tbuckley/cabot-search huggingface dataset:
Programmed cell death-1 ligand (PD-L1) expression on circulating CD45(-) cells is an independent prognostic factor for overall survival in patients (Pts) with lung cancer in a prospective, multicenter cohort.
Authors: Daniel J Boffa, Jorge J. Nieva, Lyudmila Bazhenova, Rachel Krupa, David Lu, Ryon Graf, Jessica Louw, Lyndsey Dugan, Adam Jendrisak, Michelle Salazar, Samir Makani, Marisa Magana, Sarah Orr, Kelly Bethel, Yipeng Wang, Dena C. Marrinucci, Ryan Vance Dittamore
Journal: Journal of Clinical Oncology (2016)

8524 Background: Lung cancer pts currently require biopsies to diagnose and profile tumors prior to treatment. There is a need for tumor profiling from circulating biomarkers to avoid invasive procedures. PD-L1 expression on lung cancer biopsy specimens correlates with efficacy of immune checkpoint therapy. However, the expression of PD-L1 on circulating cells has not been fully characterized, limiting their ability to guide therapy. Using the Epic Sciences PD-L1 assay, we sought to correlate patient outcome with PD-L1(+) circulating CD45(-) cells, as a prerequisite to prospective evaluation as a predictive biomarker. Methods: Peripheral blood was collected from pts at three clinical sites prior to diagnostic biopsy (baseline), or at follow-up. 100 lung cancer pts with diverse histology were selected for interim analysis. All nucleated cells were plated onto glass slides and circulating cells of interest identified by immunofluorescence and morphological features. Prognostic capacity of PD-L1(+) cells (CK+/-, CD45-, PD-L1+, malignant nuclear morphology) were assessed with Kaplan-Meier and Cox Proportional Hazard (PH) models. Results: (See Table.) PD-L1 localization was primarily membranous in (+) cells. Pts with >1 PD-L1(+) cell/mL in baseline samples had worse overall survival (OS) (n=16/100, mOS: 16.1 months vs. not reached, HR = 3.46, p = 0.0022) and follow-up (n=4/16 mOS = 0.6 months vs. not reached, HR = 9.62, p < 0.0001). Adjusting for AJCC staging, high PD-L1(+) cell burden remained significant in multivariate models at both baseline (HR = 2.41, p = 0.0492) and follow-up (HR = 11.5, p = 0.0407). Single-cell sequencing is underway to further assess malignant origin of PD-L1(+) cells. Conclusions: In a prospectively enrolled, multicenter cohort, PD-L1(+) cell burden prognosticated OS in univariate and multivariate settings, independent to AJCC staging in pre-biopsy and follow-up samples. This lays the groundwork for PD-L1(+) CTCs to be prospectively assessed as a predictive biomarker to immune checkpoint inhibitors in lung cancer. AJCC Stage n = 100 Baseline n = 16 Follow-Up I 40 2 II 16 2 III 25 5 IV 19 7
A phase II randomized study: Outcomes after cytoreductive surgery (CRS) with or without carboplatin hyperthermic intraperitoneal chemotherapy (HIPEC) followed by adjuvant chemotherapy as initial treatment of advanced stage (stage III/IV) ovarian, fallopian tube, and primary peritoneal cancer.
Authors: Teresa Diaz-Montes, Michelle Sittig, Hyung Ryu, Vadim Gushchin, Armando Sardi
Journal: Journal of Clinical Oncology (2016)

e17080 Background: Ovarian cancer is the deadliest of gynecologic cancers. Cytoreductive surgery (CRS) is the cornerstone treatment for advanced stage ovarian cancer. Following CRS, hyperthermic intraperitoneal chemotherapy (HIPEC) has the potential to provide immediate regional therapy to low volume residual disease. We are conducting a phase II randomized study to evaluate CRS/HIPEC as a primary treatment for newly diagnosed, untreated advanced ovarian, primary peritoneal, and fallopian tube cancers. Methods: Untreated women with newly diagnosed, advanced stage ovarian cancer (n = 48) are prospectively randomized, by block design. Group 1 (n = 24) will undergo CRS/HIPEC (Carboplatin) with adjuvant IV chemotherapy, carboplatin/paclitaxel x6 cycles. Group 2 (n = 24), will undergo CRS alone, with standard of care adjuvant IV paclitaxel/IP cisplatin/IP paclitaxel x6 cycles. Gynecologic and surgical oncologists operate as co-surgeons for each study participant. Institutional Review Board approval has been obtained. Results: Feasibility of recruitment will be assessed. Grade III/IV surgical complication rates will be compared between the groups. Morbidity/mortality risk factors, completion rates of adjuvant chemotherapy, progression free survival, and quality of life will be determined. Quality of life will be assessed through the Functional Assessment of Cancer Therapy with Ovarian Cancer (FACT-O) questionnaire. Information gained from this study may be used to implement a larger, phase III trial. Conclusions: This protocol was designed to evaluate the use of upfront HIPEC (Carboplatin) with optimal CRS as initial therapy for ovarian, primary peritoneal, and fallopian tube cancers. We propose that CRS/HIPEC should be a standard first line treatment, ultimately improving quality of life and extending patient survival. Clinical trial information: NCT02124421.
New and Emerging Therapies for Pulmonary Arterial Hypertension
Authors: Edda Spiekerkoetter, Steven M. Kawut, Vinicio A. de Jesus Perez
Journal: Annual Review of Medicine (2018)

Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that causes right ventricular dysfunction and exercise limitation and progresses to death. New findings from translational studies have suggested alternative pathways for treatment. These avenues include sex hormones, genetic abnormalities and DNA damage, elastase inhibition, metabolic dysfunction, cellular therapies, and anti-inflammatory approaches. Both novel and repurposed compounds with rationale from preclinical experimental models and human cells are now in clinical trials in patients with PAH. Findings from these studies will elucidate the pathobiology of PAH and may result in clinically important improvements in outcome.
Mutational signature distribution varies with DNA replication timing and strand asymmetry
Authors: Marketa Tomkova, Jakub Tomek, Skirmantas Kriaucionis, Benjamin Schuster-Böckler
Journal: Genome biology (2018)

DNA replication plays an important role in mutagenesis, yet little is known about how it interacts with other mutagenic processes. Here, we use somatic mutation signatures-each representing a mutagenic process-derived from 3056 patients spanning 19 cancer types to quantify the strand asymmetry of mutational signatures around replication origins and between early and late replicating regions.
Effect of dopamine receptor D2 on NF-κB signal pathway abrogation in non-small cell lung cancer cells.
Authors: Wei Zhao, Chenxi Zhang, Xiaoyuan Wu
Journal: Journal of Clinical Oncology (2016)

e23194 Background: Increasing evidence proved that dopamine plays important role(s) in cancer tumorigenesis and progression. The use of dopamine antagonist confers significant risk of breast cancer. In mice model, dopamine increases the efficacy of anticancer drugs to breast, colon and lung cancer. Methods: Here, luciferase screening assay was employed to identify the potent signal pathway which affected by dopamine receptor D2 (DRD2) agonist, quinpirole in A549 and NCI-H1703. Luciferase assay, Western blot and qRT-PCR detected quinpirole effect on NCSLC cells NF-κB signal pathway. The NSCLC cells proliferation and growth abilities were measure by MTT and soft agar assays, respectively. Results: The activation of DRD2 inhibits NF-κB signal pathway. The inhibition of quinpriole on NF-κB signal pathway was through deceased p-p65 (ser276) level. Quinpriol treatment also caused NSCLC cells proliferation and growth arrest. Conclusions: We proved activation of DRD2 inhibits NF-κB signal pathway through deceased p-p65 (ser276) level in NSCLC cells, and agonist of DRD2 may be served as a new potential NSCLC therapy drug.
Cancer driver genes in luminal and triple negative breast cancer from young women.
Authors: Simone Maistro, Ana Carolina Ribeiro Chaves De Gouvea, Gláucia Fernanda de Lima Pereira, Maria Lucia Hirata Katayama, Lívia Munhoz Rodrigues, Pedro Adolpho de Menezes Pacheco Serio, Rosimeire Aparecida Roela, Maria A. A. Koike Folgueira
Journal: Journal of Clinical Oncology (2018)

e13527 Background: Our aim was to identify cancer driver genes in tumor samples from women ≤35 years with luminal (LUM) and triple negative (TN) breast cancer. Methods: Somatic variants derived from exome or genome sequencing, deposited in the COSMIC database or in published manuscripts, regarding 29 LUM HER2 negative and 23 TN tumors in women ≤ 35 years was searched for cancer driver genes catalogued in Cancer Gene Census (CGC) or Candidate Cancer Gene Database rank A or B (CCGD). The genes was searched for DNA repair genes. Function of genes affected by pathogenic mutations (frameshift FS and nonsense NS) was verified. Results: In LUM tumors, a median of 29 single nucleotide variants (SNV) per tumor, including a median of 6 potential drivers: 2 CGC, 2 CCGD A, 2 CCGA B, was detected. The most frequently affected cancer genes according to CGC were PIK3CA (31%), GATA3 (24%), TP53 (17%); 26 tumors presented SNV in at least one cancer drive CGC; 3 tumors solely in 1 or 2 genes from CCGD A, but neither CGC. SNVs affected genes involved in DNA repair in 48% samples and unique or combinations of pathways were involved. The highest number of SNVs was found in one tumor with alterations in genes from BER, NER and HRR; the other in genes from MMR and HRR. A median of 2 NS and 2 FS mutations was detected per tumor and 48% of the tumors presented at least one pathogenic mutation in a gene involved in positive regulation of gene expression. In TN tumors a median of 54 SNVs per sample was found, including a median of 13 potential drivers, 3 CGC, 4 CCGD A and 4 CCGD B. 21 tumors presented SNVs in at least one cancer driver (CGC); 2 tumors showed variants only in driver candidates from CCGD A (MBD2) or CCGD B (AP3D1). The most frequently altered cancer causing genes (CGC) were TP53 (69%); FAT3, AKAP9, CSMD3, IL6ST, MET, MUC4 (8.7%). Besides TP53, affected genes involved in DNA repair were detected in 3 tumors: RAD54L2, PARPBP and PCNA; RHNO1 and RFC4; and RECQL4. A median of 3 NS and 2 FS mutations was found per tumor, however these genes do not integrate a common biological process. Conclusions: In LUM BC from young patients a variety of DNA repair mechanisms as well as gene expression may be altered while in TN BC there is a trend towards a higher number of potential driver genes affected and TP53 is the main gene altered.
Prognostic and predictive factors for overall survival (OS) in metastatic esophagogastric cancer (EGC): A meta-analysis.
Authors: Emil ter Veer, Jessy Joy van Kleef, Sandor Schokker, Stephanie Van Der Woude, Marety Laarman, Nadia Haj Mohammad, Martijn G.H. van Oijen, Hanneke W.M. Van Laarhoven
Journal: Journal of Clinical Oncology (2017)

4048 Background: Prognostic and predictive factors for metastatic EGC are important to estimate prognosis, inform clinical decision-making and design future trials. We performed a systematic review with meta-analysis to identify these factors. Methods: We searched Medline, EMBASE and CENTRAL for phase 2/3 randomized controlled trials (RCTs) until January 2016 on palliative chemotherapy and targeted therapy for metastatic EGC. Prognostic and predictive factors were identified from respectively multivariate cox regressions and stratified treatment comparisons. Hazard Ratio’s (HR) for OS were extracted and pooled with meta-analysis if possible. Prognostic factors were considered independent if the multivariate HR was significant (P≤0.05). Predictive factors were clinically relevant if P for subgroup interaction was ≤0.20 and the HR in one of the subgroups was significant (P≤0.05). Results: We identified 47 RCTs (14,853 patients), wherein 54 potential prognostic and 40 predictive factors were reported. Eight independent prognostic factors for poor OS reported in ≥2 RCTs based on ≥300 patients were: performance status of ≥1 vs 0 (pooled HR, 95% confidence interval: 1.47, 1.25-1.73) or 2 vs 0-1 (1.52, 1.32-1.76); metastatic vs locally advanced disease (1.55, 1.39-1.72); diffuse vs intestinal/other histology (1.38, 1.12-1.71); ≥3 vs &lt; 2 metastatic sites (1.35, 1.07-1.70); presence of metastases in peritoneum (1.24, 1.01-1.51) or liver (1.45 (1.28-1.64); measurable vs non-measurable disease (1.31, 1.04-1.66); and no prior vs prior surgery (1.33, 1.16-1.53). Predictive factors for specific treatment comparisons based on ≥300 patients were: age (≥65 vs &lt; 65); performance status; tumor location (GEJ vs stomach); disease stage; number of metastatic sites; peritoneal metastasis; measurable disease; histology; HER2; KRAS; VEGF A; and Neuropilin-1 for first line treatments; and time to progression on first line therapy ( &lt; 3, 3-6 or ≥6 months) for second-line treatments. Conclusions: Eight independent prognostic factors for OS and thirteen clinically relevant predictive factors for treatment efficacy of EGC were found.
NCOG-09. THE LEVEL OF REPORTING OF NEUROCOGNITIVE OUTCOMES IN RANDOMIZED CONTROLLED TRIALS OF BRAIN TUMOR PATIENTS: A SYSTEMATIC REVIEW
Authors: Esther Habets, Martin Taphoorn, Martin Klein, Thomas Vissers, Linda Dirven
Journal: Neuro-Oncology (2018)

Neurocognitive impairment is frequently present in brain tumor patients and is therefore considered an important outcome in brain tumor research. To use neurocognitive outcomes (NCO) in clinical decision-making, neurocognitive evidence should be of sufficiently high quality. One important aspect in the generation of high quality evidence is the level of reporting. We aimed to investigate the level of neurocognitive functioning reporting in randomized controlled trials (RCTs) in brain tumor patients. We conducted a systematic literature search in several databases up to August 2017. Of the selected relevant RCTs, the following data were retrieved: basic trial demographics and NCO characteristics, quality of NCO reporting, and risk of bias. We also analyzed studies that should impact clinical decision-making based on their quality of reporting. We identified 65 RCTs, of which NCO was the primary endpoint in 14 (22%). The included brain tumour types varied, with 20 RCTs studying glioma patients (31%) and 17 studying brain metastatic patients (26%) only. Radiotherapy and chemotherapy were the most studied treatments (both in 31% of studies). In five studies (8%), rehabilitation of neurocognitive impairments was investigated. Important methodological limitations were related to the documentation of statistical approaches for dealing with missing data, and to discussing limitations and generalizability issues uniquely related to the NCO components. Risk of bias was high regarding blinding of personnel and incomplete outcome data. Twenty RCTs (31%), eight with NCO as primary endpoint and 12 as secondary endpoint, satisfied a sufficient number of criteria to be classified as high-quality NCO evidence. Most of these studies did contribute to clinical decision-making. Investigators involved in brain tumor research should give attention to methodological challenges related to NCO reporting as identified in this review, as high-quality reporting of NCO evidence can be of value in clinical decision-making.
Patterns of recurrence in patients with sinonasal undifferentiated carcinoma (SNUC) treated with multimodality therapy at a single center.
Authors: Cristina P. Rodriguez, Jay Justin Liao, Andrew W. Liu, Upendra Parvathaneni, George E Laramore, Ian Humphreys, Greg Davis, Renato G. Martins, Marc C. Chamberlain
Journal: Journal of Clinical Oncology (2017)

e17575 Background: SNUCs are rare and without established therapeutic standards. This is a retrospective review of therapeutic outcomes in pts with SNUCs treated at our center. Methods: Data was collected retrospectively on pts with a confirmed diagnosis of SNUC treated at the University of Washington Medical Center. Demographic data, tumor/treatment characteristics,and dates of recurrence/progression and death were recorded. The Kaplan Meier method was used to estimate survival outcomes; the log-rank and Wilcoxon tests were used to explore associations of clinical characteristics with outcome. Results: Between 5/1992 and 11/2016, 32 pts were treated, 1 was excluded due to incomplete data. The median age was 52 (range 22-82) years, 14(45%) were female, 26(83%) were white, 17(54%) reported current or former tobacco use. One presented with distant metastases, 1 had T2N0 disease, and all other pts had locally advanced disease. Six pts had nodal involvement on initial staging, and 25 patients had T4 disease. Eleven(35%) pts had no skull base/CNS invasion, 7(22%) had skull base extension up to the cribriform plate, 13(42%) had extension beyond the cribriform plate and into the CNS. Twenty-one(67%) pts underwent surgical resection, 29(93%) underwent radiation(XRT) with a median dose of 70 (range 54-72) Gy, and 28(90%) received cisplatin based chemotherapy, with 24 of these given concurrent with XRT, 19(60%) were treated with surgery followed by chemoradiation. With a median 61 months of follow up, 15 pts have recurred, 10 of these recurrences occurred in local sites, with 6 having intracranial progression, 2 of which were leptomeningeal. The median time to progression was 15 months and median overall survival was 58 months . Any vs no tobacco use (58 vs 35 mo p = 0.8), was not predictive of overall survival. The presence of nodal disease (87 vs 7 mo p = 0.005), and CNS invasion beyond the cribriform plate (NR vs 14 mo p = 0.04) was associated with inferior median overall survival. Conclusions: Local/CNS recurrence was the predominant failure pattern in our pts. CNS invasion beyond the cribriform plate and nodal disease were associated with significantly worse survival.
Immune effects by selective heating of membrane rafts of cancer-cells.
Authors: Magdolna Dank, Nora Meggyeshazi, Gyula Szigeti, Gabor Andocs
Journal: Journal of Clinical Oncology (2016)

e14571 Background: The immune stimuli by local selective excitation of membrane rafts of malignant cells may extend the local method to systemic effect (abscopal effect). Our objective is to study this process from local action to systemic result. Methods: Impedance controlled RF current (modulated electro-hyperthermia, mEHT) is applied with time-fractal pattern modulated 13.56 MHz carrier frequency [1]. mEHT selectively targets the membrane raft domains of malignant cells [2]. We applied different murine tumor models (xenografts and allografts) to investigate the effects. The tumor samples were evaluated by various histomorphological and immunohistochemical methods using a digital microscopy technology to qualitatively and quantitatively evaluate the samples. Results: mEHT induced massive apoptotic cell death in the treated tumors by caspase independent subroutine in HT29 colorectal adenocarcinoma xenografts [3]. This programmed cell death procedure has also shown a damage associated molecular pattern (DAMP) formation, which is a prerequisite of the immunogenic cell-death process (ICD) [4]. The abscopal effect was measured in C3H/He allograft mouse model in conjunction with intratumoral dendritic cell (DC) injection, [5]. In this model, not just the directly treated tumor but the distant untreated tumor lesions have also shown the signs of the effective damage. mEHT plus DC administration significantly inhibits the CT26 tumor growth in BALB/c mouse model, while even the re-challenging of the tumor inoculation became impossible [6]. Conclusions: mEHT induces DAMP associated ICD and creates a favorable tumor microenvironment for an immunological chain reaction that improves the success rate of intratumoral DC immunotherapy. The tumor specific immune reaction became abscopal effect and acted systemically despite the certainly local application of mEHT. Reference [1] Szasz A et.al. Oncothermia, Springer, 2010 [2] Szasz O et.al J Clin Oncol 33, 2015 (suppl; abstr e22176) [3] Meggyeshazi N. et.al. Strahlenther Onkol, 190:815-822; 2014 [4] Andocs G. et.al. Cell Stress and Chaperones, 20:37-46; 2015 [5] Qin W et.al. Oncol Rep 32:2373-2379; 2014 [6] Tsang Y-W et al. BMC Cancer 15:708; 2015
Concordance evaluation of an artificial intelligence technology with a multidisciplinary tumor board in gastric cancer.
Authors: Daolu Yuwen, Wenwen Zhang, Jiaying Wu, Juan Zhang, Yunzhu Shen, Junfeng Shi, Cuiju Tang, Irene Dankwa-Mullan, Kyu Rhee, Jinfei Chen
Journal: Journal of Clinical Oncology (2018)

e18569 Background: Gastric cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence clinical decision-support technology have the potential to help address this challenge. IBM Watson for Oncology (WFO) is a clinical decision support technology platform that uses natural language processing and machine learning to reveal insights from large amounts of structured and unstructured data. Methods: We conducted a cross-sectional concordance study comparing WFO suggested treatment recommendations with that of a multidisciplinary tumor board (MDT) for 314 gastric cancer cases diagnosed between 2008 - 2013 at Nanjing First Hospital, Nanjing Medical University, China. We assessed survival outcomes for patients whose regimen were the same as WFO suggested treatment categories: Recommended (REC), For Consideration (FC) and Not Recommended. (NR). Results: Overall concordance was 34%. [REC (28.3%), FC (5.7%) and NREC (44.7%)] 21.3% of the treatment provided by MDT was not available in any category since WFO was trained in U.S. Concordance for patients with stage I disease (8.33%) was lower than in other stage disease (II: 35.90%; III: 34.21%; IV: 43.02%). Concordance in the invasion depth groups were as follows: [T3 (32.09% p = 0.02); T2 (22.92% p = 0.01); and T1(19.23% p = 0.037)] and T4 (45.28%). Age, sex, tumor location, histologic differentiation and lymphatic metastasis status did not influence concordance. Median OS was 28.26 and 25.39 months in concordant and non-concordant groups, respectively (p = 0.0929). Patients in the concordant group had a longer median OS in stage I (52.67 VS 28.66 months; p = 0.0091) and III (29.78 VS 23.13 months; p = 0.0155). Patients in REC group had longer OS (median OS: 29.24 VS 25.07 months; p = 0.0201). Conclusions: Due to differences in clinical practices and limitations to FDA-approved drugs in WFO, there were varying degrees of low concordance for the gastric cancer cases examined compared to previous studies. Improved outcomes in REC/FC groups demonstrates that WFO holds promise for cancer care in MDT settings, for supporting evidence-based treatment decisions