazards model with stepwise forward selection of covariates. Results: IDH mutations were more common in SVZ- GBMs (7% vs. 2% in SVZ+ GBMs; p=0.04). Consequently, only IDH wildtype GBM were analyzed. Demographic (age, sex) and treatment-related factors (Karnofsky performance status, completion of Stupp regimen, treatment within clinical trials) were balanced between groups with two exceptions: SVZ+ GBMs were found to have a lower frequency of complete resections at first diagnosis (p<0.0001) and lower non-surgical treatment intensity at recurrence (p=0.0009). Regarding growth and recurrence patterns, multifocal disease both at first diagnosis (p=0.031) and at recurrence (p=0.0006) was more common in cortex+ GBMs, together with a higher frequency of distant recurrences (28% vs. 2% in cortex- GBMs; p<0.0001). Besides established clinical prognostic factors (higher age, subtotal resection, lower treatment intensity at first diagnosis and recurrence), multivariate survival analysis identified SVZ involvement as the only independent prognosticator of inferior overall survival (p=0.018; HR=1.58) and survival after relapse (p=0.015; HR=1.58). Conclusions: In this large-scale analysis of IDH wildtype GBMs, SVZ involvement significantly contributed to their dismal prognosis. In contrast, cortical involvement determined growth and recurrence patterns. This holds out the prospect for location-tailored prognostication and treatment planning. Interestingly, IDH mutations were enriched in non-SVZ GBM that, together with distinct clinical features, supports the hypothesis of location-dependent cells of origin.
P16.25 Surgical resection and cellular proliferation predict prognosis for papillary glioneuronal tumor
Authors: A. Ahmed, H. Y. Dawood, J. Gerard, T. R. Smith
Journal: Neuro-Oncology (2017)

Object: The World Health Organization classifies papillary glioneuronal tumor (PGNT) as Grade I, however, several malignant cases have been reported. PGNT is a rare brain tumor that occurs in the white matter and affects young adults. The purpose of this study was to establish the clinical characteristics of this unfamiliar entity. Methods: PubMed/NCBI was queried for patient-level reports of PGNT, resulting in 132 cases. Six additional cases treated at Brigham & Women’s Hospital and Massachusetts General Hospital were assessed for a total of 138. A Kaplan-Meier and Cox regression analyses were conducted to determine predictors of progression-free survival (PFS). Results: PGNT has a higher prevalence in males (1.4:1), and presents at age 27.1 ± 16.4 (SD). Presenting symptoms include headache (64%) and seizure (37.8%), with a mean duration of 13.3 months. Average radiological size is 4.3 cm. Common locations of occurrence were frontal (32.1%) and temporal (22.4%) lobes. Tumors were periventricular (48.2%, effacing), proximal to a ventricle (20%, <1.0 cm) and intraventricular (11.8%). They were commonly cystic/solid (39.8 percent). Tumors often demonstrated calcification (47.7%) and edema (45.5%). Enhancement on magnetic resonance imaging showed a heterogeneous (32%) or ring pattern (25.2%). The average Ki-67 index of proliferation was 3.6, with six cases greater than 10. Treatment included gross-total resection (GTR), subtotal resection (STR), and adjuvant radiation, chemotherapy or both. Five years post-treatment, PGNT had an 85.1 PFS rate (95% CI:75.2-91.2). In patients treated with surgery alone, PFS was higher after GTR compared to after STR (Mantel-Cox analysis, p<0.0001). Cox regression analysis demonstrated that recurrence is nearly 10 times more likely after STR than after GTR (p<0.001). A Ki-67 index less than 5 percent resulted in a greater PFS than an index greater than 5 percent (p<0.001). Conclusion: PGNT is a benign tumor, but can present atypically as high-grade. GTR is the most common treatment, and cases can warrant radiation and chemotherapy. Maximal surgical resection and cellular proliferation are prognostic indicators for PGNT. This study represents the most comprehensive clinical understanding of this rare tumor. More research is needed to evaluate the diverse presentation of PGNT.
Understanding Neuroendocrine Tumors—A NET Gain
Authors: Pamela L. Kunz
Journal: JAMA Oncology (2017)

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P09.38 Pattern of recurrence and factors associated with progression to non-local recurrence in glioblastomas
Authors: M. Ohno, Y. Miyakita, M. Takahashi, Y. Matsushita, S. Miki, Y. Kitagawa, T. Yamaguchi, K. Ichimura, Y. Narita
Journal: Neuro-Oncology (2017)

Objective: Glioblastomas (GBMs) mainly occur locally, and develop distant or disseminated recurrence (non-local recurrence) in the time course of disease. Non-local recurrences indicate tumor cells invasion into normal brain or cerebrospinal fluid (CSF) space, and the treatment will be difficult. We studied the pattern of recurrence in GBMs treated with prolonged temozolomide (TMZ) maintenance and the risk factors to progress to non-local recurrence. Methods: We investigated 102 GBM patients with single lesion, who were treated with combined chemoradiotherapy using TMZ for a total of 24 cycles or until disease progression between May 2006 and May 2013. Pattern of recurrences were classified as local (at the regional tumor), distant (intraparenchymal, but distant from the original tumor site), and disseminated (distant from the original tumor and exposed to the CSF space, including subarachnoidal, subependymal, intraventricular, and spinal lesion). IDH1/2 mutation and O-6-methylguanine DNA ­methyltransferase (MGMT) promoter methylation were analyzed by direct sequencing and pyrosequencing, respectively. Results: Of 102 patients, 76 developed radiological recurrences including 48 (63.2%) local, 13 (17.1%) distant, and 15 (19.7%) disseminated. Of 48 the local recurrent tumors, 37 developed radiological recurrences including 24 (64.9%) local, 9 (24.3%) distant, and 5 (13.5%) disseminated. Finally, of the 76 recurrences, 50 (65.8%) developed non-local recurrences. The median time to local recurrence was 17.6 months, whereas that to disseminated was 42.4 months (p = 0.0023), and that to distant was not reached (p < 0.0001). Multivariate analyses of 76 patients who were available for IDH1/2 and MGMT promoter status analysis indicated that extent of resection, IDH1/2 mutations, and MGMT promoter methylation were correlated with non-local recurrence. In 45 GBMs with IDH1/2 wildtype and MGMT promoter unmethylation (IDH-WT-Unmet GBMs), the median time to local recurrence was 9.6 months, whereas that to disseminated was 24.5 months (p = 0.025), and that to distant was 17.4 months (p = 0.023). Conclusions: The predominant pattern of recurrence is local, and non-local recurrences increase cumulatively. The risk factors of developing non-local recurrence are partial/biopsy, IDH1/2 wildtype, and MGMT promoter unmethylation. Our results indicate that intensifying local tumor control before progression of non-local recurrence is the mainstay of treatment, especially in IDH-WT-Unmet GBMs.
Megakaryocyte Expansion and Platelet CD34 Expression Observed in GFI1BQ287*-Related Bleeding and Platelet Disorder Is Caused By Quenching of the Lysine Specific Demethylase LSD1/KDM1A
Authors: Rinske van Oorschot, Anna E. Marneth, Marten Hansen, Saskia M. Bergevoet, Alexander B. Meijer, Britta A.P. Laros-van-Gorkom, Joop H. Jansen, Marieke Von Lindern, Emile van den Akker, Bert A. van der Reijden
Journal: Blood (2016)
P01.30 In vivo effects of isoform-specific inhibition of TGF-β3 in glioblastoma
Authors: K. Seystahl, I. Burghardt, D. Gramatzki, H. Schneider, A. Papachristodoulou, K. Hasenbach, K. Frei, M. Janicot, P. Roth, M. Weller
Journal: Neuro-Oncology (2017)

Introduction: Transforming growth factor (TGF)-β has been considered a therapeutic target in glioblastoma since decades. However, despite promising preclinical research data, the efficacy of TGF-β-targeted compounds in in vivo models and in clinical trials has been limited. Most recent approaches used inhibition of the TGF-β-receptor system but not of the ligand(s). Since three isoforms (TGF-β1/2/3) are expressed in glioblastoma, inhibiting one of the isoforms might not be sufficient. So far, an isoform-specific function in glioblastoma has not been reported. METHODS: We studied two different antisense oligonucleotides (ISTH2020 and ISTH2023) specific for TGF-β3 in in vitro and in vivo glioblastoma models. In patient glioblastoma tissue samples (64 newly diagnosed glioblastoma, 16 recurrent glioblastoma), the mRNA expression pattern of TGF-β isoforms was analyzed and correlated with survival. Results:In vitro, ISTH2020 and ISTH2023 reduced TGF-β3 mRNA and protein without affecting the isoforms TGF-β1/2 in human LN-308 cells. Inhibition of TGF-β3 led to reduced phosphorylation of SMAD2 and SMAD1/5 and reduced invasiveness in vitro. Depletion of TGF-β3 also diminished signaling induced by stimulation with TGF-β1 or TGF-β2. In orthotopic syngeneic (SMA-560) and xenograft (LN-308) in vivo mouse glioma models, systemic application of ISTH2020 or ISTH2023 led to isoform-specific inhibition of TGF-β3 expression. Expression of plasminogen-activator-inhibitor (PAI)-1 expression as a downstream target was also reduced in these models. In tumor tissues of patients with glioblastoma, TGF-β3 mRNA expression was significantly lower than expression of TGF-β1/2. High expression of either isoform was not correlated with patient survival when using the median expression level as a cutoff. CONCLUSION: Targeting TGF-β3 leads to inhibition of downstream mechanisms in vitro and in vivo although TGF-β1/2 are present and overall expression levels of TGF-β3 are lower than of TGF-β1/2. Therefore, targeting TGF-β3 represents a promising strategy interfering with aberrant TGF-β signaling in glioblastoma.
P11.05 Visual impairment in intracranial germinomas
Authors: D. Frappaz, C. Pedone, P. Thiesse, C. Faure-Conter, C. Carrie, A. Szathmari, C. Mottolese
Journal: Neuro-Oncology (2017)

Blurred vision is common among patients with brain tumor. It may result from increased intracranial pressure and/or compression and/or invasion of the optic pathway. We assessed the incidence and etiology of visual impairment in patients with intracranial germinoma tumors (ICGT). METHODS AND MATERIALS: We performed a blinded retrospective review of the charts and initial imaging of 28 patients with ICGT. Thirteen tumors were pineal; 5 were supraoptic, 7 bifocal; and one each involved the optic nerve, corpus callosum, and brainstem. RESULTS: Twelve patients reported decreased visual acuity. Six of them demonstrated no clinical or radiological signs of raised intracranial pressure; five showed invasion and/or compression of the anterior optic pathway. Two of those were initially managed as “retrobulbar neuritis” when endocrinological symptoms prompted magnetic resonance imaging. The involvement of the optic pathway was underestimated and both relapsed. Three further patients had supraoptic mass with contiguous involvement and/or compression of the chiasm. None of the patients with loss of visual acuity and headache and none of those with no loss of visual acuity had invasion/compression of the anterior optic pathway and none relapsed. CONCLUSIONS: Compression and/or invasion of the optic pathway by germinoma is not rare and should not be overlooked when thickening and/or contrast enhancement is detected. Radiotherapy fields should be extended accordingly.
Comparisons of RNA-seq results for cryopreserved (CRYO) and formalin fixed, paraffin-embedded (FFPE) samples.
Authors: Umar Farooq, Prashant Singh, Michael Gooch, Linda Burian, M. Melinda Sanders, Richard Bernard Everson
Journal: Journal of Clinical Oncology (2013)

e22211 Background: FFPE is the worldwide clinical standard for preservation of tissue samples. Although CRYO tissues are widely used for research, most gene expression assays in clinical use analyze FFPE by RT-PCR. Use of RT-PCR limits numbers of transcripts that can be studied with material available. Next Generation Sequencing promises to overcome those limitations, but for FFPE, there are concerns related to its accuracy including bias associated with RNA truncated at the 3’ end. Little data is available illustrating the extent of truncation or considering implications for bioinformatics analysis of sequencing results. Methods: Total RNA was extracted from patient consented specimens of tumor and normal bladder tissue split with matching halves processed by CRYO and FFPE. Paired end sequencing libraries 100 bp in length were generated using Illumina TruSeq RNA sample kits with minor modifications for FFPE samples. Sequencing was performed on the Illumina HiSeq 2000, aligned with TopHat using the hg19 reference sequence, and further analyzed using open source bioinformatics tools. Results: Comparing Cryo and FFPE reads for a representative specimen, the proportion of reads that mapped to the reference genome were 69% and 63% for normal, and 66% and 63% for tumor specimens. Mapped reads yielded over 25,000 significantly expressed transcripts, isoforms, and splice variants. The extent of 3’ bias was investigated by viewing data in the Integrated Genome Viewer and using Picard tools. Preliminary estimates of 3’ bias in FFPE showed 2.22 for normal and 1.48 for tumor. After accounting for bias, transcripts in CRYO vs FFPE were significantly correlated for both normal tissue and tumor (R 2 = 0.76 and 0.95, respectively). Mutations previously identified in these samples by SureSelect hybrid capture system (Agilent) were also observed in the RNA-seq data. Conclusions: FFPE samples can be successfully analyzed by RNA-Seq, allowing the analysis of standard clinical samples and vast quantities of richly annotated archival specimens. Results from CRYO and FFPE analyses are similar when performed using minor modifications to sequencing library preparation and careful attention to appropriate analysis.
P01.32 NDRG1 induced downregulation of CCL2 influences the migration of macrophages and impacts the tumor microenvironement
Authors: C. Thomé, J. Blaes, P. Rübmann, A. Hertenstein, T. Kessler, J. Sonner, K. Deumelandt, M. Breckwoldt, M. Platten, W. Wick
Journal: Neuro-Oncology (2017)

BACKGROUND: Malignant gliomas belong to the most aggressive neoplasms in humans. The interactions and intercellular communication between malignant and non-malignant cells in the tumor microenvironment are tumor-promoting and critically to improve the understanding of the disease. N-myc downstream regulated gene 1 (NDRG1) is a stress inducible gene and key determinant of resistance towards alkylating chemotherapy in glioblastoma. NDRG1 promotes invasive growth and acts antiapoptotic in hepatocellular carcinoma. In human pancreatic cancer cells NDRG1 suppresses chemokine expression, decreases macrophage infiltration and microvascular density. Further understanding the influence of NDRG1 on the tumor microenvironment may lead to new therapeutic approaches in glioma. METHODS: To analyze the NDRG1 effects on the glioma microenvironment, we used human and murine NDRG1 knockdown (KD) cells. In orthotopic xenograft experiments control and KD microenvironments were compared for infiltrating immune cells dependent on NDRG1. Interaction and signaling mechanisms were evaluated in vitro using western blots, cytokine and migration assays and treatment with the NF-kB inhibitor JSH-23 as well as SGK1 inhibitor EMD638683 to assess the influence of NDRG1. Results: Orthotopic NDRG1 KD tumors were significantly larger compared to control tumors. Ex vivo flow cytometry analyses of the tumor microenvironment revealed a significant increase in peripheral macrophages, dendritic cells and monocytic myeloid derived suppressor cells in NDRG1 KD tumors. In vitro cytokine array analyses showed an increase of the chemokine CCL2 in NDRG1 KD cells compared to control cells. This was confirmed by ELISA. Macrophages showed an increased migration rate in the NDRG1 knockdown environment. To analyze molecular mechanisms CCL2 secretion was blocked with a NF-κB inhibitor (JSH-23) and stimulated with a SGK1 inhibitor (EMD638683). We found that NDRG1 induced NF-κB signaling attenuation is mediated through decreases in IKK α expression and IκBα phosphorylation. CONCLUSION: We identified CCL2 as a NDRG1-induced NF-κB target gene that triggers macrophage recruitment. Our findings support an immunomodulatory effect of NDRG1 on the tumor microenvironment and provide novel insights into the biological relevance of the tumor stroma and the function of NDRG1 with important implications for the development of cancer therapeutics.
P09.28 MGMT promoter methylation status in glioblastoma (GBM) patients: a quantitative pyrosequencing approach and its prognostic role
Authors: G. Lombardi, L. Bellu, R. Bertorelle, A. Pambuku, M. Gardiman, P. Fiduccia, A. Della Puppa, F. Berti, D. D’Avella, V. Zagonel
Journal: Neuro-Oncology (2017)

Background: MGMT gene promoter methylation status is acknowledged as a prognostic factor and predictive marker for temozolomide (TMZ) treatment. Although MGMT status determined by pyrosequencing was showed to correlate with progression free survival (PFS) and overall survival (OS), it is still unclear a cut-off value that discriminates between methylated and unmethylated patient (pts) and its correlation with the patient clinical outcome. Matherials and Methods: We analyzed the tissue samples from 128 PTS diagnosed with GBM from November 2009 to December 2015. All PTS underwent treatment with RT + TMZ and had an ECOG-PS 0-2. Methylation percentage for each sample was obtained by calculating the average methylation of all 10CpG sites (75-84) of MGMT promoter by pyrosequencing analysis. PTS with 0-6% of methylation were classified as unmethylated (UM), PTS with 7-24% as low methylated (LM) and PTS with ≥ 25% as high methylated (HM). 25% was the median value of methylation of our PTS having >6% of methylation. Results: Median age was 60 yrs (range 25-84), 60.9% were male, 74.2% had an ECOG PS 0-1, 50.8% underwent radical surgery, 85 PTS were dead at the time of analysis. 75 PTS were UM, 26 PTS were LM and 27 PTS were HM. On univariate analysis HM, LM and UM showed a PFS of 15.8, 10 and 9.1 ms, respectively (p=0.1). OS was 38.7, 21 and 18.8ms (p= 0.06). On multivariate analysis UM and LM PTS had a statistically lower PFS vs HM PTS (HR=2.57; p=0.001; HR= 2.5; p=0.007, respectively) and statistically lower OS (HR=3.47; p<0.001; HR=2.63; p=0.016; respectively). No significant difference was showed between UM and LM PTS in terms of PFS and OS, both on univariate and multivariate analyses. Conclusions: MGMT promoter methylation status determined by pyrosequencing analysis may correlate to PFS and OS. We found a cut-off of 25% of methylation which determined two sub-groups of PTS having different clinical outcome; in particular, HM PTS had a significant longer PFS and OS.
P01.36 Confirmation of TERT promoter mutation as a prognostic marker in a greek cohort with glioma
Authors: A. Vernadou, G. Nasioulas, G. Rigakos, S. Papadopoulos, A. Tsimpidakis, P. Nomikos, S. Lampropoulos, E. Razis
Journal: Neuro-Oncology (2017)

Introduction: Telomerase reverse transcriptase (TERT) has received a great deal of attention in recent years for its role as a prognostic and predictive molecular marker of glioma. Mutation in the TERT promoter (TERTp mut), which results in enhanced telomerase activity and shortened telomeres, is seen in both the most aggressive human glioma (glioblastoma) and the least aggressive diffuse human glioma (grade II oligodendroglioma). Materials and Methods: We sequenced for TERTp-mut in 48 glioma DNAs and analysed TERT expression by RT-PCR. TERTp-mut status was correlated with histology, genomic profile, other biomarkers and clinical outcome. Results: TERT promoter mutations were observed in 35 out of 48 tumor samples. Of these, C228T (-124 bp upstream start codon) mutation was detected in 28 samples and C250T (-146 bp) mutation in 7 cases. Of the TERT-mutant gliomas, 32 were glioblastomas, one was an anaplastic astrocytoma, one was an anaplastic oligodendroglioma and another one was a grade II oligodendroglioma, IDH mutant and 1p19q co-deleted. TERT promoter mutations have been associated with shorter overall survival in high grade gliomas while a longer survival in low grade tumors (the small number of low grade gliomas in our cohort is not representative). The median overall survival was 11 months for C228T mutated gliomas and 6 months for C250T mutated, while the overall survival was 13 months for the TERT wild-type gliomas. We defined four prognostic groups, based on TERTp-mut and IDH mutation status: (1) TERTp-mut and IDH-mut (3 patients) associated with 1p19q codeletion, with overall survival 10 months (because of the small number of patients tested until now, the results in this subgroup are not reliable); (2) TERTp-wt and IDH-mut (4 patients), with overall survival 31 months; (3) TERTp-wt and IDH-wt (9 patients), with overall survival 13 months; (4) TERTp-mut and IDH-wt (32 patients), with overall survival 12 months. The 5 out of 6 EGFRvIII gliomas were found to belong in the fourth group, with a median overall survival 20 months. CONCLUSION: The presence or absence of TERT promoter mutations, IDH mutations, and 1p/19q co-deletion can be used to define four principal groups of gliomas with characteristic distributions of age at diagnosis, clinical behavior, acquired genetic alterations, and other biomarkers. In our cohort, the poor prognosis of TERT- mutated high grade gliomas is confirmed, while in the low grade the sample is not representative. Further analysis of TERTp-mut in more samples is pending, as is its association with other biomarkers, clinical characteristics and treatment.