tbuckley/cabot-search huggingface dataset:
P01.103 Molecular landscape of diffuse gliomas associated with seizures
Authors: S P Baluszek, J Mieczkowski, B Kamińska
Journal: Neuro-Oncology (2018)

Glioma is the most common primary brain tumour and often confers a grave prognosis. In low-grade gliomas seizures occur frequently (70–80%) and usually are pharmacoresistant. While genes coding for interleukins and implicated in neurotransmitters signalling have been associated with focal seizures, a molecular profile of glioma-associated epilepsy (GAE) remains largely understudied. To fill this gap, we analysed whole-genome expression and DNA methylation profiles of almost 500 glioma samples to find seizure-related correlates. Uncontrolled seizures are associated with 1% annual mortality, but GAE correlates with a favourable prognosis. Therefore, characterization of epileptogenesis in GAE could allow to identify new glioma prognostic markers. Gene expression and DNA methylation profiles of WHO grade II and III diffuse gliomas samples were downloaded from The Cancer Genome Atlas website and analysed using R statistical software. The genes expressed differentially between samples with and without seizure history were identified using multtest. Fast Gene Set Enrichment Analysis followed by motif enrichment analysis done using PWMEnrich and Differential Gene Correlation Analysis were performed to extract functional correlations. The expression levels of the identified genes were compared with DNA methylation profiles, using minfi, and heterogeneity of cell subpopulations was assessed using xCell. Majority of the upregulated genes were positive prognostic factors, whereas the downregulated correlated with shorter survival. Among the differentially expressed genes, FOXG1 and SEZ6 have established roles in epileptogenesis and cancer biology. We found that genes encoding components of G protein-coupled receptors signalling and development of neural cells characterised GAE history, whereas genes related to angiogenesis, immune cell infiltration, protein synthesis and epithelial-mesenchymal transition were associated with seizure free samples. Moreover, VEPH1, a gene involved in most of the former processes, and DGCR5, a lncRNA associated with prolonged survival in other neoplasms, were correlated with GAE and better survival. Overall, differentially expressed genes were enriched in the Neuron-Restrictive Silencer Factor (REST) motif and its expression had a prognostic role. This study identified molecular features characteristic for GAE. The majority of found features correlated with prolonged survival. Our results provide novel insight into pathobiology of GAE and its potential treatment in the future. This study was supported by TEAM TECH CORE FACILITY FNP: NGS platform for comprehensive diagnostics and personalized therapy in neuro-oncology.
OS3.4 Intra-tumour DNA methylation heterogeneity in glioblastoma
Authors: A Wenger, S Ferreyra Vega, T Kling, T Olsson Bontell, A S Jakola, H Carén
Journal: Neuro-Oncology (2018)

A hallmark of glioblastoma (GBM) is the cellular and molecular heterogeneity both inter- and intra-tumourally. This adds to the complexity of GBM regarding risk for sampling bias and tumour escape of targeted therapy. Heterogeneity of gene expression within GBM is well documented, but little is known regarding the epigenetic heterogeneity. This could have implications for diagnostics, as DNA methylation can be used for tumour classification, subtyping and determination of the clinically used biomarker MGMT promoter methylation status. We therefore aimed to profile the intra-tumour epigenetic heterogeneity in GBM. Three biopsies per tumour from spatially separated regions were collected from 10 adult GBM patients. Only samples that were highly fluorescent using Gliolan (5-ALA) were collected and the location was documented with neuronavigation. We then performed genome-wide DNA methylation analysis to determine the methylation level of ~850 000 CpG sites and compared inter and intra-tumour variation. The tumour content of the biopsies was assessed based on histology by a specialist in clinical neuropathology. Hierarchical clustering of the CpG sites with the most variable methylation clustered the biopsies from each patient respectively together except for the biopsies from one patient. A large number of differentially methylated probes (DMP) existed between the intra-tumour biopsies and some were located in GBM-related genes. All samples were classified as GBM by methylation profiling, but the strength of the classification and the subtype differed within tumours. We also found intra-tumour heterogeneity in the methylation status of the MGMT promoter in one of the patients. Intra-tumour biopsies did not cluster together for all patients and displayed many DMP demonstrating that intra-tumour DNA methylation heterogeneity exists in GBM. The tumour type (GBM) is classified homogenously within the tumour for all patients, while the strength of the classification and the subtype differs. The observed intra-tumour heterogeneity in DNA methylation needs to be taken into consideration for methylation-based biomarkers and future stratification of GBM subtypes.
Light-enhanced VEGF121/rGel: A tumor targeted modality with vascular and immune-mediated efficacy
Authors: Anette Weyergang, Ane S. Fremstedal, Ellen Skarpen, Qian Peng, Khalid A. Mohamedali, Marius S. Eng, Lawrence H. Cheung, Michael G. Rosenblum, Johannes Waltenberger, Kristian Berg
Journal: Journal of Controlled Release (2018)
P01.041 Secondary prophylaxis with romiplostim for temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma
Authors: E Le Rhun, P Devos, C Houillier, S Cartalat-Carel, O Chinot, A Di Stefano, N Reyns, F Dubois, M Weller
Journal: Neuro-Oncology (2018)

Thrombocytopenia is a major adverse event of temozolomide (TMZ) chemotherapy. It may lead to dose reduction/interruption or bleeding. Platum (NCT02227576) was a phase II open label, multicenter single arm trial evaluating the thrombopoetin receptor agonist, romiplostim, for secondary prevention of TMZ-induced thrombocytopenia in patients with newly diagnosed glioblastoma. Patients diagnosed with CTCAE grade 3/4 thrombocytopenia during standard treatment of glioblastoma received weekly subcutaneous injections of romiplostim at a starting dose of 750 µg. Dose adjustments were based on weekly platelets counts. The study aimed at demonstrating that the percentage of thrombopenic patients treated with romiplostim able to complete 6 cycles of maintenance TMZ chemotherapy exceeded 10% (p0=0.10; pA=0.35) (Gerber et al., 2007). Using type I error equal to 0.05 and 95% power, 31 patients had to be recruited. According to a Fleming’s two step design, an interim analysis was planned after recruitment of 20 evaluable patients. Three scenarios were pre-defined: (1) 2 patients or less meeting the endpoint: termination for futility (p<P0), (2) 6 patients or more meeting the endpoint: termination for success (p>P0), (3) 3 to 5 patients meeting the endpoint: enrollment of 11 more evaluable patients. Twenty patients (13 females) were enrolled in step 1 between July 2014 and December 2016. Median age was 60.5 (range: 33–72 years). Surgery included biopsy (n=7), partial (n=5), subtotal (n=2) or gross total resection (n=6). Isocitrate dehydrogenase 1R132H mutations were noted in 2 cases. The median lowest count of platelets at screening was 25,500/mm3 (range 9,000–59,000). Sixteen patients were enrolled after radiotherapy and before maintenance initiation, 4 were enrolled after maintenance TMZ initiation. Twelve patients enrolled in step 1 received the 6 planned maintenance TMZ cycles, corresponding to a success rate of 60% (95% confidence interval 36–81). Four of 8 patients discontinued TMZ because they did not respond to romiplostim, 2 for progression and 1 for clinical deterioration prior to completion of six cycles, 1 due to an adverse event. Eighteen severe adverse events were observed, none was judged to be related to romiplostim. The trial was terminated early for success. Thrombopoetin receptor agonists such as romiplostin allow to assure adequate exposure to chemotherapy in glioblastoma patients experiencing early, severe chemotherapy-induced thrombocytopenia.
Strong immunoexpression of midkine is associated with multiple lymph node metastases in BRAFV600E papillary thyroid carcinoma.
Authors: Tae Jun Park, Yong Won Choi, Jang-Hee Kim, In Kyoung Lim
Journal: Journal of Clinical Oncology (2016)

e17552 Background: Midkine is a multifunctional, heparin-binding growth factor that is frequently expressed in patients with malignancies but is undetectable in healthy adults. In various cancers, high expression of midkine is associated with aggressive clinical behavior and a poor prognosis. In the present study, we investigated the expression of midkine in papillary thyroid carcinoma (PTC) and assessed its association with a BRAFV600E mutation and the clinicopathological parameters. Methods: We determined the presence of a BRAFV600E mutation in 79 cases of PTC and examined the effects of the BRAFV600E mutation on midkine expression in primary thyrocytes. In addition, we evaluated the association between midkine expression and various clinicopathological parameters. Results: We found that midkine is more frequently expressed in BRAFV600E PTC (68.3%) than in BRAF wild-type PTC (18.8%). BRAFV600E transduction could up-regulate midkine expression in primary thyrocytes. Moreover, midkine expression was associated with multiple lymph node ( ≥ 5) metastases in BRAFV600E PTC. Conclusions: Our results demonstrated that activation of the BRAFV600E oncogene increases the expression of midkine in PTCs and that midkine expression could be a clinically useful predictive marker of multiple lymph node metastases in patients with BRAFV600E-positive PTCs.
TCT-750 Radial Artery Occlusion - Incidence, Predictors and Long term outcome after TRAnsradial Catheterization: Clinico-Doppler ultrasound based Study (RAIL-TRAC Study)
Authors: Santosh Sinha, Puneet Aggarwal, Mukesh Jha, Vikas Mishra, Amit Goel, Santosh Kumar Sinha, Kumar Himanshu, Vinay Krishna
Journal: Journal of the American College of Cardiology (2018)
Comprehensive proteomic and genomic profiling to identify therapeutic targets in adenoid cystic carcinoma.
Authors: Sheeno P. Thyparambil, Yeoun Jin Kim, Andrew Chambers, Dongyao Yan, SHANKAR SELLAPPAN, Chao Gong, Andrew Sedgewick, Yulia Newton, J Zachary Sanborn, Charles Joseph Vaske, Stephen Charles Benz, Fabiola Cecchi, Hyunseok Kang, Todd A. Hembrough
Journal: Journal of Clinical Oncology (2018)

6053 Background: Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands accounting for 10% of salivary gland cancers and 1% of head and neck cancers. ACC rarely responds to chemotherapy or targeted therapy and there is no standard therapy for advanced ACC. Comprehensive molecular profiling of ACC tumors could identify targets of FDA-approved or investigational therapies. Methods: ACC specimens (n = 24) were analyzed with the GPS Cancer test, which includes whole genome sequencing, RNA-seq, and mass spectrometry-based targeted proteomic analysis. Tumor areas of FFPE tissue sections were marked by a pathologist, microdissected and solubilized for mass spectrometric quantitation of 30 clinically relevant proteins. A subset of tumors was further analyzed by global proteomics and compared with results from squamous cell carcinoma of the head and neck (SCCHN). RNA-seq results from ACC tumors was compared with that of various solid tumor types using the k-nearest neighbors algorithm. Results: Targeted proteomic analysis of chemopredictive proteins suggested that 17% of patients were likely to respond to irinotecan, while 33% were likely to be resistant to taxane. The vast majority of patients (96%) did not express any target proteins of FDA-approved targeted therapies. Global proteomic analysis with unsupervised hierarchical clustering of 4,002 proteins from 8 ACC specimens and 6 SCCHN specimens revealed a clear separation between the two groups. In genomic analysis, tumor mutational burden was lower in ACC than in SCCHN (1.53 vs 3.53 per MB). In ACC, MYB-NFIB fusion and missense mutations involved in transcriptional regulation (ZNF43, ZNF519 and ZNF429) were frequent. Expression of CDK6 protein and CDK6 mRNA (transcripts per million) were 4-fold and 3-fold higher in ACC than in SCCHN, respectively. None of the ACC tumors exhibited RB1 deficiency. Among solid tumors, breast cancer was closest to ACC based on mRNA expression. Conclusions: Proteogenomic analysis identified CDK6 overexpression at both protein and mRNA levels in ACC. The combination of CDK6 overexpression and RB1 proficiency suggests that ACC patients may benefit from CDK6 targeted therapy.
Trends in biomarker testing among metastatic colorectal cancer patients: A temporal description of KRAS, NRAS, and BRAF testing in the EU5.
Authors: Kimberly Lowe, Xin Niu, George Kafatos
Journal: Journal of Clinical Oncology (2017)

e15136 Background: The European Medicines Agency (EMA) changed its indication language from wild-type KRAS to wild-type RAS ( KRAS and NRAS) for metastatic colorectal cancer (mCRC) patients treated with panitumumab in July 2013. The objective of this study was to describe patterns of KRAS, NRAS, and BRAF testing among mCRC patients in the EU5 (United Kingdom (U.K.), Germany, France, Italy and Spain) and to evaluate if there were demographic or clinical differences in the patients who were/were not tested. Methods: This descriptive study utilized a serial physician survey from Oncology Analyzer data (IMS Health Oncology, Fairfield, CT, USA), which provides real-world epidemiologic and clinical data. Trends in biomarker testing were evaluated by calculating the proportion of patients who were /were not tested for combinations of KRAS, NRAS, and BRAF within each of the five countries. KRAS and BRAF data were available in all countries from quarter three (Q3) 2012 to quarter two (Q2) 2015. NRAS was available in all countries from quarter 1 (Q1) 2014 to Q2 2015. Frequencies and proportions were also calculated to summarize patient demographic and clinical characteristics between groups with different testing choices. Results: The study included 32,961 mCRC patients. Prior to July 2013, most patients were tested for only KRAS. The proportions of patients tested for both KRAS and NRAS increased substantially during the period of data availability for NRAS, including &lt; 1% to 19.1% in the U.K., 8.8% to 31.9% in France, 13.1% to 43.2% in Germany, 5.9% to 24.6% in Italy, and 8.7% to 31.4% in Spain. The proportions of patients tested for all three biomarkers also increased during the period of data availability for all three biomarkers (Q1 2014 to Q2 2015), including 2.3% to 16.4% in the U.K., 4.8% to 26.6% in France, &lt; 1% to 2.4% in Germany, 4.2% to 22.3% in Italy, and 1.5% to 9.3% in Spain. There were few differences in patient demographic or clinical characteristics between those with different testing choices. Conclusions: This analysis provides a description of the patterns of biomarker testing using read-world data and suggests a consistent increase in testing among mCRC patients in the EU5.
A phase I/II study of ribociclib plus everolimus in patients (pts) with metastatic pancreatic adenocarcinoma (mPAC) refractory to chemotherapy.
Authors: Benjamin Adam Weinberg, Hongkun Wang, Agnieszka Katarzyna Witkiewicz, John Marshall, Erik S. Knudsen, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2018)

TPS4150 Background: mPAC has a poor prognosis, with a 5-year survival rate of 2.3%. CDK4/6 is often deregulated in mPAC due to loss of CDKN2A via homozygous deletion or epigenetic silencing, resulting in the loss of the p16INK4a protein that naturally inhibits CDK4/6. CDK4/6 inactivates the retinoblastoma protein (RB), allowing E2F family transcription factors to promote cell cycle progression. Inhibitors of CDK4/6 have been ineffective as single agents in part due to Ras-mediated activation of alternate signaling pathways including the PI3K-mTOR pathway. We have shown that co-inhibition of the CDK4/6 and mTOR pathways suppresses growth in mPAC patient-derived xenografts. We are investigating the activity of the combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) in pts with mPAC. Methods: This is a phase I/II, single-arm, open-label study. Eligible pts are ≥ 18 years old, have histologically confirmed mPAC with progression on at least 1 prior 5-FU- and 1 gemcitabine-based regimen, an ECOG performance status of 0-1, normal bone marrow and hepato-renal function, and no concurrent anticancer therapy. Exclusion criteria are use of prior CDK or mTOR inhibitors or known CNS metastases. Pts in the phase I portion will be enrolled in a 3+3 design to find the recommended phase II dose (RP2D) of ribociclib with dose escalation and de-escalation levels. Pts in the phase II portion will receive ribociclib at the RP2D daily for 21 days out of a 28 cycle with everolimus 2.5 mg daily continuously. The phase II portion will use a Simon’s Minimax 2-stage design. Disease will be assessed by imaging every 8 weeks. Treatment will continue if it is tolerated and there is no disease progression. The primary endpoint of the phase II portion is progression free survival (PFS) at 8 weeks. Secondary endpoints are median PFS, median overall survival, best overall response rate by RECIST 1.1, and safety. Correlative studies include assessment of the pharmacodynamic effects on the RB pathway using pre- and on-treatment tumor biopsies, tumor sequencing, and analysis of circulating tumor DNA. Enrollment began in Q2 2017 with a goal accrual of 44 pts. Clinical trial information: NCT02985125.
Long-term response and time to response to pazopanib (PAZ) and sunitinib (SUN) in metastatic renal cell carcinoma (mRCC): COMPARZ subanalysis.
Authors: Nizar M. Tannir, Camillo Porta, Viktor Gruenwald, Toni K. Choueiri, Qasim Ahmad, Marlene Carrasco Alfonso, Luca Dezzani, Jackie Han, Cora N. Sternberg
Journal: Journal of Clinical Oncology (2017)

4572 Background: COMPARZ (NCT00720941) was a phase 3, randomized, controlled, open-label trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in 1110 patients with mRCC (NEJM 2013;369:722). The objectives of this study were to identify patients from COMPARZ who exhibited a long-term response (LTR) to PAZ and SUN, determine time to response, and describe the clinical characteristics of patients who achieved LTR. Methods: Patients in the intention-to-treat population of COMPARZ were analyzed for differences in LTR (≥10 months [mos]) as measured by responder rate with either complete response or partial response (CR/PR) and PFS rate, and time to response. We also compared the clinical characteristics between long-term and shorter-term responders within and between each treatment arm. Results: The overall percentage of long-term responders with CR/PR (PAZ = 14%, SUN = 13%) and PFS (PAZ = 31.4%, SUN = 33.6%) in the PAZ and SUN groups were similar. This similarity was observed regardless of the cut-off for long-term duration of response. However, a shorter time to achieve CR/PR was observed in the overall population with PAZ (11.9 weeks [95% CI, 11.3–12.1] vs 17.4 weeks; [95% CI, 12.7–18.0]). Analysis conducted to identify baseline clinical characteristics that may be related to LTR will be reported. Conclusions: These exploratory subanalyses in long-term responders support the overall efficacy results with PAZ and SUN, which were reported in the COMPARZ trial. However, the results here demonstrate that the time to response was shorter with PAZ versus SUN. Clinical trial information: NCT00720941.
Association of vitamin D insufficiency with inferior prognosis in follicular lymphoma.
Authors: Sean I. Tracy, Matthew John Maurer, Thomas E. Witzig, Matthew Drake, Stephen Maxted Ansell, Grzegorz S. Nowakowski, Carrie A. Thompson, David James Inwards, Patrick B. Johnston, Ivana N. M. Micallef, Cristine Allmer, William R Macon, George J. Weiner, Susan L. Slager, Thomas Matthew Habermann, Brian K. Link, James Robert Cerhan
Journal: Journal of Clinical Oncology (2016)

e19067 Background: Vitamin D insufficiency (VDI) is associated with inferior outcomes in patients with follicular lymphoma (FL) treated with chemotherapy and an anti-CD20 monoclonal antibody (immunochemotherapy; IC). We sought to determine whether this association persists amongst all FL patients regardless of treatment type. Methods: We tested the hypothesis that serum 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival at 12 months (EFS12), overall survival (OS), and lymphoma-specific survival (LSS) in a prospective cohort of 659 patients with FL enrolled from 2002-2012. 25(OH)D was measured by liquid chromatography-tandem mass spectroscopy, and VDI was defined as serum total 25(OH)D < 20 ng/mL determined within 120 days of diagnosis. We used logistic regression to estimate ORs and 95% CIs and Cox regression to estimate HRs and 95% CIs. We adjusted for FLIPI, BMI, and month of blood draw; for pooled patients, we also adjusted for treatment. Results: The mean age at diagnosis was 60 yrs (range 23-93); 34% of patients had VDI. The median follow-up period was 59 months, with 311 events and 82 deaths (46 due to lymphoma). Treatment included IC (N = 264), observation (OBS; N = 222), rituximab monotherapy (R-mono; N = 76), or other (OTH; N = 97). For pooled patients, VDI was associated with inferior EFS12 (OR = 1.63; 95% CI 0.99-2.66), OS (HR = 2.25; 95% CI 1.32-3.83), and LSS (HR = 2.70; 95% CI 1.40-5.22). In the IC subset, VDI was associated with inferior EFS12 (OR = 2.42; 95% CI 1.14-5.11), OS (HR = 2.60; 95% CI 1.29-5.25), and LSS (HR = 2.59; 95% CI 1.16-5.80). VDI was also associated with inferior OS in the OBS (HR = 2.75; 95% CI 1.17-6.46) and OTH (HR = 3.08; 95% CI 1.02-9.28) subsets. VDI was modestly associated with inferior EFS12 in the OBS (OR = 1.31; 95% CI 0.59-2.93) and OTH subsets (OR = 1.40; 95% CI 0.24-8.14) though power was low; LSS could not be estimated due to lack of deaths. There were too few events (N = 35) and deaths (N = 5) in the R-mono group for analysis. Conclusions: VDI was associated with inferior OS, and where it could be estimated LSS, irrespective of treatment type. VDI was associated with inferior EFS12 amongst all patients combined and those treated with IC. Whether treating VDI improves outcomes in FL warrants assessment.