bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors.
Authors: Drilon Alexander E. , DuBois Steven G. , Farago Anna F. , Geoerger Birgit , Grilley-Olson Juneko E. , Hong David S. , Sohal Davendra , van Tilburg Cornelis Martinus , Ziegler David Simon , Ku Nora , Cox Michael Craig , Nanda Shivani , Childs Barrett H. , Doz Francois P. 
Published: May 2019

2006 Background: TRK fusions are oncogenic drivers of a variety of cancers, many of which can involve the central nervous system (CNS). Larotrectinib is an FDA-approved selective TRK inhibitor for the treatment of TRK fusion cancer (Drilon et al, NEJM 2018). While larotrectinib has been shown to cross the blood–brain barrier (Ziegler et al, Br J Cancer 2018), its clinical activity in a series of TRK fusion cancers with primary or metastatic intracranial disease has not been described. Methods: Patients (pts) with non-primary CNS solid tumors with brain metastases, or primary CNS tumors harboring a TRK fusion treated with larotrectinib in 2 clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression (PD), withdrawal, or unacceptable toxicity. Disease status was investigator-assessed (RANO and RECIST). Data cutoff: July 30, 2018. Results: 14 pts were identified: 5 non-primary CNS solid tumors (3 lung cancer, 2 thyroid cancer; fusion type: 2 ETV6-NTRK3, 2 SQSTM1-NTRK3, 1 EPS15-NTRK1; age range 25–79 y) and 9 primary CNS tumors (3 glioma, 2 glioblastoma, 1 astrocytoma, 3 NOS; fusion type: 3 BCR-NTRK2, 2 KANK-NTRK2, 1 each of AFAP1-NTRK1, AGTPBP1-NTRK2, ETV6-NTRK3, SPECC1L-NTRK2; age range 2–79 y). In the 5 pts with non-primary CNS tumors, the best objective response to therapy was PR in 3 (60%, 1 pending confirmation), SD in 1 (20%), and not evaluable (NE) in 1 (20%). Duration of response ranged from 9+ to 13 mo. In the 9 pts with primary CNS tumors, disease control was achieved in all evaluable pts (primary PD not observed; 1 pt required dose increase). The best objective response to therapy was PR in 1 (11%; pending confirmation, −55% tumor shrinkage, ongoing at 3.7 mo), SD in 7 (78%; tumor shrinkage range −1% to −24% for pts with measurable disease, 5 had SD > 4 mo), and NE in 1 (11%). Duration of treatment ranged from 2.8–9.2+ mo. Conclusions: Larotrectinib is active in pts with TRK fusion cancers with intracranial disease. Confirmed responses and durable disease control were seen in metastatic disease and primary CNS tumors of various histologies. These results further support expanded testing for TRK fusions across all cancers, including primary CNS tumors. Clinical trial information: NCT02637687 and NCT02576431.
Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.
Authors: Wick Wolfgang , Kessler Tobias , Platten Michael , Meisner Christoph , Bamberg Michael , Herrlinger Ulrich , Happold Caroline , Weisang Sarah , Boelting Hanna , Steinbach Joachim , Reifenberger Guido , Sahm Felix , von Deimling Andreas , Wick Antje , Weller Michael 
Published: May 2019

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.
Genomic characterization of lung tumors and metastatic (Met) sites in advanced (Adv) NSCLC.
Authors: Willard Melinda D , Nash Smyth Emily Nash , Tiu Ramon Velasquez , Beyrer Julie , Zhu Yajun Emily , Bowman Lee , Sheffield Kristin M , Han Yimei , Brastianos Priscilla 
Published: May 2019

2014 Background: Molecular alterations (MA) found in brain (Br) mets of NSCLC pts can differ from primary and/or other met sites, which may explain why therapies targeting primary tumors are less effective at preventing and treating intracranial disease. We analyzed the frequency of known driver genes in adv NSCLC pts and the association with overall survival (OS). Methods: This retrospective observational study identified pts from the Flatiron- Foundation Medicine NSCLC Clinico-Genomic Database who were diagnosed with adv NSCLC from 1 Jan 2011 to 31 Oct 2017 and had tumor tissue analyzed at any time following initial diagnosis via targeted DNA sequencing by FoundationOne. Descriptive statistics summarized MA from lung and met sites (Br and non-brain [NB]). OS was measured from adv diagnosis to death or last activity date (censored). Multivariable Cox proportional hazard regression model was used for time-to-event analysis. Results: Of 3257 pts, data were available from lung (n = 1621), Br (n = 180), and NB sites (n = 377): liver (n = 167), bone (n = 124), adrenal (n = 63), and spine (n = 23). Median age at adv diagnosis was 66.2 yrs. TP53(63.3%), KRAS(28.8%), EGFR(15.6%), STK11 (13.5%), and CDKN2A(8.5%) were frequently mutated genes in lung samples. Genes for Br vs NB sites included TP53(70.6%; 64.7%), KRAS(36.1%; 26.5%), EGFR (9.4%; 18.8%), STK11 (18.9%; 12.7%), and CDKN2A(6.1%; 10.1). KEAP1alterations were also present in 10% (Br), 7.4% (NB), and 6% of lung samples. In treated pts, lack of alterations in select genes ( STK11, TP53, KEAP1) was associated with longer OS, whereas lack of other alterations ( ARID1A, EGFR, ALK, ROS1) was associated with a shorter OS (p < 0.05). Patients with select mutations co-occurring with KRAS had higher risk of death compared to those with KRAS only (p < 0.05). Conclusions: Based on pts with NSCLC whose tumor tissue underwent DNA sequencing, the most frequently altered genes in lung and Br samples included TP53, KRAS, EGFR, STK11, and CDKN2A, with some being significantly associated with OS. Prognosis of NSCLC pts depends on clinical, demographic, and genomic factors and should be carefully considered to optimize clinical outcome.
Barriers to accrual and enrollment in brain tumor trials.
Authors: Lee Eudocia Quant , Chukwueke Ugonma Nnenna , Hervey-Jumper Shawn L. , De Groot John Frederick , Leone Jose Pablo , Armstrong Terri S. , Chang Susan Marina , Arons David , Oliver Kathy Rose , Galanis Evanthia , Friday Bret Edward Buckley , Lin Nancy U. , Mehta Minesh P. , Penas-Prado Marta , Vogelbaum Michael A. , Sahebjam Solmaz , Van Den Bent Martin J. , Weller Michael , Reardon David A. , Wen Patrick Y. 
Published: May 2019

2024 Background: A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. Methods: We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. Results: We describe selected factors contributing to poor trial accrual and possible solutions. Conclusions: We will implement strategies with the intent to double trial accrual over the next 5 years. [Table: see text]
Phase 1/2a study of once daily oral BAL101553, a novel tumor checkpoint controller (TCC), in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.
Authors: Lopez Juanita Suzanne , Kristeleit Rebecca Sophie , Rulach Robert , Haris Noor Md , Scaranti Mariana , Mulholland Paul James , Crawford Donna , Bashir Saira , Aversa Caterina , Hannah Alison L. , Anderson Stephanie , Engelhardt Marc , Kaindl Thomas , Larger Patrice , McKernan Phil , Evans TR Jeffry , Plummer Elizabeth 
Published: May 2019

2025 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule shown in rodents to penetrate the brain (brain/plasma ratio around unity), with promising antitumor activity in orthotopic preclinical GBM models as monotherapy or in combination with radiotherapy (RT) with or without temozolomide. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients, with an MTD of 16 mg/d and DLTs of G4 hyponatremia and G2 hallucinations (Lopez 2018, JCO 36, 2018, suppl. A2530). Subsequently the study was expanded by including a separate cohort of patients with progressive or recurrent GBM or high-grade glioma (Ingles Garces 2017, JCO 35, 2018, suppl. TPS2601). Methods: Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, received once-daily oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G), and tumor response by RANO every two cycles. Pharmacokinetics (PK) were evaluated on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 23 pts (13M/10F; median age 50 y), median (min–max) number of prior regimens = 2 (1–5), received doses of 8, 15, 20, 25 or 30 mg oral BAL101553 once daily. One DLT of reversible G2 depression and fatigue occurred at 20 mg. Both mean Cmax and AUC increased with dose between 8 and 30 mg. The PK exposure in GBM patients was lower than for solid tumor patients, in particular at 20 and 25 mg. At 25 mg/d (n = 3), one patient with IDH-mutated GBM had a partial response (63% area reduction per RANO) and continues on study > 8 months, and another patient had stable disease for 5 months. At 15–20 mg/d, stable disease was observed in 3/10 patients. Conclusions: The current data in patients with GBM or high-grade glioma suggest that BAL101553 is well tolerated at dose levels above the MTD established in patients with advanced solid tumors, and shows indications of clinical activity. Clinical trial information: 02490800.
GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.
Authors: Neyns Bart , Ben Salama Laila , Awada Gil , De Cremer Jennifer , Schwarze Julia Katharina , Seynaeve Laura , Du Four Stephanie , Fischbuch Lydia , Vanbinst Anne-Marie , Everaert Hendrik , Michotte Alex , Rogiers Anne , Theuns Peter , Duerinck Johnny 
Published: May 2019

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.
Effect of grade on survival in IDH-mutant grade II and grade III gliomas.
Authors: Lamberti Giuseppe , Franceschi Enrico , Tosoni Alicia , Mura Antonella , Paccapelo Alexandro , Foschini Maria Pia , Asioli Sofia , De Biase Dario , Pession Annalisa , Tallini Giovanni , Bartolini Stefania , Giangaspero Felice , Brandes Alba Ariela 
Published: May 2019

2036 Background: The 2016 WHO classification dramatically changed the diagnosis of gliomas. Diffuse gliomas are classified according to the presence of IDH-mutation (IDH-mut) and the deletion of both 1p and 19q chromosome arms (1p/19q codel). Now debate is whether grade still has an independent prognostic value. The aim of this study was to find out if grade is a prognostic factor independently of molecular status. Methods: We analyzed our institutional data warehouse for all consecutive patients (pts) with newly diagnosed, histologically proven Grade II or Grade III IDH-mut gliomas. IDH 1/2 assessment by polymerase chain reaction (PCR)or immunohistochemistry (IHC) was accepted. Next Generation Sequencing (NGS) for IDH1(exon 4) and IDH2(exon 4) was performed on all specimens wild-type for the IDH. Results: The analysis included all the 399 pts who had a grade II (n = 250, 62.7%) or grade III (n = 149, 37.3%). Median follow-up time was 105.3 months. After surgery, 72 pts (18.0%) received RT alone, 44 (11.0%) received CT alone, 135 (33.8%) received both RT and CT, and 142 (35.6%) follow-up without any treatment. Median survival was 148.1 months. In multivariate analysis Grade (HR = 0.342, 95%CI: 0.221 – 0.531; P < 0.001) and 1p/19q codeletion (HR = 0.440, 95%CI: 0.290 – 0.668; P < 0.001) were independently associated with a lower risk for death. The difference in survival remained when adjusted for histological subtype. Residual disease after surgery or biopsy negatively affected survival (HR 2.151, 95%CI 1.375 – 3.367, P = 0.001). Post-surgical treatment with RT + adjuvant CT improves survival in respect to follow-up and other treatments (HR: 0.316, 95%CI 0.156 – 0.641, P = 0.001). Conclusions: Grade still affects survival in IDH mutant Grade II and III gliomas. This effect was independent onmolecular features, surgical extension and post-surgical treatments. Clinical management of gliomas should continue to take into account grade as well as molecular characteristics.
Adjuvant chemotherapy to improve survival in average-risk adult medulloblastoma patients: Long-term results.
Authors: Lamberti Giuseppe , Franceschi Enrico , Tosoni Alicia , Minichillo Santino , Di Battista Monica , Paccapelo Alexandro , Sturiale Carmelo , Mascarin Maurizio , Masotto Barbara , Volpin Lorenzo , Bartolini Stefania , Giangaspero Felice , Brandes Alba Ariela 
Published: May 2019

2037 Background: Medulloblastoma is extremely rare in adults and, therefore, it is difficult to accrual patients in clinical trials. Radical surgery and radiotherapy (RT) provide a significant control of disease. Nevertheless, about 25% of average-risk patients have a relapse and die because of disease progression. The role of chemotherapy (CT) after standard RT for average-risk adult patients remains controversial. Methods: We analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016. Median age was 29 years (range 16-61), M/F ratio was 26 (54.2%)/22 (45.8%). Fifteen patients had classic medulloblastoma (31.3%), 15 patients had desmoplastic medulloblastoma (31.3%), 5 patients had extensive nodularity (10.4%) and 2 patients had large cells/anaplastic histology (4.2%). The patients were homogeneously distributed in the two groups: 24 (50%) received adjuvant RT alone and 24 (50%) received RT + CT that consisted in a platinum-etoposide based combination. Results: After a median follow-up of 12.5 years, CT increases progression-free survival rate at 15 years (PFS-15 82.3 ± 8.0% in RT-CT group vs. 38.5% ± 13.0% in RT group p = 0.05) and overall survival rate at 15 years (OS-15 89.3% 7.2% vs. 52.0% 13.1%, p = 0.02). Among patients receiving CT, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia; 6 cases of G3 neutropenia (25%) and 3 cases of G4 neutropenia (13%), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%). Conclusions: Our study with a long follow up period suggests that adding adjuvant chemotherapy to RT might improve PFS and OS in average-risk adult medulloblastoma patients.
A gene signature of response to radiotherapy in patients with grade II-III oligodendrogliomas.
Authors: Moyal Elizabeth , Gilhodes Julia , Peyraga Guillaume , Uro-Coste Emmanuelle , Pouessel Damien , Larrieu-Ciron Delphine , Carpentier Catherine , Ducray Francois , Dehais Caroline ,   POLA Network
Published: May 2019

2041 Background: Grade II and III Oligodendroglioma associate mutations of isocitrate deshydrogenase 1 or 2 genes and the whole-arm chromosomal loss of 1p and 19q and have a better prognosis than other gliomas. However, even if the preferred treatment consists of a combination of radiotherapy (RT) and chemotherapy, some patients will less respond to this treatment and will relapse faster , in part because of an heterogeneity in the response to RT. In the aim to identify factors of response to RT, we analyzed clinical and molecular data of patients with grade II-III oligodendroglioma exclusively treated with RT in the POLA cohort. Methods: Gene expression profiles on Affymetrix expression arrays of patients from the POLA cohort with co-deleted 1p/19q grade II/II gliomas treated by exclusive RT were used to identify a gene expression set predictive of radiation sensitivity. The primary endpoint was the progression free survival (PFS), defined as the time from treatment start until progression or death. A supervised approach with penalized regression was applied to select most informative predictors, and then a risk score was created based on the linear predictor given by the multivariable model. Results: Forty-five patients corresponded to the study criteria, with a median age at diagnosis of 45 (range 23- 64). The supervised approach allowed identifying a three-gene prognostic set including Semaphorin -3C (SEMA3C), Neuronal Pentraxin 2 (NPTX2 ) and the Metabotropic Glutamate Receptor 5 (GRM5), involved in proliferation, migration and inflammation. The risk score associated to these three genes was statistically associated to PFS (HR = 2.72, p = 0.00005) and remains significant when adjusted on clinical covariates age at diagnosis, necrosis, endothelial proliferation and type of surgery (complete, partial or subtotal surgery) (HRadj = 2.36, p = 0.001). Conclusions: We report an independent three genes SEMA3C-NPTX2-GRM5 risk score signature of response to radiotherapy in patients with oligodendroglioma, which highlights the heterogeneous response in this reputed good prognosis population. This signature could help in determining the adapted treatment as well as potential new targets to address.
A preliminary comprehensive molecular-based nomogram for individualized estimation of survival in patients with newly diagnosed glioblastoma utilizing global microRNA expression data.
Authors: Fabian Denise , Bell Erica Hlavin , McElroy Joseph P. , Cui Tiantian , Fleming Jessica L. , Becker Aline P. , Geurts Marjolein , Haque Jahar , Robe Pierre A. , Chakravarti Arnab 
Published: May 2019

2044 Background: Glioblastoma (GBM) is the most aggressive and common primary brain tumor. Nomograms are prediction models that help form individualized risk scores for cancer patients, which are valuable for treatment decision-making. The aim of this study is to create a refined nomogram by including novel molecular variables beyond MGMT promoter methylation. Methods: Clinical data and miRNA expression data were obtained from 226 newly diagnosed GBM patients. Clinical data included age at diagnosis, sex, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase ( MGMT) promoter methylation status, IDH mutation status and overall survival. Due to low representation of less than 13 cases each, IDH mutant glioblastomas and patients submitted to biopsy-only were excluded. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissues; miRNA expression was subsequently measured using the NanoString human miRNA v3a assay. A Cox regression model was developed using glmnet R package with the elastic net penalty while adjusting for known prognostic factors. A dichotomized genomic score was created by finding the optimal cutpoint (maximum association with survival) of the linear combination of the selected. A nomogram was generated using known clinical prognostic factors, specifically age, sex, KPS, and MGMT status along with the dichotomized genomic score. Results: Four novel miRNAs were found to significantly correlate with overall survival and were used to create the dichotomized miRNA genomic score (GS). This score split the cohort into a poor performing group (GS_high) and a better performing group (GS_low) (p = 0.0031). A final nomogram was created using the Cox proportional hazards model (Figure 1). Factors that correlated with improved survival included younger age, KPS > 70, MGMT methylation and a low genomic score. Conclusions: This study is a proof of concept demonstrating that integration of molecular variables beyond MGMT methylation improve existing nomograms to provide individualized information about patient prognosis. Future directions include a more comprehensive analysis, including proteomic and methylation data, and subsequent validation in an external cohort. Finally, network analysis integrating molecular signatures of poor performers will help identify therapeutic targets.