bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissemination of universal genetic testing to three unique oncology care settings.
Authors: Bednar Erica , Muse Kimberly I. , Oakley Holly D. , Baker Ellen , Walsh Michael T. , Krukenberg Rebekah C. , Dresbold Cara S. , Morman Nichole A. , Bowdish Elizabeth C. , Cooper Julia N. , Wise Emaline E , Eppolito Amanda L. , Teed Kelly B. , Klein Molly H. , Chao Han , Method Michael W. , Grainger Andrew V. , Henson John W. , Lu Karen H. 
Published: September 2018

1590 Background: Efforts are occurring across the United States to improve the rates of identification and standard of care genetic counseling (GC) and genetic testing (GT) of pts with breast and ovarian cancer. Following a successful quality improvement (QI) initiative to increase referrals and utilization of GC/GT among pts with breast and ovarian cancer to >80% at our host site (HS), we sought to disseminate the QI project to three unique oncology care settings (OCS). Methods: The OCS described in the Table are certified members of the HS network, were strategically identified, and agreed to participate in the QI project. Genetic counselors at the HS and OCS built teams to plan and initiate the project. A 130-item environmental scan was created by the HS team to assess OCS structure, resources, and GC/GT processes. OCS teams completed the environmental scan and a semi-structured interview with the HS; and from this, barriers to GC/GT were identified, then categorized using Ishikawa diagrams. Clinical interventions were designed to address these barriers. Resulting QI protocols follow the PDSA-cycle QI model. A database was built for retrospective and prospective data collection of eligible pts and rates of GC/GT referral and completion from 2015-2018. Results: Although unique barriers were identified at each OCS, all identified: pt referral/scheduling issues, technology and electronic medical record system inefficiencies, and inconsistent physician referral/GT practices. OCS interventions include: implementation of physician-coordinated GT, GC within chemo infusion suites, physician education sessions, GC scheduling improvements, creation of pt education documents, and development of referral tracking processes. Conclusions: Genetic counselors collaborated, planned, and initiated dissemination of a QI project to improve GC/GT utilization at three unique OCS. QI interventions were developed to address the unique environment and barriers at each OCS. [Table: see text]
Phase 1b open-label randomized study of the oncolytic adenovirus DNX-2401 administered with or without interferon gamma for recurrent glioblastoma.
Authors: Lang Frederick F. , Tran Nam D. , Puduvalli Vinay K. , Elder J. Bradley , Fink Karen L. , Conrad Charles A. , Yung W. K. Alfred , Penas-Prado Marta , Gomez-Manzano Candelaria , Peterkin Joanna , Fueyo Juan 
Published: September 2018

2002 Background: DNX-2401 is a replication-competent, tumor-selective, oncolytic adenovirus with enhanced infectivity that causes durable tumor control by killing tumor cells and eliciting antitumor immunity. To increase immune activation, a phase 1b randomized study of intratumoral DNX-2401 alone versus DNX-2401 with interferon gamma (IFN) was conducted. Methods: A total of 27 patients with biopsy-confirmed glioblastoma at first or second recurrence received a single intratumoral injection of 3e10 vp DNX-2401. Patients were randomized in a 2:1 ratio to receive 50 mcg/m2 of subcutaneous IFN (Actimmune) Q3W initiated 14 days after DNX-2401 or to be followed without further treatment for safety and survival. Results: Twenty-seven (27) patients were enrolled following first (59%) or second (41%) recurrence having previously failed surgery, radiation, and temozolomide (100%). The median longest tumor diameter was 40 mm (range 20-77 mm). Patients were randomized to DNX-2401 followed by IFN (n = 18) or to DNX-2401 alone (n = 9). Due to the poor tolerability of IFN, the median duration of treatment was only 6 weeks (range 0-30 weeks), and two patients did not initiate treatment as scheduled due to early clinical deterioration. The most frequent grade 3-4 AEs across treatment groups were fatigue, headache, and seizures consistent with pre-existing symptoms, underlying disease and/or surgery. Based upon a preliminary intent-to-treat analysis, IFN did not appear to provide additional benefit. However, OS-12 and OS-18 for all patients enrolled was 33% and 22%, respectively regardless of treatment assignment. Three patients remain alive at 19, 21, and 22 months (DNX-2401, n = 1; DNX-2401 + IFN, n = 2). Interestingly, 50% of patients with a baseline tumor diameter of ≤ 42 mm survived beyond 12 months, potentially identifying a sub-population of patients that may live longer following intratumoral DNX-2401. Conclusions: DNX-2401 was well tolerated as monotherapy. Although the addition of IFN did not improve survival, clinical activity following a single injection of DNX-2401 is encouraging and supports an ongoing Phase II study of DNX-2401 for recurrent glioblastoma. Clinical trial information: NCT02197169.
Efficacy analysis of ABT-414 with or without temozolomide (TMZ) in patients (pts) with EGFR-amplified, recurrent glioblastoma (rGBM) from a multicenter, international phase I clinical trial.
Authors: Lassman Andrew B. , Van Den Bent Martin J. , Gan Hui Kong , Reardon David A. , Kumthekar Priya , Butowski Nicholas A. , Lwin Zarnie , Mikkelsen Tom , Nabors Louis B. , Papadopoulos Kyriakos P. , Penas-Prado Marta , Simes John , Wheeler Helen , Gomez Erica J. , Lee Ho-Jin , Roberts-Rapp Lisa , Xiong Hao , Bain Earle E. , Maag David , Merrell Ryan Thomas 
Published: September 2018

2003 Background: GBM is the most common malignant primary brain tumor in adults. Pts with rGBM have a poor prognosis. EGFR is amplified (amp) in ~50% of GBMs and is a compelling therapeutic target. ABT-414 is an antibody-drug conjugate composed of an EGFR-directed antibody conjugated to a microtubule toxin, MMAF. ABT-414 binds a unique epitope exposed during EGFR activation, either through ligand stimulation or mutation such as EGFR variant III (EGFRvIII), releasing MMAF into the cancer cell. Here, we report a pooled safety and efficacy analysis of ABT-414 +/- TMZ in EGFR amp, rGBM. Methods: M12-356 is a Phase 1, open-label, multi-arm study. Results from the 2 arms accruing rGBM pts were pooled for analysis. Eligible adults had rGBM, centrally confirmed EGFR amp, and KPS ≥ 70. Pts received 0.5-1.25 mg/kg ABT-414 on days 1 and 15 +/- 150-200 mg/m2 TMZ on days 1-5 of 28-day cycles until progression (per RANO). Results: As of 11 January 2017, 126 pts were treated. The most common adverse events (AEs, ≥ 25% pts) were ocular (90%) and included blurred vision (64%) and photophobia (31%), which were mainly reversible. Common non-ocular AEs were fatigue (36%) and headache (30%). Grade 3/4 AEs (≥ 5% pts) included ocular toxicities (29%) and decreased platelets/thrombocytopenia (10%). Serious AEs included seizure and keratitis (2% each). Of 125 pts evaluable by RANO, 52% had improvement or stabilization as best response (2 CR, 9 PR, 54 SD), and the remaining 60 (48%) had PD. Of 115 pts with measurable disease at baseline, the objective response rate (ORR) was 10% (2 CR + 9 PR). For 5 pts, re-resection for radiographic PD revealed mostly necrotic tissue and pts were classified as SD, suggesting the ORR may be an underestimate. Of all 126 pts, the 6-month PFS rate (PFS6) was 26%; median OS was 8.5 months. Conclusions: In this Phase 1 trial of EGFR amp, rGBM, we observed encouraging disease control (52%, CR + PR + SD) and PFS6 (26%) rates. Toxicity was mainly ocular, and reversible. A global, randomized trial of ABT-414 vs. ABT-414 + TMZ vs. TMZ/lomustine in EGFR amp, rGBM has completed accrual with results expected later this year (NCT02343406). Clinical trial information: NCT01800695.
Cambridge Brain Mets Trial 1 (CamBMT1): A proof of principle study of afatinib penetration into cerebral metastases (mets) for patients (pts) undergoing neurosurgical resection, combined with low-dose, targeted radiotherapy (RT)—Phase 1b results.
Authors: Baird Richard D. , Garcia-Corbacho Javier , Linossi Constanza , Kumar Sanjeev Srinivas , Smith Donna , Williams Michael , Qian Wendi , Machin Andrea , Ahmad Saif , Matys Tomasz , Jena Raj , Pacey Simon , Caldas Carlos , Jodrell Duncan Ian , Jefferies Sarah , Price Stephen , Watts Colin , Ramenatte Nicola 
Published: September 2018

2008 Background: Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure in pts with brain tumours. Preliminary data suggest that low-dose RT may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. CamBMT1 is a phase 1b/2 pre-operative window-of-opportunity trial designed to test if the delivery of afatinib into brain mets might be enhanced by targeted, low dose-RT. Methods: Pts with operable brain mets from breast or lung origin were treated with afatinib for 11 days prior to surgery on day 12. Pts also received a single fraction of targeted RT on day 10 (pts in either 2Gy or 4Gy arm). In phase 1b, afatinib dose (20, 30, or 40mg QD) was escalated in each arm using an accelerated titration design. Primary endpoint: steady-state afatinib concentration in resected brain mets, compared with plasma. Secondary endpoints: safety and tolerability. Results: 10 pts were treated (4 breast, 6 lung), with no dose-limiting toxicities seen, thus completing recruitment to phase 1b. Treatment was generally well tolerated. Median afatinib concentrations on day 12 were: plasma 22.7ng/mL (range 9.94-179); and tumour 405ng/g (range 120-1129). Conclusions: It was feasible to conduct a window-of-opportunity study of afatinib plus RT in pts with operable brain mets. The recommended phase 2 dose of afatinib was 40mg QD for both 2Gy and 4Gy arms. Afatinib concentrations in resected tumour were on average >15-fold higher than those in plasma. Phase 2 of CamBMT1 is now underway in multiple UK sites, and randomises patients into 3 treatment arms (n=20 per arm): 1. afatinib 40mg QD; 2. afatinib 40mg QD + 2Gy# RT; 3. afatinib 40mg QD + 4Gy# RT. Clinical trial information: NCT02768337. [Table: see text]
A phase II of everolimus and octreotide for patients with refractory and documented progressive meningioma (CEVOREM).
Authors: Graillon Thomas , Sanson Marc , Peyre Matthieu , Peyrière Hadrien , Autran Didier , Kalamarides Michel , Roche Pierre-Hugues , Fuentes Stephane , Tabouret Emeline , Barrie Maryline , Campello Chantal , Idbaih Ahmed , Dufour Henry , Chinot Olivier L. 
Published: September 2018

2011 Background: After iterative surgeries and radiotherapy (RT)/radiosurgery (RS) failure, aggressive meningiomas remain an unmet medical need. We have shown in vitro that everolimus (EVE) combined to octreotide (OCT) is active in meningiomas. Methods: Prospective multicentric single arm phase II study (NCT02333565) including pts with recurrent meningioma with documented progression ( > 10% increase of tumor surface over 6 months) after surgery and RT/RS. EVE was orally administrated at 10mg/day and OCT by IM injection 30 mg/28 days. MRI was performed every 3 months with planned central review of imaging including volumetric progression at inclusion and during treatment. The primary endpoint was PFS6. The criteria for success was defined as a PFS6 > 40%. Results: 20 pts were included, aged 30-75 years (median 55) with 37 progressive intra cranial meningiomas (WHO: 2 grade I, 27 grade II, 8 grade III) including 4 NF2 pts. Median KPS was 70%. All pts previously underwent at least one surgery and more than 1 in 18/20 patients. 19/20 pts were treated with radiotherapy or radiosurgery and 5 pts with prior chemotherapy. 1 pt was not evaluable at 3 months. With a median f/u of 12.3 months (2-24 months), PFS6 was 58.2% (95% CI 33.5-76.5%) and PFS12 was 38% (95% CI 16-60%). Volumetric analysis at 3 months demonstrated a decrease in tumor volume superior to 10% in 8 tumors (4 pts). Pre therapeutic growth rate was decreased of more than 50% in 29/35 tumors (18/20 pts) during the first 3 months. Inclusion (I)-to-3 months tumor growth rate (mean at 1.9%/month) was significantly lower than pre inclusion (Pre-I)-to-I growth rate (mean at 18.5%/month) (p = 0.0003). 3 highly aggressive tumors (3 pts) were separately assessed: Pre-I-to-I growth rate superior to 1000%/month was decreased to 3%, 15% and 44%/month in the first 3 months. Toxicity included 7 grade III AE (stomatitis, 3; pneumopathy, 1). AE of special interest included stomatitis (10, 50%), rash (8, 40%), abdominal pain and diarrhea (11, 55%) and nausea and vomiting (4, 20%). Conclusions: Everolimus and octreotide combination appears active in refractory aggressive and progressive meningiomas with acceptable and manageable toxicity and should request further evaluation. Clinical trial information: NCT02333565.
Use of targeted next generation sequencing (NGS) to assess mutational load in glioblastoma (GBM).
Authors: Bagley Stephen Joseph , Velu Priya , Bigdeli Ashkan , Hess Paul , Desai Arati Suvas , Linette Gerald P. , Nasrallah MacLean , O'Rourke Donald M. , Brem Steven , Morrissette Jennifer J. 
Published: September 2018

2027 Background: Trials of immune checkpoint inhibitors in GBM are ongoing. Evidence from other tumors suggests that high mutational load predicts response to these agents. We estimated mutational load in adults with newly diagnosed GBM using targeted NGS and assessed its association with other clinicopathologic parameters. Methods: NGS was performed for all patients diagnosed with isocitrate dehydrogenase wild-type (IDH-WT) GBM at our institution since September 1, 2016. Our panel performs targeted exome sequencing of 153 cancer-related genes (+/- 10 bp at intron/exon boundaries) and detects insertions, deletions, and single nucleotide variants at an allele frequency of 2%. Polymorphisms present in > 0.1% of the population according to the ExAC database and 1000 Genomes Project were filtered to reduce germline variants in the absence of matched normals. To avoid upward skewing of mutational load due to the panel’s preferential detection of genes recurrently mutated in cancer, alterations with known or likely functional disruption per the COSMIC database and/or our internal variant knowledge base were also not counted. The number of mutations counted was divided by the coding region target territory of the NGS panel (~0.5 Mb) to extrapolate mutational load to the whole exome. The Mann-Whitney U test was used to compare mutational load according to sex, age (≥65 vs. < 65), and MGMT methylation status (positive vs. negative). Results: Of 28 patients, median age was 65, 75% were male, and 37% were MGMT-methylated. Mean mutational load was 3.6 mutations/Mb (range 0-8, standard deviation 2.3) and was higher in males (4.3, 95% CI 3.3-5.3) compared to females (1.4, 95% CI 0.03-2.8) (p = 0.004). Mutational load did not differ according to age or MGMT methylation. Conclusions: In newly diagnosed IDH-WT GBM, targeted NGS revealed an estimated mutation rate similar to that reported in whole exome sequencing studies. In addition, we detected a higher mutational load in males compared to females. The latter finding adds to recent evidence suggesting sex-specific differences in the biology of GBM, and implies that future studies should account for sex when assessing mutational load as a predictive marker of immune checkpoint inhibition.
Neurocognitive outcome in children with sensorineural hearing loss after treatment of malignant embryonal brain tumors.
Authors: Dahl Christine , Moxon-Emre Iska , Ramaswamy Vijay , Bartels Ute Katharina , Tabori Uri , Huang Annie , Cushing Sharon , Papaioannou Vicky , Laperriere Normand , Mabbott Donald J , Bouffet Eric 
Published: September 2018

2029 Background: Neurological side effects associated with childhood brain tumors and their treatments contribute to long term neurocognitive morbidity. The aims of this study were to identify the incidence of sensorineural hearing loss (SNHL) in a large sample of children treated for malignant brain tumors, and to evaluate the potential relationship between SNHL and intellectual functioning following the completion of treatment. Methods: We conducted a prospective follow-up study at a single center with review of 119 patients treated for embryonal brain tumors at the Hospital for Sick Children, between 1996-2015, to analyze the impact of significant SNHL (Chang > 2b) on intellectual function. Hearing was assessed post-treatment (median age: 13.5y (+4.5)) and the median age for neurocognitive testing was 12.8y (+ 4.1). The median interval from time of diagnosis was 5.8y (+ 3.7). Results: Severe SNHL was identified in half the patients (50.4%, n = 60/119). We identified a subset of patients (n = 61) who had assessments of intellectual function. In this cohort, intellectual function was significantly poorer in the group with severe SNHL, even after controlling for the effect of craniospinal radiation (severe SNHL 22.4 Gy + 13.3, no or mild hearing loss 20.4 Gy +12.8) and boost dose and volume. Children experiencing severe SNHL had lower overall IQ (severe SNHL 72.4 + 16.6; no/mild hearing loss 92.0 + 20.5) p < 0.001 and in significantly lower verbal comprehension (severe SNHL 78.7 + 15.9; no/mild hearing loss 94.7 + 13.8) p < 0.001, and working memory (severe SNHL 78.2+ 17.6; no/mild hearing loss 94.8 + 16.4) p < 0.001, scores. Conclusions: Hearing loss is a much more significant complication in children with embryonal brain tumors than previously estimated. We show the profound impact of hearing loss on intellectual deficit in children. Namely, patients with severe SNHL have difficulty using and understanding verbal language, and they have a reduced ability to concentrate and manipulate information in short-term memory. Our results have implications on future trial designs and follow-up of children treated for embryonal brain tumors.
Benefits and costs of bevacizumab in recurrent glioblastoma: A quality adjusted survival and cost analysis (EVALUATE).
Authors: Conen Katrin Lisa , Matter-Walstra Klazien , Schädelin Sabine , Mariani Luigi , Hess Viviane 
Published: September 2018

2032 Background: Routine clinical use of bevacizumab (Bev) in recurrent glioblastoma (rGBM) is controversial, as no large RCT has shown a survival advantage. We describe treatment algorithms, survival (OS), quality-adjusted survival (QAS) as well as costs of patients (pts) with GBM treated at an academic hospital in Switzerland, where Bev is registered and reimbursed for rGBM. Methods: Pts’ and treatment characteristics from diagnosis until death (including neurological symptoms and toxicities) of all pts over a 5-year period were retrospectively retrieved from our GBM database. For each treatment period (1st-line, recurrence and “best supportive care”) time to next treatment (TNT), OS and QAS were calculated and modelled for prognostic factors (Cox regression). QAS was evaluated as previously described (Murray et al). In- and out-patient costs were calculated from time of diagnosis until death in respect of Bev treatment (+Bev vs. –Bev). Results: 82 newly diagnosed GBM pts with a median age of 66 years (range 39-85), median KPS of 90% (range 50-100%), who were treated with 1 (n = 75), 2 (n = 36) or 3 (n = 14) lines of therapy, respectively, lived for a median OS of 11.9 (SD 9.7) months (mos). QAS was 5.3 (SD 6.9) mos i.e. 44% of the numerical survival time. 40% of patients were treated with Bev at 1st or 2nd recurrence. Pts, who were selected for BEV treatment, had a longer time from diagnosis to 2ndline treatment (median 5.2 (SD 6.3) mos) as compared to pts in the -Bev group (median 2.1 (SD 1.8) mos). Younger age and Bev treatment were associated with longer OS and QAS. QAS to OS ratio was 52% (9.4 out of 18.1 mos) for BEV treated patients and 34% (2.8 out of 8.2 mos) for the –Bev group, respectively. Bev treatment increased the overall treatment costs by 1.7x. The population adjusted incremental cost-effectiveness ratio (ICER) was CHF 75,669 per life year gained. Conclusions: QAS in patients with GBM is short (one third to half of OS). In our cohort, pts selected for Bev treatment had longer OS and longer QAS - at costs below the accepted threshold of 100,000 CHF per life year gained. Whether this gain of lifetime is a direct result of Bev treatment or a consequence of a selection bias needs to be addressed prospectively.
PD-L1 expression of high grade glial tumors at diagnosis and change of expression status at recurrence.
Authors: Oyan Basak , Eren Seyma , Sonmez Ozlem , Ozkan Ferda , Yaltırak Kaan , Ture Ugur 
Published: September 2018

2035 Background: PD-L1 expression status is the main predictive factor for response to immune checkpoint inhibitors. PD-L1 status may change over time with the impact of therapies. The aim of this study is to determine if PD-L1 expression status changes in recurrent gliomas after chemoradiotherapy. Methods: Thirty eight patients with recurrent high grade gliomas who had surgical excision at least two times were included in this retrospective cross-sectional study. Nine patients were excluded because of the lack of appropriate pathology slides for pathologic evaluation. PD-L1 expression of 29 patients was evaluated by an expert pathologist with immunohistochemical methods. PD-L1 positivity was defined as expression in ≥1% of tumor cells. Change in PD-L1 expression status was defined as an absolute 5% difference between two resections. Results: Of the 29 patients, 15 patients (51.7%) had PD-L1 expression in ≥1% of tumor cells and 7 patients (24.1%) had PD-L1 expression in ≥10% of tumor cells. Tumor PD-L1 expression (defined as expression in ≥1% of tumor cells) was positive in 15 (51.7%) of 29 patients at diagnosis and at the time of recurrence. The PD-L1 status did not change in 17 patients (58.6%). 8 patients had PD-L1 negative tumors both at diagnosis and at recurrence, while 9 patients had PD-L1 positive tumors both at diagnosis and at recurrence. In 6 patients (20.7%) a negative-to-positive switch and in 6 patients (20.7%) a positive to negative switch were seen. Tumor PD-L1 expression increased in 7 of 29 patients (24.1%) and decreased in 9 of 29 patients (31.1%). PD-L1 expression remained stable in 13 of 29 patients (34.4%). The change in PD-L1 status over time was not statistically significant. Conclusions: More than 50% of high grade glial tumors express PD-L1 at diagnosis, so these tumors are good candidates for immune checkpoint inhibitors. The expression status changes in more than 40% of high grade glial tumors at recurrence, so immune responsiveness of glial tumors can be modified by treatments like chemotherapy and radiotherapy.