tbuckley/cabot-search huggingface dataset:
OS2.4 Angiotensin II Receptor Blockers, steroids and radiotherapy in glioblastoma - A randomized multicenter trial (ASTER Trial). An ANOCEF Study
Authors: R URSU, L Thomas, D Psimaras, O Chinot, E Le Rhun, D Ricard, M Charissoux, S Cuzzubbo, F Sejalon, V Quillien, K Hoang-Xuan, F Ducray, J Portal, C Levy-Piedbois, E Vicaut, A Carpentier
Journal: Neuro-Oncology (2018)

Glioblastomas, the most common primary central nervous system tumors, induce a peritumoral vasogenic edema impairing functional status and quality of life. Steroids reduce brain tumor-related edema, but are associated with numerous side effects. It was reported in a retrospective series that angiotensin receptor blockers (ARBs) might be associated with reduced peritumoral edema. The ASTER study is a randomized, placebo-controlled trial to assess whether or not the addition of Losartan to standard of care can reduce steroid requirement during radiotherapy in patients with newly diagnosed glioblastoma. Patients with a histologically confirmed newly diagnosed glioblastoma after biopsy or partial surgical resection were randomized between Losartan or placebo in addition to standard of care (SOC) with radiotherapy (RT) and temozolomide (TMZ). The primary objective was to investigate the steroid dosage required to control brain edema on the last day of RT in each arm. The secondary outcomes were steroids dosage 1 month after the end of RT, assessment of cerebral edema on MRI, tolerance, and survival. Seventy five (75) patients were randomly assigned to receive Losartan (37 patients) or placebo (38 patients). No difference in the steroid dosage required to control brain edema on the last day of radiotherapy, or one month after completion of RT, was seen between both arms. A trend towards reduction of peritumoral edema over time was seen on MRI, but this reduction did not reach statistical significance. Median OS was similar in both arms. Losartan, although well tolerated, does not reduce the steroid requirement in newly diagnosed GBM patients treated with concomitant radiotherapy and temozolomide.
Association of circulating tumor DNA (ctDNA) tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC).
Authors: Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Wade Thomas Iams, Marcelo Rocha De Sousa Cruz, Nisha Anjali Mohindra, Victoria Meucci Villaflor, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

11537 Background: Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in NSCLC is critical. TMB is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to derive a measure of ctDNA TMB and to examine the association between TMB and clinical variables, DNA repair mutations, and response to checkpoint blockade. Methods: We retrospectively examined 136 patients with NSCLC who had undergone ctDNA next-generation sequencing (NGS) in our institution. The ctDNA testing, performed by Guardant360, is not currently clinically indicated for TMB. We derived ctDNA TMB using coding base substitutions and indel alterations both including and excluding potentially functional variants, but excluded rearrangements, fusions, and copy number variants. In addition, survival data were obtained for 17 patients who were treated with anti-PD-1/PD-L1 therapy and had ctDNA before first line therapy or within 90 days of therapy initiation. Results: ctDNA TMB was associated with the number of direct and indirect DNA repair gene mutations (t-test, p &lt; 0.05). Smoking was also associated with higher TMB when including functional variants (chi-square test, p = 0.034). Driver mutations (EGFR, KRAS) and prior radiation therapy were not correlated with TMB. Lower ctDNA TMB (below the median, 15 mutations/MBp) was associated with longer PFS and OS (Kaplan-Meier log-rank test, p &lt; 0.05). Conclusions: ctDNA TMB was derived and was significantly associated with greater number of DNA repair mutations. Smoking predicted higher TMB score. However, in a small subset of patients, lower ctDNA TMB predicted response to checkpoint blockade. Potential reasons include the small sample size, the possibility of ctDNA reflecting tumor burden, and the limited length of DNA sequenced (~78,000-138,000 bp). Larger, prospective studies are necessary to validate these findings.
TCT-611 Prognostic Impact of Underweight in Patients with Severe Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation or Surgical Aortic Valve Replacement – Prospective Data from the German Aortic Valve Registry (GARY)
Authors: Lisa Voigtländer, Raphael Twerenbold, Ulrich Schäfer, Lenard Conradi, Stephan Ensminger, Thomas Walther, Andreas Beckmann, Christian Frerker, Christian Hamm, Jochen Cremer, Helge Möllmann, Sabine Bleiziffer
Journal: Journal of the American College of Cardiology (2018)
T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency
Authors: Erik L. Clarke, A. Jesse Connell, Emmanuelle Six, Nadia A. Kadry, Arwa A. Abbas, Young Hwang, John K. Everett, Casey E. Hofstaedter, Rebecca Marsh, Myriam Armant, Judith Kelsen, Luigi D. Notarangelo, Ronald G. Collman, Salima Hacein-Bey-Abina, Donald B. Kohn, Marina Cavazzana, Alain Fischer, David A. Williams, Sung-Yun Pai, Frederic D. Bushman
Journal: Genome Medicine (2018)

Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. Here we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples. Comparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure. This multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544.
Advanced biliary tract cancer: Experience with ABC-02 regimen in a tertiary care center in the United States.
Authors: Rishi Agarwal, Nabeela Iffat Siddiqi, Shuchi Gulati, Arun Sendilnathan, Changchun Xie, Olugbenga Olanrele Olowokure
Journal: Journal of Clinical Oncology (2016)

e15624 Background: The ABC-02 trial defined gemcitabine plus cisplatin (GC) as the standard regimen for advanced biliary tract cancers (BTC). This single institution retrospective review evaluates the University of Cincinnati experience with GC in advanced intrahepatic (IHC)/extrahepatic cholangiocarcinoma (EHC) and gall bladder carcinoma (GBC). Methods: Retrospective analysis of advanced BTC pts seen between 01/2008 and 01/2015 was done. This study was approved by University of Cincinnati IRB. Kaplan Meyer method was used to calculate progression free survival(PFS), and overall survival(OS). Cox model was used to test the association between baseline variables and OS/PFS, adjusting for gender and age at diagnosis. Pts were identified using ICD code for BT tumors, 26 pts met inclusion criteria: histologically proven advanced BTC that received GC as their initial chemo. GC was given as per ABC 02 protocol with appropriate modifications until disease progression or unacceptable toxicities. Results: Median age at diagnosis was 62 y (R:31-81). 69%(18) IHC, 5 EHC, 3 GBC. 61% Male, 73% whites. PS 0 -1: 69%, PS 2: 31%. Baseline CA19-9 data was available on 21pts, (R:1- 69,543), of those with abnormal CA19-9 (14 Pts), follow up CA19-9 was available in 11 pts, of these 7 had a drop. It decreased > 50% & 75% from baseline in 71% & 57% respectively. PFS was 4.5 months (95 % CI: 3.1- 8.9) and OS was 10.5 months (95 % CI: 7.9-18.8). OS at 6 and 12 m was 69 %( 18/26) and 42% (11/26). 38% (10/26) received 2nd line chemotherapy, of these 9/10 received 5FU based chemotherapy. 11 % (3/26) received 3rd line chemotherapy. Increase in baseline carcinoembryonic antigen(CEA), alanine aminotransferase, alkaline phosphatase(ALP) and total bilirubin was associated with increase risk of death while increase in baseline CEA and ALP was associated with increased risk of progression (p- valve < 0.05). Conclusions: Our data supports the use of GC as a first line regimen for advance BTC in a non clinical trial setting. Results are comparable to those reported in ABC-02 trial, despite inclusion of ECOG PS 2 pts whom constituted 31% of our population. Baseline CEA and liver function tests could be used to predict response to GC in advanced BTC.
Cardioprotective effect and safety of dexrazoxane in all breast cancer stages in patients treated with anthracyclines with or without trastuzumab: A systematic review and meta-analysis.
Authors: Ariane Macedo, Angelica Nogueira Rodrigues, Rafael Brant Costa, Antonio Luiz Pinho Ribeiro
Journal: Journal of Clinical Oncology (2018)

10072 Background: Anthracyclines continue to rank among the most effective agents in Breast Cancer (BC) treatment, but its use is limited by a dose-dependent cardiotoxicity. Clinical studies have suggested that dexrazoxane (DZR) could reduce this toxicity, however it is unclear whether the effect is maintained during an adjuvant treatment followed by trastuzumab(TTZ). DZR is frequently used in the metastatic setting, when higher anthracycline cumulative doses are needed, but is often omitted in adjuvancy. We aimed to analyse whether DZR is cardioprotective in all BC stages in patients receiving anthracycline-based chemotherapy followed or not by trastuzumab. Methods: We performed a systematic review and meta-analysis.The review was registreded in PROSPERO database. We searched data from 1990 to august 2017 in Cochrane Central Register of Controlled Trials, google scholar, MEDLINE/pubmed, LILACS, web of science, articles references and ASCO proceedings. Studies assessing congestive heart failure or cardiac event (cardiac function alterations without cardiac symptoms or hospitalization for cardiac reasons) as primary endpoints were included. Secondary outcomes were potential adverse effects of DZR on response (complete or partial, overall and progression free survivals). Two reviewers independently performed the studies selection, risk of bias assessment and data extraction. Meta-analysis was done using random effect model for estimation of treatment effect. Heterogeneity was assessed by visual inspection of forest plots and by Q test. Results: Nine studies were identified, including 1545 patients. DZR reduced heart failure incidence (RR 0.182, CI95%: 0.080-0.413, p < 0.0001) and cardiac events (RR 0.262, CI95%:0.169-0.407, p < 0.0001), without impact on response rate or survival. In a subgroup analysis of studies using TTZ after anthracycline, the overall benefit and safety of DZR was maintained. Conclusions: DZR delayed and reduced anthracycline induced cardiac toxicity, with or without trastuzumab. These findings may have significant implications for clinical practice
Upper tract urothelial carcinoma with isolated lymph node involvement following surgical resection: Implications for multi-modal management.
Authors: Aryeh Pelcovits, Anthony E. Mega, Dragan Golijanin, Ali Amin, Boris Gershman
Journal: Journal of Clinical Oncology (2018)

e16594 Background: Upper tract urothelial carcinoma (UTUC) with isolated lymph node (LN) involvement (pN1 M0 UTUC) is a rare clinical entity with limited data on oncologic outcomes following surgical resection. We examined pN1 M0 UTUC in a large, nationwide oncology dataset to characterize its natural history, describe trends in utilization of perioperative chemotherapy, and identify clinicopathologic features associated with survival. Methods: We identified 794 patients aged 18-89 years who underwent radical nephroureterectomy (RNU) with lymph node dissection (LND) for pN1 M0 UTUC from 2006-2013 in the National Cancer Database (NCDB). Overall survival (OS) was estimated using the Kaplan-Meier method. The associations of clinicopathologic features with OS were evaluated using Cox regression models. Results: A total of 794 patients underwent RNU with LND. Median number of LNs removed was 3 (IQR 1, 8), and median number of positive LNs was 1 (IQR 1, 3). Median follow-up was 16.7 months, during which time 555 (70%) patients died. Neoadjuvant chemotherapy utilization increased from 6.7% in 2006 to 14.2% in 2013, while adjuvant chemotherapy (AC) utilization remained stable (42.7% in 2006 and 44.3% in 2013). One-, 5-, and 8-year OS was 64%, 24%, and 19%, respectively. On multivariable analysis: older age, uninsured insurance status, higher pT stage, larger tumor size, positive surgical margins, number of positive LNs, and non-receipt of AC were associated with worse overall survival. Conclusions: In this large, contemporary cohort, pN1 M0 UTUC was associated with a poor prognosis, with a 5-year OS of only 24%. AC was independently associated with improved survival, but it was only utilized in approximately 40% of pN1 M0 patients. These results highlight the need for more effective multi-modal management paradigms in such patients.
Preoperative and non-invasive prediction of chromosome arm 1p/19q codeletion in oligodendroglial tumors using MRI-based radiomics.
Authors: Jingwei Wei, Dongsheng Gu, Jie Tian
Journal: Journal of Clinical Oncology (2018)

2049 Background: Oligodendroglial tumor (OT) is a main subtype of gliomas, carrying poor prognosis. Fortunately, part of OT patients with chromosome 1p/19q codeletion show favorable response to chemo/radiotherapy and improved survival. Preoperative knowledge of 1p/19q codeletion could beyond doubt provide seasonable evidence for personalized treatment decision making. However, the 1p/19q co-deletion genotype is currently examined via invasive biopsy-based methods, which are highly risky causing neurologic deficit. Thus, it arouses an urgent need to develop a non-invasive approach for early prediction of 1p/19q codeletion. Hence, we used a new technique termed radiomics to perform the prediction on 1p/19q status using magnetic resonance imaging in this study. Methods: A cohort of 262 OT patients was collected from Beijing Tiantan Hospital and divided into training (n = 175) and validation (n = 87) datasets. We extracted 647 three-dimensional imaging features on T2-weithed images to describe the archetypal cancer phenotypes. Qualified features were selected by reproducibility and stability analysis. Random forest algorithm was finally adopted to perform the classification between 1p/19q codeletion and non-codeletion groups. Moreover, comparisons were explored between relevant clinical predictors and the proposed radiomics model. Results: The radiomics model demonstrated satisfactory performance on both the training and validation cohorts with areas under curve (AUCs) of 0.889 and 0.743, respectively. Among the top three most significant features, there were two first-order intensity features (Coif1_fos_kurtosis, ori_fos_skewness), and one textural feature (ori_glcm_cluster_shade). The radiomics model outperformed the clinical factor: heterogeneous intensity, the AUCs of which were 0.580 and 0.616. When combining the radiomics features and the clinical factor together, it turned out to be the best predictive result with AUCs of 0.891 and 0.739. Conclusions: Our study highlights that radiomics model can effectively identify the 1p/19q codeletion in OTs by a non-invasive manner, thereby offering preoperative evidence for the treatment regime planning.
Comparison of tumor mutational burden (TMB) across tumor tissue and circulating tumor DNA (ctDNA).
Authors: Andrew A. Davis, Young Kwang Chae, Sarita Agte, Alan Pan, Nicholas I Simon, Timothy J. Taxter, Amir Behdad, Benedito A. Carneiro, Massimo Cristofanilli, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

e23028 Background: TMB is a potential biomarker for response to checkpoint blockade. Prior studies have associated tissue TMB with genomic instability and neoantigen binding sites for activated effector T cells. The goal of our study was to compare TMB in patients with paired next-generation sequencing (NGS) tests from tissue and ctDNA. Methods: Ninety-seven patients with NSCLC (N=53), breast cancer (N=34), and other solid tumors (N=10) with paired tissue (FoundationOne) and ctDNA (Guardant360, currently not clinically indicated for TMB) were examined retrospectively. Insufficient samples were eliminated (e.g., poor tissue quality or no mutations detected). TMB was compared using variants of unknown significance and synonymous mutations both with (N=74) and without potentially functional/driver variants (N=55). Results: Paired samples were compared using both continuous and binary TMB classifications (Table 1). TMB scores were significantly different using both comparisons (paired t-test, p&lt;0.05). In addition, correlation coefficients between the two assays were low (Pearson Correlation, r=0.24-0.33). No significant differences were found based on timeframe between biopsies. Conclusions: This study demonstrated a lack of concordance between TMB for tissue and ctDNA in paired samples. Potential reasons include differences in sequencing length (~0.79-1.1 million bp for tissue vs. 78,000-138,000 bp for ctDNA), mutation detection, and methods of determining TMB. Future studies are warranted to determine whether ctDNA TMB can predict response to immunotherapy. [Table: see text]
TCT-673 Two years clinical outcomes with the state-of-the-art PCI for the treatment of bifurcation lesions: A Sub-analysis of the SYNTAX II study
Authors: Rodrigo Modolo, Carlos Collet, Ply Chichareon, Taku Asano, Chun Chin Chang, Yuki Katagiri, Norihiro Kogame, Kuniaki Takahashi, Erhan Tenekecioglu, Simon Walsh, Maciej Lesiak, Raul Moreno, Javier Escaned, Adrian Banning, Yoshinobu Onuma, Patrick Serruys
Journal: Journal of the American College of Cardiology (2018)
Uncommon low-grade brain tumors
Authors: Thankamma Ajithkumar, Naduni Imbulgoda, Elliott Rees, Fiona Harris, Gail Horan, Amos Burke, Sarah Jefferies, Stephen Price, Justin Cross, Kieren Allinson
Journal: Neuro-Oncology (2018)

The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I-II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.
Off-label use of everolimus and associated factors in non-elderly cancer patients with private insurance in the United States.
Authors: Yan Xing, Ying Guo, Jenny Chee Ning Chang, Tejal Amar Patel, Ed Kheder, Funda Meric-Bernstam, Ya-Chen T. Shih
Journal: Journal of Clinical Oncology (2018)

e18718 Background: The prices of targeted oral cancer medications have increased sharply over the last decade. We aim to assess off-label use of everolimus and associated factors among non-elderly cancer patients with private insurance in the United States. Methods: Using MarketScan data from 2009 to 2016, we defined off-label use of everolimus as utilization of this drug by all advanced cancer patients except for those with renal cancer in 3/2009-12/2016, pancreatic neuroendocrine tumors (NET) after 3/2011, breast cancer after 7/2012 and NET after 3/2016. Among 4,278,100 cancer patients identified from MarketScan, 4,837 (1‰) patients had at least one everolimus prescription were included in the analyses. Multivariate logistic regression model was used to identify the factors associated with off-label use of everolimus. Results: Among patients that were prescribed everolimus, off-label use of everolimus increased from 18% in 2009 to 47% in 2011 then decreased to 25% in 2016. Among 1,321 patients received everolimus as off-label use, the top five most common cancer diagnoses were NET (27%), breast cancer (19%), pancreases (12%), other malignancies (11%) and lung cancer (5%). For breast cancer, the average number of patients received off-label use of everolimus per month has > 7 fold increase from 4 to 30 since 1/2012 until FDA approval on 7/20/2012. Compared to on-label use, off-label everolimus use was positively associated with younger age ( < 30 years vs. ≥50 old) (OR: 13.63; 95%CI: 6.03–30.8); geographic region (Northeast vs. West) (OR: 1.29; 95%CI: 1.02–1.64) and genomic profiling (OR: 1.86; 95% CI: 1.44–2.4). Conclusions: Analyses of MarketScan data suggested off-label use of everolimus in breast cancer is more common through peer-review process based on publications of data ahead of FDA approval among US cancer patients. Off-label use of everolimus was also more likely in younger, northeast, and patients who had genomic profiling study. Further research should focus on the long-term effects and economic implication associated with off-label use of everolimus.
Bone marrow–specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis
Authors: Anna Chorzalska, John Morgan, Nagib Ahsan, Diana O. Treaba, Adam J. Olszewski, Max Petersen, Nathan Kingston, Yan Cheng, Kara Lombardo, Christoph Schorl, Xiaoqing Yu, Roberta Zini, Annalisa Pacilli, Alexander Tepper, Jillian Coburn, Anita Hryniewicz-Jankowska, Ting C. Zhao, Elena Oancea, John L. Reagan, Olin Liang, Leszek Kotula, Peter J. Quesenberry, Philip A. Gruppuso, Rossella Manfredini, Alessandro Maria Vannucchi, Patrycja M. Dubielecka
Journal: Blood (2018)