tbuckley/cabot-search huggingface dataset:
HIC1 deletion promotes breast cancer progression by activating tumor cell/fibroblast crosstalk
Authors: Yingying Wang, Xiaoling Weng, Luoyang Wang, Mingang Hao, Yue Li, Lidan Hou, Yu Liang, Tianqi Wu, Mengfei Yao, Guowen Lin, Yiwei Jiang, Guohui Fu, Zhaoyuan Hou, Xiangjun Meng, Jinsong Lu, Jianhua Wang
Journal: Journal of Clinical Investigation (2018)

Breast cancer (BrCa) is the malignant tumor that most seriously threatens female health; however, the molecular mechanism underlying its progression remains unclear. Here, we found that conditional deletion of hypermethylated in cancer 1 (HIC1) in the mouse mammary gland might contribute to premalignant transformation in the early stage of tumor formation. Moreover, the chemokine (C-X-C motif) ligand 14 (CXCL14) secreted by HIC1-deleted BrCa cells bound to its cognate receptor GPR85 on mammary fibroblasts in the microenvironment and was responsible for activating these fibroblasts via the ERK1/2, Akt, and neddylation pathways, whereas the activated fibroblasts promoted BrCa progression via the induction of epithelial-mesenchymal transition (EMT) by the C-C chemokine ligand 17 (CCL17)/CC chemokine receptor 4 (CCR4) axis. Finally, we confirmed that the HIC1-CXCL14-CCL17 loop was associated with the malignant progression of BrCa. Therefore, the crosstalk between HIC1-deleted BrCa cells and mammary fibroblasts might play a critical role in BrCa development. Exploring the progression of BrCa from the perspective of microenvironment will be beneficial for identifying the potential prognostic markers of breast tumor and providing more effective treatment strategies.
Comprehensive evaluation of place of death for patients with hematological malignancies, 1999-2015.
Authors: Fumiko Ladd Chino, Arif Kamal, Junzo P. Chino, Thomas William LeBlanc
Journal: Journal of Clinical Oncology (2018)

10024 Background: Patients with hematologic malignancies (HM) are more likely to receive aggressive care at the end of life than patients with solid tumors, and less often utilize hospice care. However, most prior research in this area is Medicare-based (only patients ≥65), or limited to hospice reporting, thus more comprehensive US-based analyses are needed. Methods: CDC WONDER contains death certificate data for all US counties and is maintained by the National Center for Health Statistics. Place and year of death was obtained for all HM deaths from 1999- 2015, as well as sociodemographic information. Place of death was dichotomized to death at home or hospice facility, vs other location. Data from 2015 was used to test for disparities in place of death associated with sociodemographic variables or primary cancer on univariate (UVA) and multivariate (MVA) logistic regression. Results: In the study period, there were 951,435 deaths due to HM. 26.1% of HM deaths were in those aged < 65. HM inpatient deaths decreased from 54.6% in 1999 to 38.2% in 2015, while home (25.9 to 32.7%) and hospice facility deaths (0 to 12.1%) increased (p < 0.001). On MVA of all cancers, including solid tumors, patients with HM had the lowest odds of home or hospice facility death (OR 0.56, 95% CI 0.55-.057). Compared to any other cancer type, in 2015 patients with HM were 65% more likely to die in the hospital (38.2% HM vs 23.2% non-HM) and 25% less likely to die at home (32.7% HM vs 43.6% non-HM) (both p < 0.001). On MVA of HM cancers, older age (40-64: OR 1.57, 95%CI 1.35-1.82 and 65+: OR 2.29, 95%CI 1.97-2.65), being married (OR 1.44, 95%CI 1.44-1.73) and having myeloma (OR 1.32, 95%CI 1.25-1.39) were associated with death in home or hospice facility, while being black (OR 0.71, 95%CI 0.66-0.77), Asian (OR 0.55, 95%CI 0.48-0.64) or Hispanic (OR 0.83, 95%CI 0.76-0.90) or having a chronic leukemia (OR 0.81, 95%CI 0.76-0.87) had decreased odds of dying at home or hospice. Conclusions: Despite a 30% decrease in hospital deaths over time, patients with HM remain more likely than solid tumor patients to die in the hospital, and disparities exist along age, racial, and ethnic lines. Continued efforts are needed to improve the provision of quality end-of-life care in hematology.
Results of a phase II trial of selinexor, an oral selective inhibitor of nuclear export (SINE), in patients with metastatic castration resistant prostate cancer (mCRPC) refractory to abiraterone or enzalutamide.
Authors: Xiao Wei, Adam Phillip Siegel, Rahul Raj Aggarwal, Amy M. Lin, Terence W. Friedlander, Lawrence Fong, Mirela Paraganlija, Emily Chang, Li Zhang, Charles J. Ryan
Journal: Journal of Clinical Oncology (2017)

e16533 Background: Patients (pts) with abiraterone (abi) or enza (enza) refractory mCRPC typically have limited treatment options. Selinexor is a first in class SINE that specifically inhibits the nuclear export protein Exportin-1 (XPO-1) which is overexpressed in prostate cancer (PCa), leading to cytoplasmic mislocalization of tumor suppressor proteins. In preclinical models of PCa, selinexor reduced tumor growth and decreased the incidence of bone metastasis. Methods: Eligibility criteria included progressive mCRPC with primary or acquired resistance to abi, enza, or their combination. Prior chemotherapy for mCRPC was not allowed. All pts must have &gt; 1 bone metastasis. The primary objective was radiographic progression free survival (rPFS). Results: Fourteen pts were enrolled between Oct 2014 and Oct 2016. The median age was 72 years (range 56-79) and median baseline PSA was 73.8 ng/mL (range 12.8-686.9). Eleven pts (79%) had both prior abi and enza. The initial selinexor dose was 65 mg/m 2 on Day 1 (D1) and Day 3 (D3) weekly. For toxicity concerns, after the first 2 pts, dose was reduced to 60 mg on D1 and D3 for the first 3 wks followed by a 1-wk rest period (28-day cycle). All pts received ondansetron and olanzapine to prevent nausea and anorexia. The median treatment duration was 3 cycles (range 1-12), and median follow-up was 4 months. One pt (7.1%) had &gt; 50% PSA decline, 5 pts (35.7%) had &gt; 30% PSA decline, and 7 pts (50%) had any PSA decline. Of 10 pts evaluable, 9 pts had stable disease as best radiographic response, and 1 pt had progressive disease on the first radiographic evaluation. The median rPFS was 3.6 months (95% CI 2.1-not reached). The most common AEs of any severity were anorexia (86%), nausea (64%), weight loss (50%), fatigue (50%), thrombocytopenia (50%), anemia (36%), and vomiting (36%). Grade 3/4 AEs included nausea (14%), vomiting (14%), anemia (14%), anorexia (7%), weight loss (7%), thrombocytopenia (7%) and neutropenia (7%). Conclusions: Selinexor demonstrated limited clinical activity in mCRPC. Toxicity, in particular anorexia and weight loss, hinders further development in this pt population. Clinical trial information: NCT02215161.
Improving documentation of pain and constipation management within the cancer center of a large public healthcare network.
Authors: Giselle Dutcher, Darica Flood, Marjorie Adams Curry, Antonio Washington, Pooja Mishra, Corey Streetman, Jennifer Ann LaFollette, Winifred Bell, Sandra Smith, Maxine Chanel Senchery, Steve Power, Leon Bernal-Mizrachi
Journal: Journal of Clinical Oncology (2018)

6596 Background: Cancer patients commonly suffer from pain and constipation, and a high number of patients have inadequate control of these symptoms. At the Cancer Center for Excellence at Grady Health System, a large public healthcare network in Atlanta, baseline QOPI measures for pain and constipation documentation were below benchmark levels. We conducted a quality improvement (QI) initiative to improve the management of pain and constipation. Methods: Given the low baseline rates of QOPI documentation for pain (58%) and constipation (60%) assessment, we aimed for a 20-percentage point increase in documentation of these measures. Cause and effect analysis identified causal factors. This led the team to develop a new note template that automatically integrates pain and constipation assessment data from the nursing note into the practitioner’s documentation. We developed a new process in the electronic medical record (EPIC) to link appropriate orders with the pain and constipation plan. Mandatory use of the new note began in June 2017. We reviewed documentation pre- (12 months) and post- (4 months) intervention. Results: Integrating a nursing assessment into the note for the practitioner increased pain score documentation from 66% to 87% and pain management from 47.2% to 83.2%. Similarly, documentation of constipation assessment increased from 18.9% to 82.8% and constipation management increased from 11.78% to 75%. This QI intervention improved pain control by the 3rd visit from 47% to 57%. This strategy also reduced emergency department (ED) visits and hospitalizations from 21% to 9%. Conclusions: Using a standardized visit template and mandated assessment of constipation and pain lead to an increase greater than the 20% goal for documentation of these symptoms. This intervention resulted in improved pain and constipation control. This strategy suggests a reduction in ED visits.
Correlation of radiomic features with PD-L1 expression in early stage non-small cell lung cancer (ES-NSCLC) to predict recurrence and overall survival (OS).
Authors: Pradnya Dinkar Patil, Kaustav Bera, Pranjal Vaidya, Prateek Prasanna, Monica Khunger, Arjun Khunger, Vamsidhar Velcheti, Anant Madabhushi
Journal: Journal of Clinical Oncology (2018)

e24247 Background: Outcomes in patients with ES-NSCLC (stages 1 and 2) remain dismal despite curative intent surgical resection and adjuvant chemotherapy. With low dose chest CT screening for lung cancer, we are likely to see an increase in patients diagnosed with ES-NSCLC. There is a need for clinically validated biomarkers to predict risk of recurrence. PD-L1 is a transmembrane protein which has been shown to significantly modulate immune responses in carcinogenesis. PD-L1 expression has been associated with poor prognosis in ES-NSCLC. Radiomics has been used to successfully differentiate between patients with high and low risk of recurrence from pre-surgical CT scans. In this study we examined whether radiomic features which were correlated with PD-L1 status could also predict risk of recurrence and OS in ES-NSCLC. Methods: A total of 166 ES-NSCLC pts who had curative surgery with or without adjuvant chemotherapy were chosen for the study. PD-L1 expression on the tumor cells was evaluated with E1L3N anti-PDL1 antibody. The cohort was divided into a training (n = 116) and independent validation set (n = 50). A total of 248 intratumoral and peritumoral radiomic textural features were extracted. Results: A statistical feature selection algorithm was used to select the top three features that separated presence of PD-L1 expression from its absence. These features included two peritumoral features (0-6 mm outside the tumor nodule) and one intratumoral feature representing textural heterogeneity inside and outside the nodule. The machine learning classifier correlated with PD-L1 expression predicted recurrence on the independent validation set (n = 50; AUC = 0.73) and was also prognostic of overall survival (p < 0.001) and recurrence free survival (p < 0.001). Conclusions: Radiomic texture features both inside and outside the tumor were found to correlate with PD-L1 expression and were prognostic of overall and recurrence free survival. Future work will involve evaluating whether these radiomic features are potentially also predictive of PDL1 expression in advanced NSCLC and hence potentially predictive of response to immune checkpoint inhibition.
TCT-154 Diagnostic Accuracy of iFR Versus FFR in the Left Versus Right Coronary Artery
Authors: Ankita Gore, Jung-Min Ahn, Marcel van 't Veer, Allen Jeremias, Stuart Watkins, Colin Berry, Keith Oldroyd, Barry Hennigan, Aaron Crowley, Akiko Maehara, Gary Mintz, Nils Johnson, Seung-Jung Park, Johan Svanerud, Ziad Ali
Journal: Journal of the American College of Cardiology (2018)
Abstract 15214: Commuting by Public Transportation is Associated With Lower Prevalence of Excess Body Weight, Hypertension, and Diabetes
Authors: Hisako Tsuji, Ichiro Shiojima
Journal: Circulation (2015)

Background: Physical activity reduces body weight and incidence of diabetes mellitus (DM). We examined associations of commuting mode with prevalence of excess body weight, hypertension and DM. Met...
Molecular subtypes of triple-negative breast cancer (TNBC) tumor samples obtained before and after neoadjuvant systemic therapy (NST) and relationship between immunomodulatory (IM) gene signature and intensity of tumor-infiltrating lymphocytes (TILs).
Authors: Hiroko Masuda, Kenichi Harano, Sakiko Miura, Ying Wang, Yuko Hirota, Oi Harada, Yuki Matsunaga, Bora Lim, Anita L Wood, Anthony Lucci, Napa Parinyanitikul, Hee Jin Lee, Gyungyub Gong, Arvind Rao, Rob Seitz, David Richard Hout, Stephan Wade Morris, Seigo Nakamura, Savitri Krishnamurthy, Naoto T. Ueno
Journal: Journal of Clinical Oncology (2018)

12069 Background: Lehmann et al have identified 4 molecular subtypes of TNBC [basal-like (BL) 1, BL2, mesenchymal (M), and luminal androgen receptor (LAR)] and an IM gene expression signature. Our group previously showed that response of TNBC to NST differs by molecular subtype, but whether NST affects TNBC subtype has not been studied. We hypothesized that certain TNBC subtypes change after NST. We also tested whether IM signature correlates with the intensity of TILs. Methods: From the World TNBC Consortium dataset, which contains TNBC samples from 4 institutions from 4 countries, we examined 68 formalin-fixed, paraffin-embedded tumor samples from patients treated with NST: 27 pairs of matched pre-NST and post-NST samples and 14 pre-NST samples. TNBC classification was performed with the Insight TNBCtype assay. We compared the molecular subtypes of TNBC samples obtained before and after NST. We used the Spearman correlation test to investigate the association between IM status and percentage of TILs in all 68 samples. Results: The distribution of TNBC subtypes before and after NST is shown in the Table. Of the 27 matched pairs, 14 (52%) showed a change in TNBC subtype after NST. Among the 14 matched pairs with a subtype change, all 7 cases of BL1 subtype before NST changed to M, and 4 of 5 cases of LAR subtype before NST converted to BL2 (one LAR changed to unclarified). As expected, a low residual cancer burden (RCB 1) was more common in patients with (4/14 [29%]) than in patients without subtype change (1/13 [8%]); however, subtype change and amount of residual cancer were not related statistically (p = 0.32), most likely due to the small sample size. There was a strong positive correlation (rho 0.95, p = 0.0008) between TIL intensity and IM gene signature positivity. Conclusions: TNBC molecular subtype frequently changed after NST. TIL intensity positively correlated with IM signature. We will validate our findings in a larger group of samples in the World TNBC Consortium dataset. Subtype Distribution Subtype Pre-NST (%) Post-NST(%) BL1 37 11 BL2 11 22 LAR 37 22 M 15 37 Unstable — 8
The impact of Th17 cell pathway-related genetic variants in metastatic colorectal cancer patients treated with bevacizumab-based chemotherapy.
Authors: Ryuma Tokunaga, Shu Cao, Alberto Puccini, Madiha Naseem, Francesca Battaglin, Afsaneh Barzi, Joshua Millsteinand, Shivani Soni, Martin D. Berger, Michelle McSkane, Wu Zhang, Fotios Loupakis, Chiara Cremolini, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

e15578 Background: Th17 cells are recognized for their role in immune activation and angiogenesis. Further, Th17 cells are associated with enhanced efficacy of 5-FU treatment, which was the rationale to test whether genetic polymorphisms in the Th17 cell pathway will predict clinical outcome in patients treated with bevacizumab-based chemotherapy in first-line treatment. Methods: Genome wide association studies were conducted on whole blood samples from 215 mCRC patients in phase III TRIBE trial treated with bevacizumab plus FOLFIRI. The correlation between selected SNPs in Th17 cell pathway (IL17A, IL17F, IL21, IL23, IL23R, RORC, BATF, and IRF4) and clinical outcomes (tumor response, progression-free survival (PFS), and overall survival (OS)) were analyzed. Subgroup analysis was also performed. Results: Patient characteristics: male/female, 132/83; age ≤65/ > 65, 156/59; tumor side right/left, 53 /147; KRAS wild/mutant, 88/90. The median follow-up time was 48.9 months, and the median PFS and OS were 9.7 months and 26.2 months. The patients carrying C/C variant in IL21 rs2221903 had significantly shorter PFS than those with any T allele (8.2 vs 10.3 months, HR: 1.86, 95% CI: 1.07–3.23, adjusted P = 0.027); the patients with IL23 rs2371494 G/A allele had significantly shorter PFS than those with G/G variant (8.8 vs. 10.3 months, HR 2.16, 95% CI: 1.12–4.17, adjusted P = 0.022); the patients with any IL23R rs10889677 A allele had significantly shorter PFS than those with C/C variant (9.4 vs. 11.0 months, HR 1.57, 95% CI: 1.10–2.23, adjusted P = 0.013). Further, the patients carrying T/T variant in IL23R rs1884444 had significantly longer OS than those with any G allele (29.1 vs 26.1 months, HR: 0.60, 95% CI: 0.38–0.94, adjusted P = 0.025). In KRAS-mutant population (n = 88), the patients with any IL23R rs10889677 A allele had much shorter PFS (8.6 vs. 12.7 months, HR 3.14, 95% CI: 1.78–5.54, adjusted P < 0.001), and OS (20.3 vs. 42.7 months, HR 2.32, 95% CI: 1.30–4.16, adjusted P = 0.005). Conclusions: Genetic polymorphisms of IL21, IL23 and IL23R may impact the angiogenic environment and patient survival. IL23R variant may be also a prognostic marker in patients with mutant RAS mCRC.
Exosite 1 thrombin inhibition with JNJ-64179375 inhibits thrombus formation in a human translational model of thrombosis
Authors: Simon J Wilson, Thomas M Connolly, Gary Peters, Atalanta Ghosh, Maureen Johnson, David E Newby
Journal: Cardiovascular Research (2018)

JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis.Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 μg/mL), bivalirudin (6 μg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively.JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 μg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both).Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications.
Dynamics of growth of transplantable sarcoma 45 (S45) in injection of autologous and allogenic serum.
Authors: Irina L Popova, Elena Yurievna Zlatnik, Liubov Yu Vladimirova, Natalya A Abramova, Aza Agieva, Mariya Yezhova
Journal: Journal of Clinical Oncology (2016)

e23009 Background: Development and administration of antibody drugs for tumor immunotherapy are now one of the growing tendencies in oncology and immunology. The purpose of the study was to study the possibility of inhibition or regression of transplantable tumor by autologous and allogenic serum injection to animals. Methods: The study included 33 rats weighing 150-200 g with S45 transplanted subcutaneously. The animals received serum injections in steadily growing doses: Group(Gr)A–5 rats, had the autologous serum; Gr B–5, the allogenic one from a tumor bearer; Gr C–5, the allogenic one from an intact rat; Gr D–5, the allogenic one from an intact rat temperature modified (warmed to 56 C); Gr E–5, the allogenic serum from an intact rat temperature modified (unfrozen 5 times); GrF-8, physiological saline. Tumor response (CR-complete regression, PR-partial regression, S-stabilization, P-progression), PFS, OS were evaluated. Results: Gr F showed P in 6 of 8 animals, S–1, PR–1. Gr A: PR in 3 rats , S–1, P–1. Gr B:PR-5, Gr C:CR-1 and PR-4.This effect was cancelled if serum temperature was modified (P in Gr D and E has occured in 4 of 5 rats). In Gr A,B,C response significantly exceeded that in Gr F (0.26±0.17, 0.52±0.2, 0.44±0.6, 1.09±0.3 cm3, р<0.05). There was difference in PFS in Gr A,B,C compared to Gr D,E,F. Max OS was found to be in Gr A and B, and the survival rate was statistically significantly higher than in Gr F(11,2±2.64 and 13.4±1.32 weeks vs 8.125±1.72 weeks). Conclusions: Courses of serum injections to animals with transplantable S45 sarcoma can result in CR or PR, increase in the number of surviving rats and their PFS and OS. Effects of native autologous and allogenic serum were found to be similar, as well as effects of serum taken from a tumor bearer and an intact animal. Temperature modification (warming and freezing) has eliminated tumor-inhibition effect, which is mediated by native thermolabile proteins of both antibody and non-immunoglobulin nature.