tbuckley/cabot-search huggingface dataset:
Second-line chemotherapy efficacy in patients with previously treated advanced thymic carcinoma: A retrospective analysis of 192 patients from NEJ023 Study.
Authors: Shunichiro Iwasawa, Ryo Ko, Takehito Shukuya, Satoshi Watanabe, Yoko Tsukita, Hironori Ashinuma, Taku Nakagawa, Ryo Ito, Kazutsugu Uematsu, Mika Nakao, Yoshiaki Mori, Kyoichi Kaira, Atsuto Mouri, Takao Miyabayashi, Hiroyuki Sakashita, Yoko Matsumoto, Tomoyuki Tanigawa, Satoshi Morita, Kazuhisa Takahashi
Journal: Journal of Clinical Oncology (2016)

8569 Background: Thymic carcinoma is a rare neoplasm. Minimal information exists regarding second-line chemotherapy efficacy in patients with previously treated advanced thymic carcinoma. Methods: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma, excluding thymoma type A/B. The patients with no indication for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group (NEJSG). Data were obtained from medical records and included demographic, clinicopathologic, treatment, and outcome information. The Kaplan–Meier method was used to calculate overall survival (OS) and progression-free survival (PFS). Results: Among 324 patients recruited for this study, 192 patients were received second-line chemotherapy. Patient characteristics were: median age 61 years (range 14–84); male/female 72%/28%; PS 0–1/2–3/unknown 77%/15%/8%; Masaoka stage IVa/IVb/postoperative recurrence/other 28%/49%/19%/4%; UICC TNM stage IV/postoperative recurrence/other 78%/19%/3%. Among 192 patients, 70% had squamous cell histology and 10% had poorly-differentiated neuroendocrine carcinoma. Regimens for second-line chemotherapies were platinum doublets in 58% of patients, monotherapy in 29%, and other multi-agent chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide: ADOC) in 13%. The median follow-up time was 18.6 months (m), and median OS from the start of chemotherapy was 22.4 m (95% confidence interval, 17.5–26.7). There were no significant differences in the response rate (RR) and OS between monotherapy and multi-agent chemotherapy (platinum doublets and other multi-agent chemotherapy) (RR: 18.2% vs. 17.5%, p = 0.871, median OS: 21.4 m vs. 22.5 m, hazard ratio = 1.164, p = 0.440). Notably, S-1-administered 18 patients, RR and median PFS and OS were 38.9% and 8.3 m and 21.4 m, respectively. Conclusions: These results suggested that adequate efficacy can be achieved by monotherapy for previously treated patients with advanced thymic carcinoma. S-1 might be a promising agent for these patients. Clinical trial information: UMIN000015649.
Safety and activity of programmed cell death-1 gene knockout engineered t cells in patients with previously treated advanced esophageal squamous cell carcinoma: An open-label, single-arm phase I study.
Authors: Zhao Jing, Ni Zhang, Lingyu Ding, Xiaoju Wang, Yuhui Hua, Mingfeng Jiang, Shi Xiu Wu
Journal: Journal of Clinical Oncology (2018)

3054 Background: We designed the clinical trial to investigate the safety and activity of Programmed death-1 (PD-1) knockout engineered T cell in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients (aged ≥18 years) with advanced ESCC whose disease had progressed after at least two systemic therapies were enrolled. Peripheral blood will be collected and PD-1 gene will be knocked out by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 in the laboratory. T lymphocytes will be selected, expanded and reinfused back into patients after about 2-3 weeks. Response was assessed 4 weeks after each infusion. Patients continued receiving treatment until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was to evaluate the safety of PD-1 knockout engineered T cells treatment. Results: Between Mar, 2017, and Jan, 2018, we enrolled 21 patients who received at least one cycle PD-1 knockout engineered T cells treatment. Among 21 treated patients, 7 accepted only 1 cycle of cell infusion, 12 accepted 2 cycles, and 2 accepted 3 cycles. Up to the study cutoff date of Jan 31, 2018, the most common adverse events were transient fever (7 patients, the highest was 39.1℃) and chills (3 patients) and moderate skin rash (1 patient). No grade 3 or 4 adverse events were observed in the study. Of the 17 evaluable patients, no complete or partial responses were observed. 6 patients had stable disease, and 11 patients had progressive disease. Disease control rate was 35% (6/17) and median overall survival was 127 days (95% CI 45–209). During the trial, 10 cancer progression related deaths occurred. Immunofluorescence analysis showed that the PD-1 knockout engineered T cells could infiltrate into and persist for a durable time in ESCC that responded to therapy. Conclusions: The results showed that PD-1 knockout engineered T cells infusion might be an effective treatment in patients with heavily pretreated advanced ESCC. The treatment was well tolerated with no unexpected safety concerns. The regimen warrant further clinical investigation. Clinical trial information: NCT03081715.
Immunotherapy with anti-GD2 antibody ch14.18/CHO±IL2 within the HR-NBL1/SIOPEN trial to improve outcome of high-risk neuroblastoma patients compared to historical controls.
Authors: Ruth Lydia Ladenstein, Ulrike Poetschger, Dominique Valteau Couanet, Juliet Gray, Roberto Luksch, Victoria Castel, Shifra Ash, Genevieve Laureys, Cormac Owens, Toby Trahair, Godfrey Chi Fung Chan, Ellen Ruud, Henrik Schroeder, Maja Beck Popovic, Hans Loibner, Guenter Schreier, Peter F Ambros, Sabine Sarnacki, Tom Boterberg, Holger N. Lode
Journal: Journal of Clinical Oncology (2018)

10539 Background: Randomization of immunotherapy versus standard was not possible in the HR-NBL1/SIOPEN trial. In order to explore an impact of immunotherapy on outcome, we used trial patients prior to availability of ch14.18/CHO as control. Methods: Trial patients received rapid COJEC, two courses of TVD if needed, surgery, HDT/SCT (BuMel or CEM) and radiotherapy. MRD treatment (MRDT) consisted of isoretinoin alone from 2002 - 2009 (control population, CP) and from 2009 - 2013 with ch14.18/CHO (5 cycles ch14.18/CHO, ± IL2) (immunotherapy population, IP). Patients (844) were ≤9 months between diagnosis and HDT/SCT, PR or better prior to HDT/SCT and had no progression after HDT/SCT until start MRDT (median time 109 days) (CP 466, IP 378). Sex, age groups, stage 4 MycN amplified (MNA) and response prior HDT/SCT were balanced between cohorts. Imbalanced (IP vs CP) were metastatic compartments (MC > 1) [80% vs 71%; p = 0.0034)], TVD given [12% vs. 32%; p < 0.001], MNA localised disease [8% vs. 13% p = 0.0019], type of HDT = CEM [8% vs. 45%; p < 0.001)], time point of surgery < day120 after diagnosis [60% vs. 73%; p < 0.0001] and radiotherapy given [94% vs. 88%; = 0.0034]. Median follow up was 5.8y (0.05-13.8y). Results: The 5y-EFS was 57%±3% for the IP and 42%±2% for the CP (p < 0.001). Univariate analysis of risk factors identified no 5y-EFS difference for sex, stage 4 ± MNA and was borderline for radiation given (5y-EFS if yes: 50%±2%, no: 38%±6%, p = 0.073). Risk factors with 5y-EFS differences were age, stage, MC > 1, delayed surgery, response pre HDT/SCT and type of HDT. However, MVA analysis identified patients at a higher risk without immunotherapy (p = 0.0002, HR 1.573), with CEM (p = 0.0029; HR 1.431), response < CR prior MRD (p = 0.0043, HR 1.494) and > 1MC at diagnosis ( < 0.001 HR 2.665). After adjustment for age, stage, MC, TVD and pre-MRD response, a benefit for immunotherapy was confirmed in BuMel- (p = 0.0066; HR 1,439) with 5yEFS of , 56±3% vs 48±3% (IP vs CP) and in CEM-treated patients (p = 0.0107; HR 2.334) with 5yEFS of 67±9% vs 35±3% (IP vs. CP). Conclusions: Introduction of ch14.18/CHO immunotherapy achieved a major improvement in outcomes for patients on the HR-NBL1 trial. Clinical trial information: NCT01704716.
Real-world data in clinically non-small cell lung cancer (NSCLC) with Chinese population harboring <i>BRAF</i> gene fusions: A multicenter study.
Authors: Jin-huo Lai, Wen xian Wang, Chunwei Xu, Yu Chen, You-cai Zhu, Yueping Liu, Hong Wang, Wu Zhuang, Xiaohui Chen, Yun-jian Huang, Meiyu Fang, Zhenghua Zhang, Ye Tao, Shuguang Xu, Xue Qian, Hongyu Zhao, Jing Ma, Gang Chen, Tangfeng Lv, Yong Song
Journal: Journal of Clinical Oncology (2018)

e13537 Background: BRAF fusions are emerging treatment targets for melanomas and other solid tumors. The frequency of BRAF fusions and targeting potential in NSCLC, which occurs rarely in Caucasian populations, has not been widely described in Chinese populations. The aim of this study was to evaluate the prevalence of BRAF fusions in Chinese NSCLC patients, and to study the association between these molecular alterations and clinicopathological characteristics in these patients. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2017. To determine the frequency of the BRAF fusions in lung cancer and other tumors, We analyzed data from 2410 clinical NSCLC cases (non-squamous/squamous =2061/349), each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort, just One (0.04%) patient was identified with a TRIM24-BRAF fusion. The patient was a 64-year-old never smoking female, who was diagnosed with lung adenocarcinoma from biopsies obtained. TMB in this case was low (median 4.2 mut/Mb), TRIM24-BRAF fusions driven NSCLC responding to vemurafenib will be presented. The patient was considered to have a partial response (PR) to vemurafenib, and the disease is stable up to now. Conclusions: The frequency of BRAF fusions in Chinese populations with NSCLC is extremely rare (0.04%) than Caucasian populations. In the future, we think it is possible that discover rare gene mutations during the routine use of multi-gene sequencing assays and explore differences in the acquired mechanism of BRAFi between sensitive BRAF V600E mutations and other uncommon mutations in NSCLC patients.
Circulating tumor cells (CTCs) in SWOG S1216: A phase 3 multicenter trial in metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Amir Goldkorn, Melissa Plets, Neeraj Agarwal, Maha Hussain, Primo Lara, Daniel A. Vaena, Gary R. MacVicar, Tony Crispino, Andrea Lynne Harzstark, Przemyslaw Twardowski, Catherine M. Tangen, Cory Michael Hugen, Tong Xu, Yucheng Xu, Jacek K. Pinski, Sue A. Ingles, Celestia S. Higano, Nicholas J. Vogelzang, Ian Murchie Thompson, David I. Quinn
Journal: Journal of Clinical Oncology (2016)

11516 Background: Novel hormonal therapies recently approved for metastatic castration resistant prostate cancer (mCRPC) are now being tested in hormone sensitive disease (mHSPC), prompting evaluation of new biomarkers to guide therapy in this earlier disease state. We are conducting CTC enumeration, sequencing, and gene expression studies in S1216, a SWOG-sponsored North American Intergroup phase 3 trial of androgen deprivation in combination with bicalutamide or orteronel, a CYP17,20 lyase inhibitor. Baseline CTC enumeration data are presented for 225 patients evaluated to date. Methods: Four 7.5mL tubes of blood are collected for CTC analysis (enumeration, sequencing, gene expression) at study entry and at progression to mCRPC. Specimens are logged in the SWOG online specimen tracking system and sent overnight at room temperature to a central site (Goldkorn Lab) for analysis. One of the 4 tubes is a CellSave tube used for CTC enumeration on the FDA-cleared CellSearch platform (Janssen/J&J). CellSearch CTC counts are transmitted to SWOG Statistical Center for analysis and correlation with clinical data. Results: From 11/2014 - 10/2015, CTCs were detected in 78 of 211 evaluable samples (37%), and detection was impacted by whether patients had already initiated therapy at the time of sample collection (29% detection in treated vs. 46% in treatment naïve, p=0.01). Median CTC count for patients with detectable CTCs was 2/7.5 ml blood (1st quartile =1, 3rdquartile =9), and median for the entire cohort was 0 (range 0-4000). Presence of baseline CTCs was associated with higher PSA (p=0.03), bony metastases (p=0.05), presence of extensive disease (p<0.001), and a trend toward worse performance status (p=0.06). Conclusions: In this phase 3 trial, the largest prospective CTC cohort in mHSPC to date, baseline CTCs were detected in >1/3 of patients and nearly half of patients who had not yet initiated therapy. Presence of CTCs wasassociated with known baseline prognostic factors and therefore may predict clinical outcome with continued follow-up. Further CTC enumeration, sequencing and gene expression are ongoing in S1216 to maximize the prognostic and predictive benefit of CTC analysis in mHSPC. Clinical trial information: NCT01809691.
TCT-793 10-year outcomes in patients with and without diabetes treated with first-generation zotarolimus-eluting and sirolimus-eluting stents: the SORT OUT III study
Authors: Kevin Kris Warnakula Olesen, Manan Pareek, Lisette Okkels Jensen, Evald Christiansen, Jens Aaroe, Steen Dalby Kristensen, Jens Lassen, Leif Thuesen, Morten Madsen, Hans Erik Bøtker, Michael Maeng
Journal: Journal of the American College of Cardiology (2018)
Inhibition of pancreatic cancer by targeting the epigenetic EZH2 complex.
Authors: Gwen Alyce Lomberk, Angela Mathison, Mckenna Missfeldt, Ann Salmonson, Sarah Kossak, Navtej Buttar, Raul Urrutia
Journal: Journal of Clinical Oncology (2016)

e15736 Background: Epigenetic regulators transmit, extend, and modify signals of oncogenes and tumor suppressors, thereby acting as effectors of the pancreatic cancer (PDAC) phenotype. The reversible inhibition of their activity forms the current foundation of emerging pharmatherapies, which are increasingly being tested in clinical trials. EZH2 is one of the best-characterized epigenetic regulators found to be overexpressed in PDAC, for which inhibitors have been recently become available. Consequently, the current study evaluates the role of EZH2 as a pharmacological target to control PDAC growth. Methods: We developed a pancreas-specific knockout of EZH2, which was evaluated by histology, immunohistochemistry and RNA-seq. The growth-promoting function of EZH2 was assessed by adenoviral-mediated gene transfer in cell culture and subcutaneous xenografts. Immunoprecitpitation combined with mass spectrometry was used to analyze changes in the composition of EZH2 complexes in response to growth factors. MTS and clonogenic assays were utilized to monitor the effects of EZH2 inhibitors. Results: Clinically, EZH2 knockout animals appeared normal, born at accurate Mendelian ratios with characteristics of good health. However, at 3 months of age they presented signs of pancreatic atrophy with an organ-to-body weight ratio approximately 50% of controls. Congruently, histological examination revealed hypoplasia with focal areas of fat infiltrate and acinar-to-ductular metaplasia. RNA-Seq confirmed deregulation of gene expression networks that serve as a signature of EZH2 deletion. Conversely, EZH2 overexpression stimulates PDAC xenografts via its ability to function as an epigenetic regulator. In response to EGF stimulation, EZH2 forms a complex with DNA replication factors, such as MCM2-MCM4, which are known to regulate cell proliferation. Finally, we find that two drugs against EZH2 inhibit PDAC cell growth. Conclusions: Combined, our data demonstrate that EZH2 regulates pancreatic cell growth in vivo in a manner that is amenable to pharmacological inhibition, raising optimism for its potential use in the development of future therapies against this malignancy.
P04.14 Multiomics analysis on primary and recurrent paired tumors reveals a possible immune evasion mechanism through reduced neoantigen expression in some glioma
Authors: T Nejo, H Matsushita, T Karasaki, M Nomura, S Takayanagi, S Tanaka, A Mukasa, K Kakimi, N Saito
Journal: Neuro-Oncology (2018)

Limited success of immune-based therapies in glioma might be in part due to the lack of enough neoantigens (neoAgs) that can be targeted by immune effector cells. In addition, gliomas also show dynamic clonal evolution over time, possibly leading to immunoediting during progression. Here we conducted multiomics analysis on glioma primary and recurrent pair samples to evaluate temporal changes of glioma-immune system interactions and clarify the immune evasion mechanism characteristic of gliomas. In total, 25 WHO grade II-IV glioma cases with primary and recurrent pair samples were enrolled [8 IDH-wildtype glioblastoma (GBM), 9 IDH-mutant astrocytoma (LGG-A), and 8 oligodendroglioma (LGG-O)]. All cases received only standard therapies, but not immunotheapies. Somatic missense mutations were identified by whole-exome sequencing. Predicted neoAgs (p-neoAgs) derived from missense mutations were identified based on the MHC class I binding prediction algorism NetMHCpan2.8. In addition, “expressed” neoAgs at mRNA levels (e-neoAgs) were specified according to RNA-seq data; the neoAg expression ratio of each sample was calculated by dividing e-neoAg count by p-neoAg. Differential gene expression analyses were performed using Gene Ontology (GO) analysis or pair-designed gene set enrichment analysis (GSEA) for the tumor-infiltrating leukocytes (TILs) and antigen presentation machinery (APM). Finally, immunohistochemistry (IHC) for CD8 and MHC class I on tumor samples was assessed for validation. Mutational load, p- and e-neoAg count did not significantly differ between primary and recurrent tumors. However, the neoAg expression ratio significantly decreased in recurrent tumors (p = 0.003) and was particularly strong in neoAgs with a higher affinity for MHC class I. Similar trends were demonstrated for GBM, LGG-A, and LGG-O, when analyzed separately. GO analysis revealed that a number of GO terms related to active immune response such as including “CXCR chemokine receptor binding” and “leukocyte migration” were significantly upregulated at recurrence in the cases with strongly reduced neoAg expression ratio (top 8 cases). In the same cases, GSEA for TILs demonstrated a few subpopulations including activated CD8+ T cells significantly increased at recurrence. On the other hand, several TIL subpopulations as well as many APM-related gene sets significantly depleted in those with less significantly reduced neoAg expression ratio (bottom 8). These findings were consistent with those of IHC for CD8 and MHC class I. These data may suggest that the tumor cells with reduced neoAg expression survived at recurrence as a result of persistent anti-tumor immune responses in some cases under the standard treatment. Reduced neoAg expression and impaired APM during progression may play complementary roles in the immune evasion of gliomas.
Concept to clinic: An open-innovation crowdsourcing challenge to develop AI-enabled software for lung cancer detection.
Authors: Guneet Walia, Greg Lipstein, Peter Bull, Casey Fitzpatrick, Isaac Slavitt
Journal: Journal of Clinical Oncology (2018)

e20552 Background: CT scans have been shown to detect lung cancer, but suffer from high false positive rates. Approaches in artificial intelligence allow radiologists to interpret scans more precisely and reduce the rate of unnecessary follow-up, however their potential remains trapped in inaccessible research code—far from direct applicability in the clinic.Methods: DrivenData and Addario Lung Cancer Foundation partnered to run a crowdsourcing challenge, aimed at catalyzing the software development process to make AI advances more useful for lung cancer detection in the clinic; using $100,000 in monetary prizes to incentivize open source software contributions across four areas (predictive model integration, backend engineering, frontend design, and community participation); addressing barriers like narrow predictive task specification & no user interface exposing predictions to practitioners; engaging radiologists & patients throughout development.Results: During August 2017- January 2018, 618 contributors from 68 countries entered the Concept to Clinic challenge, submitting > 150 software patches addressing > 130 issues. The prototype was adapted from the deep learning model that won the 2017 Data Science Bowl & can detect nodules with > 85% recall & reduced false positive rates compared to previous studies. The resulting application displays predicted locations of concerning nodules on CT scans, presents a risk score on the probability of the nodule being cancerous, & allows radiologists to interact with suggested nodules, input their own data about assessed risk & other characteristics, and automatically generate a report in the format recommended by RSNA.Conclusions: We’ve built an open-source AI application that can be used in the clinic to complement a radiologist’s workflow around 3 aspects of lung cancer detection through CT scans: Identification- detect & localize concerning nodules, Classification- predict whether the identified nodules are cancerous or benign, and Segmentation-identify nodule boundaries for radiologists to build computer-aided diagnosis. Open source software can catalyze development of user-oriented AI tools in cancer imaging.
TCT-561 Splenic Artery Denervation: Rationale, Feasibility, and Early Pre-Clinical Experience in a Porcine Model of Inflammatory Arthritis
Authors: Mazen Albaghdadi, Fernando Gacia-Polite, Brett Zani, John Keating, Raffaele Melidone, Anna Spognardi, Peter Markham, Abraham Tzafriri
Journal: Journal of the American College of Cardiology (2018)