bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inefficiencies in the phase II to phase III transition as a modifiable factor that is impeding successful drug development for glioblastoma.
Authors: Balasubramanian Adithya , Gunjur Ashray , Hafeez Umbreen , Menon Sid , Cher Lawrence , Parakh Sagun , Gan Hui Kong 
Published: May 2020

2516 Background: Improving the outcomes of patients with glioblastoma (GBM) represents one of the most significant challenges in neuro-oncology. We have observed inefficiencies in the availability and use of phase 2 data when planning phase 3 studies, and have undertaken a detailed review of key design parameters of phase 2 and 3 trials in GBM to identify and quantify the impact of this phenomenon. Methods: Studies between 2005-2019 inclusive were identified though MEDLINE search using keywords and MeSH terms, and manual bibliography searches. P2Ts were restricted to those referenced by the corresponding P3Ts. Clinical, statistical and sponsor characteristics were extracted by two reviewers (AB&AG). For each P3T, corresponding Phase 2 trial (P2T) data was “optimally matched” (OM) where same drug was used in similar schedule and similar GBM population; “partially matched” (PM) where dis-similar schedule and/or treatment setting; and “lacking” in all other circumstances. The statistical data used in the P2/3 transition were compared by Pearson Correlation, Fisher’s Exact or Chi-square testing as appropriate. Results: Of 20 P3Ts identified, 6 (30%) lacked any phase 2 data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). Further, there were 13 OM dyads and 7 PM dyads. OM dyads showed strong concordance for mPFS (r2= 0.95, p < 0.01) and mOS (r2= 0.84, p < 0.01), whilst PM dyads did not (p > 0.05). We identified several inefficiencies in translation from P2T to P3T. Firstly, 3 P3T had statistical assumptions of primary endpoint that may have been too optimistic. 2 of these P3Ts aimed for an expected endpoint that was higher than the actual outcomes from a matched P2T. 1 P3T was unable to reach the desired sample size. We note that 4 P3Ts had actual primary endpoint HRs that were < 0.9 but with P > 0.05. Finally, we investigated whether there were absolute thresholds for efficacy in P2Ts to inform whether to proceed with P3Ts. For P2Ts in the newly diagnosed setting, all those with mPFS < 14 months and/or mOS < 22 months had subsequent negative P3Ts. For P2Ts in recurrent disease, all those with mPFS < 6 months and mOS < 12 months had negative P3Ts. Applying these thresholds to the studies in our review, 10 of the 12 negative P3Ts (83%) with matched P2Ts need not have been initiated, sparing 4739 patients’ from unnecessary trial participation. Conclusions: Our data strongly supports the vital role of properly designed P2Ts in informing P3Ts for drug development for primary CNS tumours.
Immune microenvironment profiling of breast cancer brain metastases using multiplex immunofluorescence.
Authors: Griguolo Gaia , Tosi Anna , Guarneri Valentina , Dieci Maria Vittoria , Fineberg Susan , Ventura Annavera , Bauchet Luc , Jacob Jack , Rigau Valerie , Jacot William , Rosato Antonio , Darlix Amelie , Conte Pier Franco 
Published: May 2020

2526 Background: Despite clinical implications, the complexity of brain metastases (BM) immune microenvironment in breast cancer (BC) patients is poorly understood. Multiplex immunofluorescence (mIF), a novel imaging technique allowing simultaneous visualization and quantification of several IF labeled proteins while maintaining spatial information, holds promise to comprehensively describe BCBM immune microenvironment, potentially providing valuable information to improve treatment. Methods: Clinical data and archival BM samples were collected for 60 BC patients undergoing neurosurgery (2003-2018) at three institutions. BM immune contexture was characterized using a custom mIF panel, including cell subtyping (CD4, CD8, FOXP3, CD68), activation (Granzyme B) and localization (keratin for tumor recognition) markers. Mean immune cell density (cells/mm2) for each sample was determined by digital image analysis and classified in tumor and stroma areas. Associations between immune subpopulations, BC subtype and overall survival from BM diagnosis (OS) were studied. Results: Up to date, 30 BCBM samples have been analyzed; 33% HR+/HER2-, 20% HR-/HER2+, 10% HR+/HER2+, 37% HR-/HER2-. At a median follow-up of 46 months, BC subtype was the only clinical variable associated with OS (longest for HER2+ and shortest for HR-/HER2-, log-rank p = 0.002). In the total sample area, no significant difference in immune cell densities was observed according to BC subtype. In the tumor area, HR+/HER2- tumors showed higher densities of CD8+ and CD68+ cells compared to other subtypes (p = 0.036 and p = 0.016, respectively). In stroma, HR-/HER2- tumors presented numerically higher densities of CD4+ and FOXP3+ cells and higher ratio of CD4/CD8 and FOXP3/CD8 ratio (not statistically significant). Higher CD4/CD8 and FOXP3/CD8 ratio in the stroma was significantly associated with worse OS, even after correction by BC subtype (Table). Conclusions: In BCBM, immune infiltrate differs according to BC subtype. Preliminary results suggest that a more tolerogenic immune microenvironment is associated with worse OS and might represent a target for optimization of immunotherapy for these patients. Updated results for all 60 patients will be presented. [Table: see text]
Clinical outcome of patients experiencing central nervous system progression on first-line pertuzumab and trastuzumab for HER2-positive metastatic breast cancer in a real-life cohort.
Authors: Collet Laetitia , Eberst Lauriane , Fraisse Julien , Debled Marc , Levy Christelle , Mouret-Reynier Marie-ange , Desmoulins Isabelle , Goncalves Anthony , Campone Mario , Ferrero Jean-Marc , Brain Etienne , Dieras Veronique , Petit Thierry , Simon Gaetane , Leheurteur Marianne , Dalenc Florence , Vanlemmens Laurence , Darlix Amelie , Arnedos Monica , Bachelot Thomas 
Published: May 2020

2527 Background: Isolated central nervous system (CNS) progression on first-line systemic therapy with Trastuzumab (T) and Pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) is a therapeutic challenge. Our aim was to describe the clinical outcome and current treatment strategies for such patients in a large retrospective cohort. Methods: Patients (pts) were selected among all MBC pts included in the French Epidemiological Strategy and Medical Economics (ESME) database involving 18 specialized cancer centers (NCT03275311). CNS progression-free survival (CNS-PFS), progression-free survival (PFS) and overall survival (OS) from diagnostic of brain metastases (BM) were estimated using the Kaplan-Meier method. Results: Between January 2008 and December 2016, 995 pts were treated with first-line T and P for their HER2-positive MBC. They were 55 years old in median, with tumors expressing hormone-receptors in 62%. A total of 132 pts (13%) experienced isolated CNS progression on T and P, with a median time from metastatic diagnosis to CNS progression of 12 months. It was the first CNS progression for 108 pts (82%) while 24 (18%) already had BM at time of metastatic relapse. After CNS progression, T and P were continued for 58% of pts (n = 73). The remaining 47 pts were switched to another HER2-directed therapy (T-DM1 for 57%, T alone or combined with chemotherapy for 36% and lapatinib for 21%). Among those 132 pts, 37% received whole-brain radiotherapy, 18% stereotactic radiation therapy, and 11% surgery. Systemic treatment was combined with CNS-directed therapy for 50% of pts. Median follow-up is 21 months (95%CI: 14.9-25.5) from the diagnosis of CNS metastases. Median OS (mOS) of the 132 pts is 35 months (95%CI: 29.2-53,6), and median PFS 7 months (95%CI: 6.3- 9.2). A total of 77 pts (58.3%) experienced a new CNS progression with a median CNS-PFS of 9 months (95%CI: 7.6-12,0). Patient who stayed on T and P had a significantly better OS in comparison to pts who were switched to another systemic HER2-directed therapy (mOS not evaluable vs23 months), whereas PFS and CNS-PFS were similar between groups. Conclusions: In this real life setting, isolated CNS progression occurred among 13% of pts with HER2+ MBC on first-line treatment with T and P, after a median time of 12 months. Following current ASCO recommendations, continuation of T and P after CNS-directed therapy, seemed to be adequate. Nevertheless, time to subsequent progression is short and better therapeutic options are needed.
Radiation-induced changes in the inflammatory microenvironment composition of lung cancer brain metastases.
Authors: Steindl Ariane , Mair Maximilian , Starzer Angelika Martina , Dieckmann Karin , Widhalm Georg , Hainfellner Johannes A. , Schmidinger Manuela , Preusser Matthias , Berghoff Anna Sophie 
Published: May 2020

2528 Background: Radiotherapy was postulated to impact the inflammatory microenvironment composition in patients with lung cancer brain metastases (BM). Methods: Formalin fixed and paraffin embedded BM specimens from treatment naïve patients (group 1) and from patients treated with radiation therapy including whole brain radiotherapy and/or stereotactic radiosurgery (group 2) or prophylactic cranial irradiation (group 3) before BM resection were identified from the Vienna Brain Metastasis Registry. T cell subsets (CD3+,CD8+,CD45RO+,FOXP3+,PD-L1+) were investigated using the Ventana Benchmark Ultra system Definiens software. Results: Specimens from 41 patients (28/41;68.3% NSCLC, 13/41;31.7% SCLC) were included in the study. A significant difference in CD3+TIL density between group 1 (median: 964.5cells/mm2) and group 2 (median: 283.4cells/mm2; p-value=0.021; Mann-Whitney-U test), as well as group 3 (median: 168.8 cells/mm2; p-value= 0.028; Mann-Whitney-U test) were observed. Furthermore, CD8+ and FOXP3+TIL densities of group 2 (CD8+ median: 172.1cells/mm2; FOXP3+ median: 210.7cells/mm2) were numerically lower compared to group 1 (CD8+ median: 190.1 cells/mm2; FOXP3+ median: 221.2 cells/mm2). Of 10/41 (24.4%) patients further resected BM tissue specimens after initial resection were available. Here, the inflammatory microenvironment of BM treated with radiation therapy between the resections was significantly associated with lower densities of CD3+ (median: 105.1 cells/mm2) and CD8+ (median: 20.3cells/mm2) compared to radiation-naïve patients (CD3+ median: 825.4cells/mm2; CD8+median: 105.5cells/mm2; p=0.037; Mann-Whitney U-test). Conclusions: Radiation treatment was associated with lower densities of TIL subsets in our BM cohort. Although results have to be interpreted with caution due to the limited sample size, further studies investigating the sequencing of radiotherapy and immune modulating therapies might be of interest. [Table: see text]
Application of machine learning algorithms for the diagnosis of primary brain tumors.
Authors: Khammad Vasilii , Otero Jose Javier , Cabello Izquierdo Yolanda , Garagorry Guerra Francisco , Becker Aline P. , Kharchenko Nataliy , Zapirov Gadzhimurad 
Published: May 2020

2533 Background: Primary lesions of the CNS refer to a heterogeneous group of benign or malignant tumors arising in different parts of the brain and spinal cord. According to the 2016 CNS WHO classification, the accurate diagnosis of primary brain tumors requires a layered approach of histologic, anatomic and molecular features to generate an integrated diagnosis with clinical and prognostic significance. However, in the US and worldwide, scarce resources are available to perform all the required tests routinely, so methods that improve pre-test probabilities and decrease false positive results have significant clinical and financial impact. Aims: 1) validate new diagnostic workflows with implementation of modern machine learning/artificial intelligence approaches; 2) design a reliable and interactive computational platform for primary CNS tumor diagnosis. Methods: To achieve these goals we have developed a population model in Rstudio, “La Tabla”, based on the articles from open resources of MEDLINE database and the latest version of WHO classification of CNS tumors. The data of “La Tabla” is comprised of more than 100,000 adult and pediatric cases, including rare brain tumor diagnoses, such as Gangliocytoma, Diffuse Midline Glioma and etc. Results: Boruta package and weights function in R have been used to distinguish the most important features for diagnosis prediction. To visualize correlation between these features (age, ki67 level, tumor location, presence of myxoid areas, calcifications, necrosis and etc.) and all diagnoses in two-dimensional space, we used a t-SNE algorithm. Models trained with decision tree algorithms (randomForest, XGBoost and C5.0) showed high overall accuracy in predicting diagnoses of “La Tabla” (95%, 94% and 92%) and 300 patients at OSUCCC-James (93%, 74% and 87%) in the absence of IHC and molecular data. Neural networks provided by keras and nnet packages predicted diagnoses using just clinical and histological findings with 94% and 88% accuracy on “La Tabla” and James patient databases respectively. Currently, we are building “Shiny” applications with R to deliver easily operated platform for pathologists and physicians. Conclusions: In conclusion, we managed to generate models that are able to diagnose primary brain lesions using basic clinical data (age, gender, tumor location), ki67 levels and distinct features of histological architecture. Most of the models distinguish brain tumors and associated molecular status with high accuracy and will serve as a reliable tool for second opinion in clinical neuro-oncology.
Clinical outcomes of the combination of bevacizumab and ttfields in patients with recurrent glioblastoma: Results of a phase II clinical trial.
Authors: Fallah Jaleh , Chaudhary Rekha T. , Rogers Lisa R. , Wei Wei , Brewer Cathy J. , Peereboom David M. , Ahluwalia Manmeet Singh 
Published: May 2020

2537 Background: Clinical trials of bevacizumab monotherapy and TTFields monotherapy have shown activity but limited clinical benefit in patients (pts) with recurrent glioblastoma (GBM), with median progression-free survival (PFS) of 2-4 months and median overall survival (OS) of 6-9 months with either treatment modality. In a single-arm phase II clinical trial, the efficacy of the combination of bevacizumab and TTFields in pts with recurrent GBM was investigated. Methods: Pts with histologically confirmed GBM or other grade IV gliomas, who had disease progression after chemoradiation were enrolled in a phase II trial of the combination of bevacizumab and TTFields. Bevacizumab was given at a dose of 10 mg/Kg intravenously every 2 weeks and TTFields was worn by the pts continuously for more than 18 hours per day. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints were PFS at 6 months and OS at 12 months. Survival outcomes were assessed using the Kaplan-Meier method and compared by log rank test. Treatment-related adverse events were reported according to CTCAE, v4.0 criteria. Results: From April 2013 to December 2017, 25 pts were enrolled and 23 were evaluable: 18 (78%) men and 5 (22%) women, median age 60 years (range 17–78). 21 pts were Caucasian, 1 was African American and 1 of unknown race. After a median follow up of 31.6 months (range: 4.1-59.0 months), 21 out of 23 pts died (4 women and 17 men). The median PFS was 4.1 months (95%CI, 3.6-9.5) and the median OS was 10.5 months (95% CI, 8.2-14.9). The PFS rate at 6 and 12 months were 33% and 19%, respectively. The OS rate at 6 and 12 months were 82% and 46%, respectively. Women had better OS and PFS compared to men, however, the difference was not statistically significant which can be due to the small study population (table). Grade 3 and 4 toxicities considered definitely or probably related to the treatment included hypertension (n = 1) and cerebral infarction (n = 1). Other reported grade 3-4 toxicities (n = 7) included cough, dysphagia, muscle weakness, hyperglycemia, psychosis, seizure, lymphopenia, transaminitis, and muscle weakness considered unlikely to be treatment-related. Conclusions: The combination of bevacizumab and TTFields in is safe and feasible and has clinical efficacy in pts with recurrent GBM. Clinical trial information: NCT01894061 . [Table: see text]
Phase Ib clinical trial of OKN-007 in recurrent malignant glioma.
Authors: Battiste James D. , Ikeguchi Alexandra , Woo Sukyung , Sharan Satish , Zhao Yan D. , Cohoon Andrew , Sung Sarah , Wright Deborah , Teague April M. , Jensen Randy L. , Kim Eun Ha , Yang Won S. , Towner Rheal A. 
Published: May 2020

2538 Background: Despite therapeutic advances, the median overall survival for patients with recurrent, high-grade gliomas remains poor. Thus, there is an urgent need for efficacious new therapies. The nitrone compound, OKN-007 (disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is a promising novel anti-cancer agent. In orthotopic glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. Methods: NCT01672463 is a phase Ib trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. Patients with recurrence, adequate performance status and organ function, receiving clinically appropriate doses of steroids, with a life expectancy greater than 8 weeks were eligible. OKN-007 was administered by IV. The study comprised a 3+3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until recurrence (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). Results: Median age was 51 years (range, 25-62). No dose-limiting toxicities were observed and 60 mg/kg was chosen for the expansion dose. Of 123 adverse events (AE), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAE were fatigue (4.1%) and headache (3.3%). No drug-attributable grade 4 or 5 AE were observed. Grade 3 TEAE included headache, urinary tract infection, and increased prothrombin time (0.8% each). Only two grade 1 AE, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. Conclusions: OKN-007 appears safe for patients with recurrent glioma. The MTD was not reached. Our data suggest that, compared to standard therapy, OKN-007 may prolong OS in recurrent glioma. Based on new data, a trial of OKN-007 plus temozolomide is underway in patients with newly diagnosed glioblastoma (NCT03587038). Clinical trial information: NCT01672463 .
Post-marketing safety surveillance of tumor treating fields (TTFields) in patients with high-grade glioma in clinical practice.
Authors: Shi Wenyin , Blumenthal Deborah T. , Oberheim Bush Nancy Ann , Kebir Seid , Lukas Rimas Vincas , Muragaki Yoshihiro , Zhu Jay-Jiguang , Glas Martin 
Published: May 2020

2542 Background: Tumor Treating Fields (TTFields) are an antineoplastic treatment delivering low intensity, intermediate frequency, alternating electric fields through two pairs of transducer arrays locoregionally applied to tumor bed. TTFields are FDA-approved for glioblastoma (GBM; 200 kHz) and mesothelioma (150 kHz). Safety and effectiveness were demonstrated in the phase III EF-11 and EF-14 trials in recurrent GBM (rGBM) and in newly diagnosed GBM (ndGBM), respectively. The main TTFields-related adverse event (AE) was array-associated manageable skin irritation. We report AEs from TTFields-treated patients in the real-world, clinical practice setting. Methods: Unsolicited, global, post-market surveillance data from TTFields-treated patients (October 2011–February 2019) were retrospectively analyzed using MedDRA v21.1, stratified by region (US, EMEA [Europe, Middle East, Africa], or Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma and anaplastic oligodendroglioma, or other brain tumors that includes brain metastases from different cancer types), and years of age (<18, pediatric; 18 to 64, adults; or ≥65, elderly). Results: Of 11,029 patients, 53% had ndGBM, 39% had rGBM (at any line of recurrence), 6% had anaplastic astrocytoma/oligodendroglioma, and 1% had other brain tumors. Most were adults (73%) and 26% were elderly (≥65 years of age). The majority of patients were males (66.3%) compared to females (33.7%), with a ratio representative of a typical GBM population. The most reported TTFields-related AE was array-associated local skin reaction, with an incidence of 38% in ndGBM, 29% in rGBM, 38% in anaplastic astrocytoma/oligodendroglioma, 31% in other brain tumors, 37% in pediatric, 34% in adults, and 36% in elderly patients. Most skin AEs were mild to moderate and resolved with no treatment or over the counter topical ointments. Incidence of other TTFields-related AEs in patients with ndGBM and rGBM, respectively, included heat sensation (under-array warmth; 11%, 10%), electric sensation (under-array tingling; 11%, 9%), and headache (7%, 6%). Conclusions: This retrospective, global, TTFields safety surveillance analysis revealed no new safety signals, with favorable safety and tolerability comparable to published TTFields/GBM trials. The most common TTFields-related AE was array-associated local skin reaction. The safety profile remained consistent among subgroups (diagnosis, age, or region) and total cohort, indicating feasibility in multiple subpopulations, including elderly patients.