tbuckley/cabot-search huggingface dataset:
P01.005 The impact of thrombocytopenia from concomitant and adjuvant temozolomide in patients with glioblastoma
Authors: A Nivet, A Schernberg, G Louvel, S Dumont, S Ammary, A Rehalia-Blanchard, P Clavère, F Parker, J Pallud, F Dhermain
Journal: Neuro-Oncology (2018)

Temozolomide (TMZ) administered daily with radiation therapy for six weeks, followed by adjuvant TMZ for six months is standard therapy for patients (pts) with newly diagnosed glioblastoma (GBM). Thrombocytopenia (TBP) usually appears in 10 % of patients and is responsible for treatment delays or potential severe complications. We conducted a retrospective review to define the incidence, duration and consequences of TBP associated with TMZ. We reviewed the medical records and laboratory data of all adult pts with histologically confirmed GBM treated with this regimen between March 2006 and December 2015. TBP was defined according to CTCAE version 4.0. 376 pts met the criteria for the review and 327 patients received adjuvant TMZ. During the concomitant chemo-radiation part, TBP occurred in 43 (11%) and grade 3–4 thrombocytopenia in 26 (7%) pts. The median delay of TBP was 35 days and the median duration was 41 days. Three pts (0,79%) discontinued therapy and 24 pts (6,3%) stopped TMZ for thrombocytopenia, 18 (4,8%) required platelet transfusions. During the adjuvant chemotherapy, TBP occurred in 67 (20%) and grade 3–4 thrombocytopenia in 25 (8%) pts. The median cure of thrombocytopenia was 2 and the median duration was 18 days. 34 pts (10%) discontinued therapy and 6 (2%) stopped TMZ due to TBP, 14 (4,3%) required platelet transfusions. Thrombocytopenia (during concomitant or adjuvant treatment) was not a prognostic factor for survival. Independant factors predicting TBP were female gender and a treatment with Sulfamethoxazole. In this large cohort, incidence of TMZ-induced TBP was more frequent during adjuvant treatment, but more severe during concomitant treatment. This toxicity does not appear to affect survival.
Long-term causes of relative excess mortality after diagnosis of testicular germ cell tumor.
Authors: Oivind Kvammen, Myklebust Åge Tor, Arne Solberg, Bjørn Møller, Olbjørn Harald Klepp, Sophie Fosså, Torgrim Tandstad
Journal: Journal of Clinical Oncology (2017)

4553 Background: Despite today’s excellent cure rates among testicular germ cell tumor (TGCT) patients, reduced long-term relative survival (RS) is an increasing concern. We recently reported a continuing decline in RS among TGCT patients diagnosed in Norway, even beyond 30 years of follow-up. Late effects of treatment is the main culprit. Although several reports describe increased mortality from second cancer (SC), cardiovascular disease (CVD), and other causes (OC) among TGCT survivors, data beyond 20 years of follow-up are scarce. The study aim was to analyze long-term relative risks (RR) and causes of death (CD) among TGCT patients diagnosed in Norway, 1953-2014. Methods: Data sources were the Cancer Registry of Norway and the Norwegian Cause of Death Registry. All men diagnosed with TGCT in Norway during 1953-2014 were included, except spermatocytic seminomas. End of follow-up was December 31 st , 2014. Patients were classified by CD, histology, disease extent and age at diagnosis, as well as by decade of diagnosis and follow-up time. Standardized mortality ratios (SMR), compared with the general Norwegian male population, were computed. Results: At end of follow-up, 2359 of 9390 patients were deceased. CD was obtained for 2320 patients; 37.6 % TGCT, 24.5 % SC, 19.1 % CVD and 18.8 % OC. SMR for all SC were significant particularly after 20 years of follow-up (1.8 – 3.1), with similar findings in localized disease at diagnosis. SMR were most consistently elevated beyond 20-30 years for SC of the pancreas, large intestine and bladder. By contrast, SMR for CVD were significant among patients diagnosed 2000-14, both before and after one year of follow-up (2.6). There were no significant SMR for CVD beyond 20 years of follow-up. Several OC SMR were elevated, such as for digestive and genitourinary diseases beyond 20-30 years (2.2 – 5.1). Conclusions: TGCT patients have increased RR of SC and OC death even beyond 20-30 years of follow-up, while the increased RR of CVD death is mostly confined to the first decade. CVD deaths in patients diagnosed 2000-14 are a particular concern. Continuing optimization of TGCT treatment and follow-up schemes is required, including further research on toxicity mechanisms.
A legal methodology to enable broad-access sharing and investigation of clinical trial cancer data.
Authors: Dave Handelsman, Martin J. Murphy
Journal: Journal of Clinical Oncology (2018)

e18604 Background: Launched in 2014, ProjectDataSphere.org today hosts nearly 120,000 patient lives of data from oncology clinical trials sponsored by industry, academic, and government data providers. These patient-level data, de-identified by data providers, are broadly available to the research community with no prior research proposal review required. Methods: Two critical legal agreements serve as cornerstones for ProjectDataSphere.org. The first, the Cancer Research Platform Agreement, defines the terms of use for the User. This includes licensing to use the platform and parameters that constrain how the data within the platform may be used. The agreement successfully combines the desire to provide maximum utility to the user, while at the same time addressing patient privacy concerns, data providers’ information assets and intellectual property interests. The second document, the Data Sharing Agreement, establishes the legal boundaries from the perspective of the data provider. These boundaries include data use parameters, data ownership provisions, intellectual property considerations and publication attribution expectations. Over time, the Data Sharing Agreement has expanded to include experimental arm data in addition to comparator arm, and additional data use methodologies (non-downloadable in addition to downloadable). Results: To date, 11 peer-accepted papers have been written based upon investigations driven by data available through the platform. Critically, the Data Sharing Agreement has not been modified for individual data providers as a common Data Sharing Agreement is necessary to ensure investigators can comprehend the legal use of the data without introducing complexities associated with bringing data from multiple providers together for investigation. Conclusions: The foundational legal methodology established at the onset of this scientific endeavor has been critical to its success. By working with pharmaceutical manufacturers and academic centers in establishing this legal framework, strong precedent enables the finalized agreements to be for both platform users and all data providers, and is largely unchanged as the platform has grown in volume, value and usage.
Prognostic role of beta-2 microglobulin (B2M) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) treated with ibrutinib (ibr).
Authors: William G. Wierda, Jennifer R. Brown, Stephan Stilgenbauer, Steven Coutre, John C. Byrd, Anthony R. Mato, Constantine Tam, Jacqueline C. Barrientos, Ulrich Jäger, Stephen Devereux, Florence Cymbalista, Paul M. Barr, Claire Dearden, Marco Montillo, Carol Moreno, Emily Y. Liu, Anita Szoke, James P. Dean, Susan Mary O'Brien
Journal: Journal of Clinical Oncology (2018)

7521 Background: B2M is often elevated in pts with CLL and correlates with disease stage and burden. Normalization of B2M at 6 mo during ibr treatment was associated with improved progression-free survival (PFS) (Thompson et al 2016). We evaluated B2M changes over time, factors associated with B2M normalization, and correlations between B2M status and PFS in pts with R/R CLL treated with ibr. Methods: Data were pooled from 2 clinical trials of single-agent ibr (420 mg/d) in pts with R/R CLL. Pts in RESONATE were randomized 1:1 to ibr or ofatumumab. All pts in RESONATE-17 received ibr. Univariate (UVA) and multivariate (MVA) analyses were used to examine baseline (BL) factors associated with B2M normalization. PFS from time of the 6-mo B2M visit was compared based on B2M status; exploratory analyses evaluated PFS by 9-, 12-, and 15-mo B2M status. Results: In the combined ibr population (N = 339), BL elevated B2M (79% ≥3.5 mg/L; median 5.4 mg/L), del17p (61%), and unmutated IGHV (58%) were common; 15% had del11q, and 25% had creatinine clearance (CrCl) < 60 mL/min. Pts had a median of 2 prior lines of therapy. Median B2M decreased rapidly, by ~40% at 3 mo, in all patients. Overall, 50% of pts normalized B2M during ibr. Median time to B2M normalization was 17 mo and was non-significantly shorter for pts with del17p vs without del17p (14 vs 26 mo; P= 0.220). In UVA, BL B2M < 3.5 mg/L, age < 65 y, and CrCl ≥60 mL/min were significantly (P≤0.0002) associated with B2M normalization at 6 mo, while del17p was not significant. In MVA, BL B2M < 3.5 mg/L (P= 0.0002) and CrCl ≥60 mL/min (P= 0.034) were significant factors. PFS did not differ when assessed by 6-mo B2M normalization status (HR 0.699 [95% CI 0.452, 1.080]; P= 0.105), nor by 12- or 15-mo B2M status, but was significantly different by 9-mo B2M status (HR 0.579 [95% CI 0.366, 0.915]; P= 0.018); median PFS was not reached in either group. For B2M normalization at 9 mo, CrCl was significant in MVA, but age and BL B2M were not. Conclusions: Pts treated with ibr had a rapid decrease in median B2M regardless of BL parameters. BL B2M < 3.5 mg/L and CrCl ≥60 mL/min were associated with B2M normalization at 6 mo in MVA. B2M normalization status at 9, but not 6, mo predicted PFS. Clinical trial information: NCT01578707 and NCT01744691.
Development of an NGS assay to detect MRD in hematologic malignancies.
Authors: James Yu, Parth Sitlani, Prachi Nakashe, Gregory Sims, Christopher Scott, Armin Graber, Jeffrey Falk
Journal: Journal of Clinical Oncology (2018)

e24177 Background: There are significant prognostic and therapeutic benefits in monitoring minimal/measurable residual disease (MRD) in hematologic malignancies. However, monitoring of MRD requires the detection of minute cell populations with mutations present at very low allele frequencies (AFs), and is currently performed using low throughput flow cytometry or qPCR/ddPCR methodologies which are limited in their ability to monitor multiple mutations. An approach that can assay mutations in multiple genes may provide a broader understanding of MRD and patient prognosis. We have developed a Next Generation Sequencing (NGS) MRD assay using the Illumina NextSeq platform to simultaneously monitor a number of genes associated with hematologic malignancies (e.g. NPM1, RUNX1, FLT3). Here we present studies demonstrating detection of mutations at the low AFs required for the monitoring of MRD in hematologic malignancies. Methods: A custom target capture NGS assay was developed using Unique Molecular Identifier-based error correction enabling mutation detection of AFs down to 0.01%–0.1%. This assay incorporates barcoded duplex adapters and xGen Lockdown Probes (Integrated DNA Technologies) to enrich for relevant genes. Following sequencing on the NextSeq500, a custom bioinformatics pipeline was utilized for the error correction and false-positive reduction necessary to accurately detect mutations at the low AFs required for MRD detection. Results: Initial studies utilized Horizon Discovery’s TruQ Reference standards with mutations characterized at 1.0%–1.3% by ddPCR. These samples were diluted with a wildtype standard to demonstrate detection at even lower AFs. Subsequent studies were performed on peripheral blood samples from patients diagnosed with myelodysplastic syndromes and acute myeloid leukemia. Conclusions: This NGS MRD assay can accurately detect low AF mutations in both control and clinical MDS and AML samples. These results show that the NGS MRD assay described can be effectively utilized to monitor and study the course of disease in hematologic malignancies. Subsequent studies are underway to further increase the sensitivity of the assay and demonstrate its utility in a broad range of high-sensitivity applications.
Accuracy of Fractional Flow Reserve Derived From Coronary Angiography
Authors: William F. Fearon, Stephan Achenbach, Thomas Engstrom, Abid Assali, Richard Shlofmitz, Allen Jeremias, Stephane Fournier, Ajay J. Kirtane, Ran Kornowski, Gabriel Greenberg, Rami Jubeh, Daniel M. Kolansky, Thomas McAndrew, Ovidiu Dressler, Akiko Maehara, Mitsuaki Matsumura, Martin B. Leon, Bernard De Bruyne
Journal: Circulation (2019)

Measuring fractional flow reserve (FFR) with a pressure wire remains underutilized because of the invasiveness of guide wire placement or the need for a hyperemic stimulus. FFR derived from routine coronary angiography (FFRangio) eliminates both of these requirements and displays FFR values of the entire coronary tree. The FFRangio Accuracy versus Standard FFR (FAST-FFR) study is a prospective, multicenter, international trial with the primary goal of determining the accuracy of FFRangio.Coronary angiography was performed in a routine fashion in patients with suspected coronary artery disease. FFR was measured in vessels with coronary lesions of varying severity using a coronary pressure wire and hyperemic stimulus. Based on angiograms of the respective arteries acquired in ≥2 different projections, on-site operators blinded to FFR then calculated FFRangio using proprietary software. Coprimary end points were the sensitivity and specificity of the dichotomously scored FFRangio for predicting pressure wire-derived FFR using a cutoff value of 0.80. The study was powered to meet prespecified performance goals for sensitivity and specificity.Ten centers in the United States, Europe, and Israel enrolled a total of 301 subjects and 319 vessels meeting inclusion/exclusion criteria which were included in the final analysis. The mean FFR was 0.81 and 43% of vessels had an FFR≤0.80. The per-vessel sensitivity and specificity were 94% (95% CI, 88% to 97%) and 91% (86% to 95%), respectively, both of which exceeded the prespecified performance goals. The diagnostic accuracy of FFRangio was 92% overall and remained high when only considering FFR values between 0.75 to 0.85 (87%). FFRangio values correlated well with FFR measurements ( r=0.80, P<0.001) and the Bland-Altman 95% confidence limits were between -0.14 and 0.12. The device success rate for FFRangio was 99%.FFRangio measured from the coronary angiogram alone has a high sensitivity, specificity, and accuracy compared with pressure wire-derived FFR. FFRangio has the promise to substantially increase physiological coronary lesion assessment in the catheterization laboratory, thereby potentially leading to improved patient outcomes.URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03226262.
P04.68 Relation of the expression between TERT and GABPA/B isoforms in gliomas using quantitative real time-PCR
Authors: E Papazacharias, G Röhn, R Goldbrunner, M Timmer
Journal: Neuro-Oncology (2018)

Enhanced expression of TERT in gliomas is a result of two hotspot mutations, C228T and C250T, at the promoter region. The GABP of the ETS family selectively binds at these positions respectively causing an activation of the promoter and overexpression of TERT. GABP is a heterotetrameric protein consisting of GABPA and GABPB with its isoforms GABPB1, GABPB1-L, GABPB1-S, GABPB2. In this study, we investigated the association of the expression between TERT and GABPA/B isoforms in grade II, III gliomas and primary, secondary glioblastomas. For this study, glioma tumor samples have been taken from neurosurgery and stored in frozen liquid nitrogen at -80 ̊C. We performed quantitative real time-PCR for TERT and GABPA/B isoforms in controls, grade II, III gliomas and primary, secondary glioblastomas without chemotherapy with use of SYBR green and SDHA as the housekeeping gene. The statistic was analyzed with Kruskal-Wallis and Mann-Whitney-U-test. TERT is mainly expressed in primary glioblastomas. All GA-binding proteins are elevated in relation with the control. GABPB1/L/S levels are increasing with the malignancy of the gliomas. We detected higher expression of TERT in grade III gliomas compared to grade II (0.034 ± 0.039 vs. 0.001 ± 0.002; p=0.0095) which correlates with the increased level of GABPB1 (0.184 ± 0.058 vs. 0.116 ± 0.021; p=0.0004), GABPB1-L (0.319 ± 0.127 vs. 0.087 ± 0.034, p< 0.0001), GABPB1-S (0.389 ± 0.288 vs. 0.122 ± 0.039; p< 0.0001) and GABPBA (0.184 ± 0.058 vs. 0.116 ± 0.021; p=0.0004). In primary glioblastomas TERT is significally elevated compared to secondary glioblastomas (0.097 ± 0.090 vs. 0.003 ± 0.004; p< 0.0001) whereas GABPB1 and GABPB2 are mainly upregulated in secondary glioblastomas (GABPB1: 0.660 ± 0.196 vs. 0.373 ± 0.223; p=0.011 and GABPB2: 0.164 ± 0.119 vs. 0.090 ± 0.044; p=0.035). TERT expression in grade III gliomas relates with increased activity of GABPA, GABPB1, GABPB1-S, and GABPB1-L. The upregulation of TERT in primary glioblastomas is not associated with increased expression of GABPB1 and GABPB2. More detailed investigations must be made to further elucidate the association between TERT and GABPA/B isoforms in gliomas and to aim for a targeted therapy.
Subsequent primary malignancies (SPMs) after diffuse large B-cell lymphoma (DLBCL) in the modern treatment era.
Authors: Theresa H.M. Keegan, Christina A Clarke, Aaron Seth Rosenberg, Ranjana H. Advani, Brian Andrew Jonas, Christopher Flowers, Li Tao
Journal: Journal of Clinical Oncology (2016)

7543 Background: With advances in treatment, including the addition of rituximab, survival after DLBCL has improved such that managing SPMs has emerged as an important challenge. However, no population-based studies have assessed whether the risk of SPMs among DLBCL patients has changed after the standard use of rituximab in 2001. Methods: We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPMs among 23,879 patients who survived for at least 1 year after a first primary DLBCL diagnosed during 1989-2012, compared to the general population covered by the California Cancer Registry. The cumulative incidence (CMI) of SPMs, accounting for the competing risk of death, also was calculated. Results: While substantially elevated in both treatment eras, the risk of subsequent Hodgkin lymphoma decreased somewhat post-rituximab (Table). The risk of acute myeloid/monocytic leukemia (AML) nearly doubled after the introduction of rituximab. Subsequent thyroid cancer was rare pre-rituximab, but increased substantially after rituximab was introduced. Risks for lung and liver cancer were elevated, while risks for colorectal and breast cancer decreased, in the post-rituximab era. The CMI of all SPMs (P= 0.047), as well as AML (P= 0.003), thyroid cancer (P= 0.003) and melanoma (P= 0.020), were greater in DLBCL patients diagnosed in the post- versus pre-rituximab period. Conclusions: This study provides insight on the changing pattern of SPM occurrence after the introduction of rituximab as part of initial therapy, which may inform on the etiology of SPMs and should guide future cancer surveillance efforts among DLBCL patients. SPM Pre-Rituximab (1989-2000) SIR (95% CIs) Post-Rituximab (2001-2012) SIR (95% CIs) Hodgkin lymphoma 10.38 (5.36-18.13) 7.99 (4.57-12.98) Acute myeloid/monocytic leukemia 4.39 (2.51-7.13) 8.70 (6.62-11.22) All solid tumors 1.15 (1.05-1.26) 1.08 (1.01-1.16) Thyroid 0.66 (0.08-2.37) 2.27 (1.44-3.41) Melanoma 1.22 (0.72-1.93) 1.23 (0.91-1.62) Liver 1.42 (0.68-2.62) 1.66 (1.12-2.37) Lung 1.25 (1.00-1.54) 1.23 (1.03-1.46) Breast 1.25 (0.98-1.59) 0.84 (0.66-1.05) Colorectal 1.28 (0.97-1.65) 1.00 (0.77-1.27)
lncRNA GCAWKR Promotes Gastric Cancer Development by Scaffolding the Chromatin Modification Factors WDR5 and KAT2A
Authors: Mingzhe Ma, Yan Zhang, Mingzhe Weng, Ye Hu, Yi Xuan, YiRen Hu, Kun Lv
Journal: Molecular Therapy (2018)

Long noncoding RNAs (lncRNAs) have been demonstrated to play a role in carcinogenesis, but their mechanisms of function remain elusive. We explored the mechanisms of the oncogenic role of GCAWKR in gastric cancer (GC) using human tissues and cell lines. The in situ hybridization analysis was utilized to determine GCAWKR levels in samples from 42 GC patients and real-time qPCR in tissues from 123 patients. The GCAWKR levels were modulated in GC cell lines, and relevant biological and molecular analyses were performed. Levels of the GCAWKR were upregulated in GC tissues compared with normal tissues and associated with tumor size, lymph node metastasis, TNM stage, and patient outcomes. GCAWKR affected cell proliferation and cell invasion in multiple GC models. Mechanistically, GCAWKR bound WDR5 and KAT2A and acted as a molecular scaffold of WDR5/KAT2A complexes, modulating the affinity for WDR5/KAT2A complexes in the target gene's promoter region. Thus, our data defined a mechanism of lncRNA-mediated carcinogenesis in GC, suggesting new therapeutic targets in GC.
AGILE: A phase 3, multicenter, randomized, placebo-controlled study of ivosidenib in combination with azacitidine in adult patients with previously untreated acute myeloid leukemia with an IDH1 mutation.
Authors: Eytan Stein, Courtney Denton Dinardo, Jun Ho Jang, Yasushi Miyazaki, Roberto Ovilla Martinez, Julia Auer, Vickie Zhang, Daniel O. Koralek, Bin Wu
Journal: Journal of Clinical Oncology (2018)

TPS7074 Background: Acute myeloid leukemia (AML) is a hematologic malignancy with limited treatment options for patients who are ineligible for intensive chemotherapy, corresponding to a median overall survival ≤1 year (Dombret et al. 2016). Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6–10% of AML cases (Xu et al. 2017). Ivosidenib (IVO; AG-120) is a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme that has demonstrated robust clinical activity and a manageable safety profile as a single agent in patients with AML. A phase 1 study of IVO in combination with azacitidine (AZA) is ongoing (NCT02677922). As of September 11, 2017, 11 treatment-naïve patients with mIDH1 AML have been treated with IVO 500 mg QD + AZA 75 mg/m2 subcutaneously (SC) for 7 days in a 28-day schedule (DiNardo et al. ASH 2017). Patients have been treated for a median of 3 cycles (range 1–13) and adverse events are consistent with the AML monotherapy experiences of IVO and AZA. One case of IDH differentiation syndrome has been reported. The objective response rate (ORR) was 8 of 11 patients, including 4 patients who achieved a complete remission (CR). Methods: AGILE is a global, randomized, double-blind, placebo-controlled trial in patients with previously untreated mIDH1 AML who are candidates for nonintensive treatment (NCT03173248). 392 patients are being randomized 1:1 to receive either IVO 500 mg QD + AZA 75 mg/m2 SC or intravenously for 7 days in 28-day cycles, or matched placebo + AZA. Randomization is stratified by region and by de novo versus secondary AML. Key eligibility criteria include patients with previously untreated mIDH1 AML (according to WHO criteria) who are not candidates for or not willing to receive intensive chemotherapy, ECOG performance status 0–2, and no prior treatment with a hypomethylating agent or mIDH1 inhibitor. The primary outcome measure is overall survival, and key secondary outcome measures include event-free survival, CR rate, CR + CR with partial hematologic recovery (CRh) rate, and ORR. AGILE is currently open for enrollment globally. Clinical trial information: NCT03173248.