tbuckley/cabot-search huggingface dataset:
Elevation of Stromal-Derived Mediators of Inflammation Promote Prostate Cancer Progression in African-American Men
Authors: Marc Gillard, Rodrigo Javier, Yuan Ji, S. Lilly Zheng, Jianfeng Xu, Charles B. Brendler, Susan E. Crawford, Brandon L. Pierce, Donald J. Vander Griend, Omar E. Franco
Journal: Cancer Research (2018)

Abstract Progress in prostate cancer racial disparity research has been hampered by a lack of appropriate research tools and better understanding of the tumor biology. Recent gene expression studies suggest that the tumor microenvironment (TME) may contribute to racially disparate clinical outcomes in prostate cancer. Analysis of the prostate TME has shown increased reactive stroma associated with chronic inflammatory infiltrates in African-American (AA) compared with European-American (EA) patients with prostate cancer. To better understand stromal drivers of changes in TME, we isolated prostate fibroblasts (PrF) from AA (PrF−AA) and EA (PrF−EA) prostate cancer tissues and studied their functional characteristics. PrF−AA showed increased growth response to androgens FGF2 and platelet-derived growth factor. Compared with PrF−EA, conditioned media from PrF−AA significantly enhanced the proliferation and motility of prostate cancer cell lines. Expression of markers associated with myofibroblast activation (αSMA, vimentin, and tenascin-C) was elevated in PrF−AA. In vivo tumorigenicity of an AA patient–derived prostatic epithelial cell line E006AA was significantly increased in the presence of PrF−AA compared with PrF−EA, and RNA-seq data and cytokine array analysis identified a panel of potential proinflammatory paracrine mediators (BDNF, CHI3L1, DPPIV, FGF7, IL18BP, IL6, and VEGF) to be enriched in PrF−AA. E006AA cell lines showed increased responsiveness to BDNF ligand compared with EA-derived LNCaP and C4-2B cells. Addition of a TrkB-specific antagonist significantly reduced the protumorigenic effects induced by PrF−AA compared with PrF−EA. These findings suggest that fibroblasts in the TME of AA patients may contribute to the health disparity observed in the incidence and progression of prostate cancer tumors. Significance: These findings suggest that stromal cells in the tumor microenvironment of African-American men promote progression of prostate cancer by increasing levels of a specific set of pro-inflammatory molecules compared with European-American men. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6134/F1.large.jpg. Cancer Res; 78(21); 6134–45. ©2018 AACR.
Quantitative and qualitative characterization of two PTEN clones: SP218 and 138G6.
Authors: Matthew Duffy, Jacquelyn Smith, Frank Vladich, Judith Pugh, Amita Mistry, Guadalupe Manriquez Manriquez, Bharathi Vennapusa, Krista Acosta, James Hnatyszyn
Journal: Journal of Clinical Oncology (2016)

e23266 Background: The PTEN(phosphatase and tensin homolog) gene, commonly deleted on chromosome ten, encodes for a tumor suppressing protein which regulates cellular differentiation and proliferation. It is constitutively expressed in the cytoplasm of various cell types. Null or decreased expression can be prognostic of tumor progression and a predictor of the likelihood to respond to targeted therapies. In this study, we describe the optimization and comparison of immunohistochemistry (IHC) assays developed using two PTEN antibodies: SP218 and 138G6. Methods: Fully automated immunohistochemical assays were optimized for PTEN using the Spring Bioscience (Spring, Pleasanton, CA) anti-PTEN (clone SP218) Rabbit mAb antibody and the Cell Signaling Technology (CST, Danvers, MA) anti-PTEN (clone 138G6) Rabbit mAb using instruments and detection chemistries from Ventana Medical Systems, Inc. (
A randomized phase II/III trial of conventional paclitaxel and carboplatin (cTC) versus dose-dense paclitaxel and carboplatin (ddTC), with or without bevacizumab (Bmab), for stage IVb, recurrent, or persistent cervical cancer (CC): Japan Clinical Oncology Group study (JCOG1311).
Authors: Ryo Kitagawa, Mitsuya Ishikawa, Taro Shibata, Kenichi Miyamoto, Hiroaki Kobayashi, Takashi ONDA, Munetaka Takekuma, Fumiaki Takahashi, Harushige Yokota, Michihiro Tanikawa, Mika Mizuno, Tetsuro Oishi, Yoichi Aoki, Shin Nishio, Takashi Iwata, Nobuo Yaegashi
Journal: Journal of Clinical Oncology (2018)

TPS5603 Background: Patients with metastatic or recurrent CC who are not amenable to curative treatment with surgery or radiation have a poor prognosis, and systemic chemotherapy is regarded as a standard treatment. Based on the JCOG0505, we considered tri-weekly cTC as the standard regimen. We subsequently focused on dose-dense, weekly administered paclitaxel, which was more effective than conventional administration for breast cancer and, in Japan, ovarian cancer. The efficacy and safety of ddTC have not been evaluated for CC. Therefore, we designed JCOG1311 to confirm the superiority of ddTC to cTC in metastatic or recurrent CC. However, Bmab was approved in Japan for treatment of metastatic or recurrent CC on May 2016. We amended the protocol to add the criteria by which patients would receive Bmab. Methods: Major eligibility criteria are stage IVB, persistent, or recurrent CC patients including SCC or adenocarcinoma histology. We enroll patients according to institution, PS, and platinum-free interval as adjustment factors, whether they receive carboplatin (AUC of 5) on day 1 plus either paclitaxel (175 mg/m2) on day 1 (cTC), or paclitaxel (80 mg/m2) on day 1, 8, 15 (ddTC). Both treatments are repeated every 3 weeks. They can receive Bmab (15 mg/kg) every 3 weeks if not contraindicated. 14 of planned 56 with measurable lesion receiving Bmab in phase II part, of which the primary endpoint is response rate (RR), have been enrolled until January 2018. If the RR of ddTC + Bmab arm is greater than that of cTC + Bmab arm plus 5%, the study will proceed to phase III part, which has OS as the primary endpoint. We hypothesize that the 2-year OS of ddTC arm will be greater than that of the cTC arm (i.e., ≥ 45% compared to 35%). According to the Schoenfeld and Richter method, the required sample size is total 420 patients, with one-sided α of 0.05 and β of 0.20 during 3.5 years of accrual and 2 years of follow-up. This trial is supported by the Japan Agency for Medical Research and Development. And, this trial was registered at the UMIN Clinical Trials Registry as UMIN000019191. Clinical trial information: 000019191.
Adherence, quality of life, health care resource use, and functional impairment among patients with oral multiple myeloma (MM) treatments.
Authors: Brian Ung, Shaloo Gupta, Kejal Parikh, Ryan Liebert, Safiya Abouzaid, Aaron Seth Rosenberg
Journal: Journal of Clinical Oncology (2017)

e19519 Background: Few studies have assessed the relationship between adherence to prescribed therapies and patient (Pt)-reported outcomes (PRO) in Multiple Myeloma (MM). Pt-reported adherence and its association with quality of life (QoL), healthcare resource use (HRU) and functional impairment among pts on oral MM treatments were assessed. Methods: This was a cross-sectional survey of 118 US adult MM pts identified from the Light Speed Research panel, who were currently on a regimen which included an oral therapy. Pt’s experiences using the Morisky Medication Adherence Scale-4 (MMAS-4), the Work Productivity and Activity Impairment, and the Functional Assessment of Cancer Therapy (FACT)-MM were examined. Higher FACT-MM scores indicated better health-related QoL. Pts were characterized by their MMAS score; score =4 and score ≤3 (max score =4). Pts in each score grouping were summarized based on pt characteristics, treatment history, HRU and PROs. Multivariable analyses estimated the association between MMAS score group and study outcomes. Results: A total of 72 (61%) pts reported a MMAS score = 4 and 46 (39%) pts had a score ≤3. Pts with a score =4 were older (59.2 vs 50.7 years; p&lt;0.001) and were on fewer treatments (1.42 vs 2.13; p&lt;0.001) than with a score ≤3. No differences in race/ethnicity, marital status, income or education level were noted between the two groups. Pts with a score ≤3 had higher levels of absenteeism, impairment while at work (presenteeism), and overall work impairment in descriptive analysis, but only differences in activity impairment (56.5% vs. 39.8%; p=0.015) remained significant in the multivariable analyses. Pts with a score = 4 reported higher FACT-MM scores (106.9 vs 89.2; p&lt;0.001) than pts with a score ≤3, a trend seen in all FACT-MM subscores. More pts with a score ≤3 also reported being overwhelmed or frustrated by having to reschedule MM appointments (64% vs. 26%; p=0.002). Conclusions: Among MM pts on oral treatments, high adherence is associated with improved QoL and a lower level of activity impairment. There may also be a relationship between frustration in managing MM related appointments and levels of adherence.
Measuring functional HER2-driven signaling status ex vivo to predict response to HER2 therapy: Results from a mouse breast tumor xenograft study.
Authors: Lance G. Laing, David J Burns, Yao Huang, Ian A. MacNeil, Benjamin E. Rich, Sajjad Soltani, Samantha Myhre, Brian Sullivan
Journal: Journal of Clinical Oncology (2017)

e23203 Background: Clinical trials indicate a weak correlation between HER2 expression levels and HER2 targeted therapy benefit. Other biological factors, such as HER2 signaling activity, may be important to measure when identifying patients for treatment with HER2 therapies. To measure the HER2 signaling activity of a patient’s live tumor cells, a new assay using an impedance biosensor, the CELx HER2 Signaling Function (CELx HSF) Test, was developed. In this study, we evaluated whether functional HER2 signaling status was more predictive of response to a dual-HER2 kinase inhibitor than HER2 receptor or gene amplification status, using breast tumor xenograft in vivo models. Methods: Two breast cancer cell lines were studied: HCC1954, a HER2+ cell line with normal HER2 signaling according to the CELx HSF Test, and BT483, a HER2- cell line with abnormally high HER2 signaling according to the CELx HSF Test. Thus, the HER2 receptor status of each cell line was opposite its HER2 signaling status. For each cell line, twenty 4-5 week old female NSG mice were injected with two million cells. Mice were randomly assigned to either a control group that received Captisol or a treatment group that received lapatinib at a dose of 20mg/kg daily for 16 days. Results: There was no significant difference in tumor volume between the control and lapatinib-treated groups in the mice injected with the HCC1954 (HER2+, normal HER2 signaling) cells. Average tumor sizes reached 1028.7 ± 166.9 mm 3 for the control group and 893.8 ± 111.5 mm 3 for the lapatinib-treated group (P = 0.285) by the end of the study. With the BT483 (HER2-, abnormal HER2 signaling) cells, lapatinib treatment significantly slowed down the increase in tumor size. Average tumor sizes reached 328.3 ± 54.9 mm 3 for the control group and 192.4 ± 19.4 mm 3 for the lapatinib-treated group (P = 0.0049). Conclusions: The results demonstrate that functional HER2-driven signaling status in live tumor cells is more correlative to response to lapatinib in mouse xenograft tumors than HER2 expression level. These findings provide strong evidence that HER2- breast cancer patients with abnormal HER2 signaling may respond to anti-HER2 therapies.
Nivolumab in the treatment of metastatic renal cell carcinoma: A cost-utility analysis.
Authors: Jacques Raphael, Zhuolu Sun, Georg A. Bjarnason, Beate Sander, David M Naimark
Journal: Journal of Clinical Oncology (2017)

e18331 Background: Nivolumab was recently shown to improve overall survival (OS) and health-related quality of life compared to Everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with antiangiogenic therapies (CheckMate-025 trial). The aim of this study is to assess the cost-utility of Nivolumab versus Everolimus from the perspective of the Canadian publicly funded healthcare system. Methods: To evaluate the cost-utility of Nivolumab versus Everolimus, a Markov cohort model that incorporated data from the phase 3 CheckMate-025 trial and other sources was developed. The outcomes of interest were healthcare costs, life-months and quality-adjusted life-months (QALMs) gained with Nivolumab as well as the incremental cost-effectiveness ratio (ICER), and the incremental net monetary benefit. A lifetime time horizon was used in the base case with costs and outcomes discounted 5% annually. The probabilities of progression and death from cancer and utility values were captured from the CheckMate-025 trial. Expected costs were based on Ontario fees and other sources. Scenario and sensitivity analyses (SAs) were conducted to assess uncertainty. Results: Compared to Everolimus, treatment with Nivolumab provided an additional 3.9 QALMs at an incremental cost of 33,386 Canadian dollars (CAD). The resulting ICER was 8,608CAD per QALM gained. With a willingness-to-pay (WTP) of 50,000CAD per Quality-adjusted life-year (QALY) ( = 4,167CAD per QALM), Nivolumab was not cost-effective in the base case. In one-way SAs, Nivolumab cost, median OS and treatment duration on Nivolumab were sensitive to changes with plausible threshold values. Assuming a WTP of 100,000CAD per QALY ( = 8,334CAD per QALM) and a scenario of Nivolumab cost with no drug wastage, Nivolumab became a cost-effective strategy with an ICER of 7,881CAD per QALM. Conclusions: With its current price , Nivolumab is unlikely to be cost-effective compared with Everolimus for previously treated mRCC patients from a Canadian healthcare payer perspective. While mRCC patients derive a meaningful clinical benefit from Nivolumab, considerations should be given to reduce drug wastage and increase the WTP threshold to render this strategy more affordable.
Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer.
Authors: Kimberly Blackwell, Pedro Gascon, C. Michael Jones, Allen Nixon, Roumen Nakov, Pritibha Singh, Andriy Krendyukov, Nadia Harbeck
Journal: Journal of Clinical Oncology (2016)

e14089 Background: Biosimilars are approved biologics in highly regulated markets proven to be highly similar to the reference. Here we present the pooled analysis of two randomized trials comparing the efficacy, safety, and immunogenicity of LA-EP2006 with reference pegfilgrastim (Neulasta). These registration trials were performed for regulatory approval of LA-EP2006. Methods: Each multinational, prospective, double-blind Phase 3 study (EudraCT: 2011-004532-58; 2012-002039-28) was planned to include 302 chemotherapy-naïve patients aged ≥ 18 years with early breast cancer scheduled to receive ≤ 6 cycles of (neo)-adjuvant chemotherapy with docetaxel 75 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC). Patients were randomized to LA-EP2006 or reference on Day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) (number of consecutive days with ANC < 0.5 x 109/L) during Cycle 1. Equivalence was confirmed if the 95% confidence intervals (CI) for the difference in mean DSNs between groups were within a pre-defined margin of ±1 day. Safety/immunogenicity follow-up was performed during treatment and at 4 weeks (PROTECT2) or 6 months (PROTECT1). Results: A total of 624 patients were randomized (LA-EP2006: n = 314; reference: n = 310). Baseline demographics were well balanced (mean age: LA-EP2006: 49.3 years, reference: 49.8; ethnicity: LA-EP2006: 70% white, reference: 71%; median months since diagnosis: LA-EP2006: 1.33 [0.1−76.0], reference: 1.35 [0.2−11.2]; ECOG status 0: LA-EP2006: 78%, reference: 75%). Difference in DSN in Cycle 1 was -0.04 days (95% CI: -0.19, 0.11; 90% CI: -0.17, 0.09), showing equivalence. In Cycle 1, FN was reported in 5.7% with LA-EP2006 vs. 8.4% with reference (all cycles: 8.0% vs. 10.3%). AEs were similar across groups. Bone pain was reported in 5.4% (LA-EP2006) vs. 8.1% (reference). Serious AEs were reported in 14.3% (LA-EP2006) vs. 17.1% (reference). No neutralizing anti-pegfilgrastim antibodies were identified post-dose. Conclusions: LA-EP2006 is therapeutically equivalent to reference pegfilgrastim with regard to efficacy, safety and immunogenicity in patients with breast cancer receiving TAC. Clinical trial information: 2011-004532-58; 2012-002039-28.
Prognostic role of pretreatment plasma EBV DNA on stage III nasopharyngeal carcinoma staged by AJCC/UICC 8<sup>th</sup> edition TNM staging classification.
Authors: Victor Lee, Dora LW Kwong, To-Wai Leung, Cheuk-Wai Choi, Brian O'Sullivan, Vincent Lai, Chi-Chung Tong, Ka-On Lam, Ann SY Chan, Patty PY Ho, Wendy WL Chan, Dennis KC Leung, Sik-Kwan Chan, Ka-Chun Tsang, Pek-Lan Khong, Mai-Yee Luk, Anne WM Lee
Journal: Journal of Clinical Oncology (2018)

6055 Background: The AJCC/UICC 8th edition TNM staging classification for nasopharyngeal carcinoma (NPC) was launched in 2018. We previously proposed new stage groups which incorporated pretreatment plasma EBV DNA and T-, N-classifications into recursive partitioning analysis. Stage III disease remains heterogeneous with different combinations of T and N-classifications. We investigated if pretreatment plasma EBV DNA can stratify stage III into high-risk vs. low-risk groups (NCT02476669). Methods: 518 patients with non-metastatic NPC confirmed by PET-CT and MRI scans were prospectively recruited from 2010 to 2016. They all had plasma EBV DNA measured at baseline, and then 8 weeks and 6 months following IMRT with/without concurrent +/- adjunct chemotherapy. They were treated based on 7th edition TNM but were re-staged by 8th edition TNM for subsequent analysis. Covariates including age, sex, ACE-27, pretreatment LDH and plasma EBV DNA were analyzed by Cox regression for prognostic factors of progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: 234 (45.2%) patients had stage III disease (see Table). 11 (4.7%) patients received IMRT alone, 39 (16.7%) received concurrent chemoradiation alone and the remaining 184 (78.6%) received concurrent chemoradiation and adjunct chemotherapy. The median pretreatment plasma EBV DNA was 494 copies/ml (range 0-175000 copies/ml). After a median follow-up of 5.2 years, 5-year PFS, CSS and OS in this cohort were 77.1%, 90.4% and 84.4% respectively. Pretreatment plasma EBV DNA 500 copies/ml stratified patients into high-risk vs. low-risk groups (PFS: 88.9% vs. 68.2%, p = 0.009; CSS: 96.8% vs. 85.4%, p = 0.033; OS: 91.2% vs. 79.4%, p = 0.124). Cox regression with multivariable analyses demonstrated that pretreatment plasma EBV DNA 500 copies/ml was the only significant prognostic factor of PFS (p = 0.005) and CSS (p = 0.027) while no prognostic factor was found for OS. Conclusions: Patients with high pretreatment plasma EBV DNA had a higher risk of relapse and additional therapy may be necessitated. N0 N1 N2 Total T1 0 0 43 43 T2 0 0 18 18 T3 21 46 106 173 Total 21 46 167 234
Correlation between blast percentage in myelofibrosis and outcomes: A single-center experience.
Authors: Lucia Masarova, Prithviraj Bose, Kate Newberry, Abdallah Abou Zahr, Jorge E. Cortes, Hagop M. Kantarjian, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2017)

e18562 Background: Patients with accelerated phase (AP) myelofibrosis (MF; &gt;10% blasts [BL] in bone marrow [BM] or peripheral blood [PB]) have shorter overall survival (OS) than those in the chronic phase (&lt;10% BM/PB BL). However, outcomes of patients with “lower” BM/PB BL (1-9%) are not well described. Methods: Clinical characteristics and OS of 1099 patients with MF who presented to MD Anderson Cancer Center between years 1984 – 2013 were retrospectively evaluated. Kaplan-Meier analysis and Cox regression models were used for calculations and comparisons. Results: PB and BM BL were available for 1038 (94%) patients at presentation. Five percent had AP, 10% had 5-9% BM or PB BL; 45% had &lt; 5% BM BL and 1% (n=282), 2% (n=110), 3% (n=47) or 4% (n=27) PB BL; and 40% had &lt; 5% BM BL and 0% PB BL (normal range). OS was similar among patients with 5-9% BM or 4-9% PB BL and those in AP (P&gt;0.05). OS was also similar among patients with BL in the normal range and those with &lt;5% BM and 1-3% PB BL (p&gt;0.05). By grouping patients with similar OS, we have identified 2 groups with distinctive OS of 54 and 27 months, respectively (Table; p&lt;0.001; HR = 1.81 [95%CI 1.5-2.2]). Five-year leukemia free survival was 65% for those in AP, 76% for ≥ 5-9% BM or ≥ 4-9% PB blasts, and 91% for &lt; 4% BM or ≤ 3% PB BL (P&lt;0.001). Clinical characteristics were similar for patients in the AP and with ≥ 5-9% BM or ≥ 4-9% PB blasts. Both groups had significantly higher leukocytes, lower hemoglobin and platelet levels, and were more likely to be transfusion dependent, have systemic symptoms, and unfavorable karyotype than patients with ≤ 4% BM or ≤ 3% PB blasts. There was no significant difference in age, splenomegaly, BM fibrosis grade, or distribution of JAK2, MPL and CALR mutations among these groups. Conclusions: Patients with ≥ 4% PB or ≥ 5% BM BL have OS that appears to be the same as those with &gt;10% BL, suggesting that these patients may require a more aggressive treatment approach. [Table: see text]
TCT-512 A Polymer-Free Biolimus-Coated Stent for the Management of Real-World Patients with Coronary Artery Disease
Authors: Alfonso Ielasi, Fabrizio D'Ascenzo, Maurizio Di Biasi, Roberto Adriano Latini, Paolo Vicinelli, Erica Ferrara, Enrico Cerrato, Mario Iannaccone, Gaetano Senatore, luca gaido, Vincenzo Vizzi, Bernardo Cortese, Maurizio D'Urbano, Arnaldo Poli, Ferdinando Varbella, Giacomo Boccuzzi, Andrea Gagnor, Maurizio D'amico, Maurizio Tespili
Journal: Journal of the American College of Cardiology (2018)