tbuckley/cabot-search huggingface dataset:
Copy number variation of genetic loci: A predictive marker of metastasis in stomach cancer patients.
Authors: Andrey A. Maslov, Oleg Ivanovich Kit, Denis S. Kutilin, Martin Zamirovich Tatimov, Irina Tishchenko, Dmitry I. Vodolazhsky
Journal: Journal of Clinical Oncology (2016)

e23152 Background: Copy number variations of genes are critical genetic events that promote development of malignant tumors. The purpose of this work was to study relative copy number of the genetic loci responsible for apoptosis, cell proliferation and oxidative phosphorylation in tumor and healthy stomach tissues of patients with lymph node metastases and without them to search for molecular markers of metastasis. Methods: Tissues of 30 patients with histologically confirmed diagnosis of gastric cancer were studied: with lymph node metastases (9 patients, group A) and without metastases (21 patients, group B). Determination of relative copy number of genes (BAX, GSTP1, CASP3, CASP8, HIF1A, OCT4, C-MYC, SOX2, BCL2, CFLAR, NANOG, P53, CASP9, IL10, NFKB1, HV2) was performed by RT-qPCR (locus B2M– reference). Primers were designed using GenBank NCBI database. RT-qPCR was done using Thermal Cycler Bio-Rad CFX96 (Bio-Rad, USA). Results: A statistically significant (p < 0.05) reduction in the relative copy number of the OCT4 and HV2 genes by 50% and 30%, respectively, was found in the tumor tissue compared to conditionally healthy one in group B. Group A showed a decrease in the CASP3 gene copy number by 38% (p < 0.05) in tumor tissue compared to the healthy one. Comparison of gene copy number in tumor tissue in group A compared to that in group B demonstrated a decrease in copy number of the CFLAR gene by 50% (p < 0.05) and an increase in copy number of the HV2by 90% (p < 0.05). In group B ratio of copy number of genes p53 / MDM2 in normal and tumor tissue was 1.169 and 1.414 respectively, indicating the higher copy number of the p53 gene as compared to the gene copy number of its negative regulator MDM2; and in group A gene copy number ratio of p53 / MDM2 in the normal and tumor gastric tissue was 0.021 and 0.027 respectively, and these values were achieved due to increased copy number of the MDM2 gene, indicating a pronounced negative regulation of p53gene. Conclusions: The research allowed to identify genetic loci of OCT4, CASP3, CFLAR, HV2, p53 and MDM2, their relative copy number can be used directly or as a ratio of the relative copy number (p53/MDM2) as predictive markers in prognosis of metastasis development in stomach cancer patients.
Pharmacology, ADME and selectivity profile of the next generation CXCR4 antagonist balixafortide.
Authors: Garry Douglas, Giorgio Gambino, Guillaume Lemercier, Sandrine Longuet, Tobias Remus, Johann Zimmermann
Journal: Journal of Clinical Oncology (2018)

e14553 Background: Balixafortide is a potent and highly selective peptidic CXCR4 antagonist. Evidence suggests that anti-cancer effects of CXCR4 antagonists include direct suppression of metastatic spread, sensitization of tumor cells to chemotherapy, and activation of the immune system. Clinical proof-of-concept was achieved in a recent Phase 1 study in metastatic HER2-negative breast cancer (NCT01837095). Balixafortide in combination with eribulin gave higher response rates than published data for eribulin alone in breast cancer. The safety profile was comparable. Here we outline the discovery and optimization of balixafortide. Methods: Balixafortide was derived from the natural product polyphemusin following multiple iterative cycles of focused compound library synthesis optimized by analysis of structure-activity relationship. Absorption, distribution, metabolism and excretion (ADME) profiles were generated from in vitro and in vivo studies and pharmacological profiling included ligand binding, cell signaling pathways and functional assays such as calcium flux, beta-arrestin recruitment and chemotaxis. Results: Balixafortide potently inhibits pERK / pAKT signaling in cancer cells. Affinity of Balixafortide to CXCR4 and inhibition of calcium flux were about 100-fold higher than for AMD3100 (Plerixafor). A high 1000-fold selectivity window of Balixafortide was demonstrated in a panel of other receptors including CXCR7. Receptor occupancy studies with the competitive antibody 12G5 revealed a prolonged binding of Balixafortide to CXCR4 compared to AMD3100. Balixafortide has favorable mouse and human ADME properties. Conclusions: The next-generation CXCR4 antagonist Balixafortide offers a favorable balance between ADME properties, potency and safety which allows high and frequent dosing in cancer patients.
Phase II clinical trial evaluating the activity and tolerability of pazopanib in patients (pts) with advanced and/or metastatic liposarcoma (LPS): A joint Spanish Sarcoma Group (GEIS) and German Interdisciplinary Sarcoma Group (GISG) Study—NCT01692496.
Authors: Claudia María Valverde, Javier Martin Broto, Jose A. Lopez-Martin, Cleofe Romagosa, Maria Pilar Sancho Marquez, Juan Antonio Carrasco, Andres Poveda, Sebastian Bauer, Javier Martinez-Trufero, Josefina Cruz, Peter Reichardt, Pablo Luna Fra, Viktor Gruenwald, Oscar Persiva, Diego Varona Porres, Bernd Kasper
Journal: Journal of Clinical Oncology (2016)

11039 Background: Pazopanib, a multitarget TKI, has been approved as second or later line treatment for advanced non-adipocytic soft-tissue sarcoma. This open-label, phase II clinical trial was designed to assess the activity of pazopanib in patients with advanced LPS in two independent cohorts: well-differentiated/ dedifferentiated (WD/DD cohort A) and myxoid/round-cell (M/RC cohort B) LPS. Methods: Pts ≥ 18 years old, ECOG 0-1, with high- or intermediate-grade LPS (excluding pleomorphic) with locally advanced or metastatic measurable disease (per RECIST 1.1) were eligible. Pts had to be unsuitable or had failed at least one line of systemic therapy but no more than 3 lines. Central pathologic review was performed before study entry to confirm diagnosis and assign the patient into one of the two cohorts. All patients received pazopanib 800 mg once daily until tumor progression, unacceptable toxicity, death, or pt's withdrawal. The primary study endpoint was Progression-free survival (PFS) rate assessed 12 weeks (w) after start of treatment. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = .1) for each cohort. Patients had CT scan assessments at baseline, w6, w12 and every 8w thereafter. Local and central radiological review was performed. Results: 52 pts were enrolled at 12 centers in Spain and Germany between January 2013 and July 2015. 28 pts (53.8%) were male and median age was 58.3 years. Cohort B was closed after 15 pts because of lack of activity, while cohort A was completed up to 37 pts. According to local assessment PFS at 12w was 43.2% for cohort A and 13.3% for cohort B. Median PFS and overall survival was 3.5 months (m) and 16.4 m for cohort A and 1.99 m and 22.33 m for cohort B, respectively. No objective response was observed. Adverse events for pazopanib were as expected. Data on central radiologic review and growth modulation index will be presented. Conclusions: This study corroborates that pazopanib is well tolerated and is potentially active in the treatment of WD/DD LPS as it is in other sarcoma subtypes, but not in M/RC LPS. Clinical trial information: NCT01692496.
Treatment outcomes with tyrosine kinase inhibitors in patients with uncommon EGFR mutations in non-small cell lung cancer: A multi-centre retrospective analysis.
Authors: Sarah Hunter, Guillermina Nickless, Karim El-Shakankery, Nadia Yousaf, Daniel Smith, Gillian Brand, Marianne Nicolson, Michael Neat, Tom Newsom-Davies, James F. Spicer, Ana Montes, Eleni Karapanagiotou
Journal: Journal of Clinical Oncology (2017)

e20678 Background: The clinical significance of common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions and exon 21 L858 mutations) in non-small cell lung cancer is well known 1 . However, 2-8% of NSCLC patients harbour an uncommon EGFR mutation 2 . Prognosis and response to tyrosine kinase inhibitors (TKIs) is unclear in this subgroup. The most frequent uncommon EGFR mutations are exon 18 G719 and exon 21 L861. Although not frequently reported, these appear to have favourable outcomes with TKIs 3 . Methods: We conducted a retrospective review of all patients with uncommon EGFR mutations identified at laboratories in 4 UK centres, between 2012 and 2016. Patient’s not treated with a TKI were excluded. Techniques including cold PCR were in use at contributing laboratories. The T790M resistance mutation was excluded from our study. For patients with uncommon EGFR mutations, patient characteristics and response to TKIs were analysed. Results: 29 patients with uncommon EGFR mutations, with both rare point mutations (86%) and deletions (14%), were identified. All patients were treated with a TKI. Age ranged from 37 to 85 (median 67). The majority (86%) of patients were performance status 1. TKIs used were afatinib (31%), gefitinib (24%) and erlotinib (45%). 19 patients (66%) benefitted from TKI treatment (38% partial response (PR), 28% stable disease (SD). 10 patients (34%) did not respond, including all four with exon 20 mutations. 15 mutations were exon 18 G719 mutations: 40% had a PR and 40% stable disease with TKI therapy. There were two L861 mutations, both responded with a PR. 13 patients remained on TKI treatment at data cut off. The median progression free survival at this time was 8.1months. Tabulated details of response according to mutation will be presented. Conclusions: The majority (66%) of NSCLC patients with uncommon EGFR mutations benefitted from TKI therapy in this series. These high clinical benefit rates, typified by patients with G719 mutation, are in line with the limited previous reports 1,3 . Exon 20 mutations were associated with TKI resistance, in line with the literature 4 .
Abstract 15850: Cerebral Microembolization During Pulmonary Vein Isolation: A Comparison of Different Ablation Techniques
Authors: Alexandra Kiss, Edina Nagy-Baló, Marcell Clemens, Gábor Sandorfi, István édes, Zoltán Csanádi
Journal: Circulation (2013)

Background: Comparing different ablation technologies for atrial fibrillation the use of the pulmonary vein ablation catheter (PVAC) and the GENius 14.3 generator was associated with the highest in...
Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results.
Authors: Rod Ramchandren, Ranjana H. Advani, Stephen M. Ansell, Nancy L. Bartlett, Robert W. Chen, Tatyana Feldman, Andres Forero-Torres, Jonathan W. Friedberg, Ajay K. Gopal, Leo I. Gordon, John Kuruvilla, Kerry J. Savage, David J. Straus, Anas Younes, Keenan Fenton, Thomas John Manley, Gerald Engley, Joseph M. Connors
Journal: Journal of Clinical Oncology (2018)

7541 Background: ECHELON-1 is a global, phase 3 study of BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) vs ABVD as frontline therapy in patients with advanced HL (NCT01712490). The primary endpoint was modified PFS (mPFS) per independent review facility (IRF) defined as progression (PD), death, or the receipt of additional treatment for patients not achieving CR at the completion of frontline therapy. A+AVD was superior to ABVD (HR = 0.77, p = 0.035) with 2-year mPFS rates of 82.1% and 77.2%; as previously reported. Methods: Efficacy and safety of A+AVD vs ABVD in North America (NA) was examined. mPFS in NA was a prespecified analysis. Traditional PFS by investigator, where only PD or death were counted as events, was a sensitivity analysis of the primary endpoint. Results: 497 pts in NA with advanced classical HL were randomized 1:1 to receive up to six cycles of A+AVD or ABVD. There was a significant improvement in mPFS by IRF and by INV for pts who received A+AVD compared with ABVD (Table). 2-year traditional PFS by INV was also improved with A+AVD. Across subgroups, a benefit for A+AVD was consistently observed, including in pts with Stage III (HR = 0.64; 95% CI: 0.33, 1.24) and Stage IV (HR = 0.55; 95% CI: 0.33, 0.94) disease. Clinical trial information: NCT01712490. Adverse event rates for A+AVD vs ABVD (all grades) were: interstitial lung disease 3% vs 10%, peripheral neuropathy, 80% vs 56%; neutropenia, 62% vs 54%; febrile neutropenia (FN), 20% vs 9%. In A+AVD pts receiving G-CSF primary prophylaxis, FN was 9%. Two NA pts died during treatment with A+AVD vs 7 with ABVD. Conclusions: For pts treated in NA on the ECHELON-1 trial, the absolute difference between A+AVD and ABVD at 2 years for mPFS by IRF was 10.6% and for PFS by INV was 11.7%. A prospective clinical trial is planned to confirm these safety and efficacy findings in advanced stage HL pts treated with A+AVD in the NA community setting. mPFS IRF mPFS INV PFS INV A+AVD ABVD A+AVD ABVD A+AVD ABVD N 250 247 250 247 250 247 2-year survival (%) 84.3 73.7 86.4 73.6 88.1 76.4 HR (95% CI) 0.60 (0.40,0.90) 0.52 (0.34, 0.79) 0.50 (0.32-0.79) p-value 0.012 0.002 0.002
Racial Differences in Trajectories of Hemoglobin A<sub>1c</sub>
Authors: Kellee M. Miller
Journal: JAMA Network Open (2018)

Anna R. Kahkoska, BS; Christina M. Shay, PhD; Jamie Crandell, PhD; Dana Dabelea, MD, PhD; Giuseppina Imperatore, MD, PhD; Jean M. Lawrence, ScD; Angela D. Liese, PhD; Cate Pihoker, MD; Beth A. Reboussin, PhD; Shivani Agarwal, MD; Janet A. Tooze, PhD; Lynne E. Wagenknecht, PhD; Victor W. Zhong, PhD; Elizabeth J. Mayer-Davis, PhD
TCT-384 Diagnostic utility of noninvasive fractional flow reserve derived from coronary computed tomography angiography in patients with stable coronary artery disease
Authors: HIroaki Sawada, Hiroaki Takashima, Katsuhisa Waseda, Hirohiko Ando, Shinichiro Sakurai, Akihiro Suzuki, Yuki Saka
Journal: Journal of the American College of Cardiology (2018)
PD-L1 expression and tumor-infiltrating lymphocytes in lung cancer brain metastases.
Authors: Benjamin Y. Lu, Richa Gupta, Matthew Ribeiro, Tyler Stewart, Veronica Chiang, Joseph N. Contessa, Adebowale Adeniran, Harriet M. Kluger, Lucia Jilaveanu, Kurt A. Schalper, Sarah B. Goldberg
Journal: Journal of Clinical Oncology (2018)

e24116 Background: Despite advances in treating metastatic lung cancer, immune checkpoint inhibitors (ICIs) have shown efficacy in only a subset of patients. PD-L1 expression is associated with response to ICIs, but PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in brain metastases (BrM) have not been extensively studied. This study evaluates the expression of PD-L1 and TILs in lung cancer BrM, primary tumors, and extra-cranial metastases (ECM). Methods: Tumor samples from patients with lung cancer between 2002-2013 were collected and reviewed to construct a tissue microarray. Tumor and stromal/immune-cell PD-L1 protein expression was determined using the 22C3 immunohistochemistry assay and reported as tumor (tPD-L1) or stromal (sPD-L1) proportion score. TILs were analyzed using a semi-quantitative pathologist-based, four-tiered scoring system (low scores defined as 0 or 1, representing < 30%) using Hematoxylin & Eosin-stained preparations. Levels of tPD-L1 and sPD-L1 protein were measured using multiplexed quantitative immunofluorescence (QIF) and the AQUA platform. We studied PD-L1 expression and TILs in association with clinicopathologic variables. Results: 99 patients were included with a total of 29 paired samples (18 BrM-primary, 11 brain-ECM), and an additional 38 BrM, 30 primaries, and 2 ECM. Lung cancer histology included adenocarcinoma 65.4%, small cell 11.8%, squamous 8.8%, large cell 6.6%, and other 7.4%. There was a positive association between PD-L1 expression and high TIL density in all tissues (tumor p = 0.002, stromal p < 0.001). When comparing BrM to all extra-cranial (EC) sites of disease (i.e. primaries plus ECM), PD-L1 levels were comparable, though BrM displayed lower TILs than EC sites (p = 0.002). Low TILs were more common in BrM when compared with their paired primaries (82.4% vs. 50%) and paired ECM (81.5% vs. 66.7%), though statistical significance was not reached. Conclusions: Lung cancer BrM display comparable PD-L1 expression versus EC sites; however, BrM show lower TIL infiltration. Despite this, patients with active BrM treated with ICIs tend to respond similarly in the brain and in EC sites. Further studies are needed to determine activity of T-cells in cerebral samples.
Prospective Registry of Multiplex Testing (PROMPT): Feasible and sustainable.
Authors: Heather Symecko, Jamie Brower, Christine Drogan, Tricia Harstad, Erin E. Salo-Mullen, Nisha Pradhan, Jada Hamilton, Judith Balmaña, Michael Francis Walsh, Fergus Couch, Judy Ellen Garber, Kenneth Offit, Susan M. Domchek, Mark E. Robson
Journal: Journal of Clinical Oncology (2018)

1543 Background: Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals who completed multiplex panel testing for cancer susceptibility. The overall objective of this registry is to ascertain families to allow penetrance calculations for mutations in less characterized genes. Methods: Since September 2014, health care providers and commercial laboratories have provided PROMPT information to eligible participants and ordering providers with the test results. The PROMPT registry has self-enrolled those with pathogenic mutations and variants of unknown significance (VUS) in cancer susceptibility genes. Registrants consent to full participation (FP), permitting study investigators to have contact information, or partial participation (PP), with de-identified information only. In 2016, we expanded to Phase II, targeting enrollment by genes of interest for family co-segregation, and collecting additional risk factor data and saliva samples. Results: Over 4500 individuals have enrolled into PROMPT. Using initial recruitment goals, to date we have reached 250% of our initial recruitment. 94% of enrollees are women, representing 33 countries (96% from the United States). 63% of participants reported at least one cancer (67% breast cancer) and 23% reported two or more cancers. 29% report likely pathogenic/pathogenic alteration, 25% VUS, and the remaining are in the process of being verified. The most frequently reported genes are ATM (13%), CHEK2 (12%), PALB2 (7%), BRIP1 (4%), and BARD1 (4%). 58% of participants have participated more than 1 year, and of those, 28% completed the first annual follow-up survey. A gene-specific survey sent to participants with CDH1 genetic alterations had a 61% response from FP and a 32% response rate from PP. Conclusions: The continued linear enrollment since the inception of PROMPT and the willingness of participants to respond to survey studies, annual follow-up, and PROMPT II enrollment, supports the feasibility and sustainability of a prospective registry for the collection of genetic epidemiology data. Strategies to increase follow up participation are underway, including gene-specific surveys and transitioning PP to FP, for those who are willing.
The prognostic value of baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for predicting clinical outcome in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan (nal-IRI; MM-398) + 5-fluorouracil and leucovorin (5-FU/LV) vs 5-FU/LV.
Authors: Andrea Wang-Gillam, Li-Tzong Chen, Chung-Pin Li, Gyorgy Bodoky, Andrew Dean, Kyung-Hun Lee, David Cunningham, Richard Hubner, Fadi S. Braiteh, J. Marc Pipas, Bruce Belanger, Floris A. de Jong, Purvi D. Mody, Daniel D. Von Hoff, Jens T. Siveke
Journal: Journal of Clinical Oncology (2017)

e15795 Background: Increased NLR and PLR have been associated with poor survival in several malignancies. Here we report the association of NLR and PLR with overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 trial (NCT01494506), which evaluated nal-IRI+5-FU/LV for the treatment of mPDAC patients (pts) after disease progression following gemcitabine-based therapy. Methods: Pts missing baseline NLR/PLR data were excluded. Medians reflect Kaplan-Meier estimates; hazard ratios (HRs) reflect Cox regression analysis. P values in this exploratory analysis are descriptive. Results: Of 116 evaluable pts in the nal-IRI+5-FU/LV arm, 82 (71%) had NLR ≤5 and 44 (38%) had PLR ≤150 (data cutoff: Nov 16, 2015). Of 105 evaluable pts in the 5-FU/LV control arm, 73 (70%) had NLR ≤5 and 36 (34%) had PLR ≤150. In pts with baseline NLR ≤5 or PLR ≤150, median OS and PFS were significantly longer in the nal-IRI+5-FU/LV treatment arm vs the 5-FU/LV control arm (Table). In pts with baseline NLR &gt;5 or PLR &gt;150, median OS and PFS were numerically longer in the treatment vs control arm, but differences were less compelling (95% CIs for HRs included 1). Conclusions: Median OS and PFS were improved with nal-IRI+5-FU/LV vs 5-FU/LV in pts with baseline NLR ≤5 or PLR ≤150. This exploratory analysis extends the prognostic significance of NLR and PLR to the post-gemcitabine setting. Clinical trial information: NCT01494506. [Table: see text]
Population-based study predicting the probability of death resulting from non-small cell lung cancer (NSCLC) and other causes among NSCLC patients with surgery.
Authors: Bo Jia, Ziping Wang, Qiwen Zheng, Yuyan Wang, Xinmeng Qi
Journal: Journal of Clinical Oncology (2018)

8525 Background: This study aimed to predict the probability of death for non-small cell lung cancer (NSCLC) patients who received surgery and construct a comprehensive nomogram prognostic model to predict cumulative incidence of death resulting from NSCLC, other cancers, and non–cancer-related causes. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute across 18 cancer registry sites in the United States were used for the present study. We estimated probabilities of death resulting from NSCLC, other cancers, and non-cancer causes for NSCLC patients who received surgery and analyzed relationships of patients' characteristics with probability of death. A nomogram prognostic model was used to predict the probability of death. Results: The entire cohort comprised 44,880 NSCLC patients who received surgery from 2004 to 2014. Male, race, tumor anatomic sites, histologic subtype, tumor differentiation, tumor size, tumor extent, lymph node involvement, examined lymph node, positive lymph node, type of surgery showed significant associations with probability of death (P < 0.001). Chemotherapy was associated with a significantly lower cumulative incidence of death (P < 0.001) while radiotherapy was associated with a significantly higher incidence of death (P < 0.001). The nomogram was constructed based on multivariate models with training data set. The probability of 5- or 10-year death can be calculated using this nomogram. In the validation cohort, the unadjusted C-index was 0.73 (95% CI, 0.72-0.74), 0.71 (95% CI, 0.66-0.75) and 0.69 (95% CI, 0.68-0.70) for lung cancer death, other cancer death and non-cancer death causes. Conclusions: A prognostic nomogram model was developed for predicting the probability of death for NSCLC patients who received surgery. This nomogram may be useful for clinicians to develop the best treatment strategies for NSCLC patients after surgery.