tbuckley/cabot-search huggingface dataset:
Therapeutic targeting of tumor-associated macrophages through microscale engineering of the prostate cancer microenvironment.
Authors: David Kosoff, Jiaquan Yu, Jennifer L Schehr, David J. Beebe, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2017)

184 Background: The tumor microenvironment (TME) plays integral roles in prostate cancer progression and is a high value therapeutic target. The development of effective TME-targeted therapies is limited by current technologies which are insufficient to replicate or analyze this complex environment. To address these challenges, we have developed a microfluidic cell culture platform known as STACKS, which permits co-culture of up to 6 patient-derived cell populations as well as compartmentalized, multiplexed analysis of gene expression, cell signaling, and matrix remodeling. We have focused on investigation of tumor-associated macrophages (TAMs), which have been implicated in prostate cancer growth, metastasis, survival, and therapeutic resistance. Methods: Using blood and prostate tissue obtained through biomarker studies at the University of Wisconsin, we isolated patient-derived cell populations for culture and analysis within the STACKS device. Monocytes obtained from peripheral blood were differentiated into tumor inhibitory (M1) and tumor promoting (M2) macrophages in the device. RNA, protein, and secretory factor expression were analyzed following manipulations of culture surface, cytokine exposure, and multi-cell culture with tumor and stromal cell populations. Results: We report that physical properties of the TME, such as topography and hydrophilicity, impact expression of tumor-promoting genes within macrophages. We also characterized macrophage expression of pro- and antitumor genes, including CCL18, CXCL10, CXCL11, IL-10, IL-12b, VEGF, and identified expression profiles that are dependent on tumor and stromal cell populations in co-culture and diverge from classical M1/M2 characterization. Conclusions: The STACKS platform is capable of advanced modeling and analysis of the prostate cancer TME. Investigation of patient-derived monocytes within STACKS has identified physical properties of the TME that affect tumor-related functions of macrophages and has also demonstrated that an M1/M2 classification spectrum may not be sufficient for characterizing TAMs. These findings represent new therapeutic targets for prostate cancer treatment.
Evaluation of Oncotype DX testing and subsequent patterns of care in patients (pts) with early-stage breast cancer (ESBC).
Authors: Meghan Fitzgerald, Robert Hassell, Sally Haislip, James W. Gilmore, Steve Richardson, Joseph Cooper, Stephen Szabo, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2012)

569 Background: Cardinal Health Specialty Solutions (CHSS) partners with payers to manage clinical care pathways in oncology and rheumatology. Observations from one such pathway with CareFirst BlueCross BlueShield revealed that pts with estrogen receptor-positive ESBC who underwent Oncotype DX testing and were found to have high-risk Recurrence Scores (RS) received less chemotherapy than expected. To better understand physician behavior as it relates to Oncotype DX testing, CHSS examined patterns of Oncotype DX use in a large private practice oncology group with a robust electronic medical record (EMR), Georgia Cancer Specialists (GCS). We aimed to determine the RS risk distribution among pts who received Oncotype DX testing and assess the patterns of care that followed. Methods: Using GCS EMR data from 2009 to 2011, the number of pts who were eligible to undergo Oncotype DX testing was compared to the number of pts who underwent testing. Pts were considered eligible for testing if they had node-negative, estrogen receptor-positive, HER2-negative ESBC. We determined the number of pts with a RS value in the low- (RS &lt;18), intermediate- (RS 18-30), and high-risk (RS ≥31) groups along with the number of pts who subsequently received chemotherapy in each category. Results: Of the 1908 patients identified with ESBC, 788 were eligible for Oncotype DX testing and 288 (37%) underwent testing. Fifty percent of pts were in the low-, 34% in intermediate-, and 16% in the high-risk groups. Six percent of low-, 41% of intermediate-, and 83% of high-risk pts received chemotherapy. Seventeen percent of pts in the high-risk group did not receive chemotherapy. Conclusions: The use of chemotherapy in the low- and intermediate-risk groups was as expected based on adjuvant chemotherapy guidelines; however, an under utilization of chemotherapy was found in high-risk pts. There also appears to be a noteworthy underuse of Oncotype DX testing in eligible pts. Further data analysis is needed to understand the low use of Oncotype DX testing in eligible pts and to explain the lower than expected use of chemotherapy in high-risk pts.
Can index lesion tumor volume on T2 weighted MRI predict biochemical recurrence following radical prostatectomy?
Authors: Dordaneh Sugano, Abhinav Sidana, Brian P. Calio, Sonia Gaur, Mahir Maruf, Amit L Jain, Maria J Merino, Peter L. Choyke, Baris Turkbey, Bradford J. Wood, Peter A. Pinto
Journal: Journal of Clinical Oncology (2017)

32 Background: Several studies have demonstrated an association in prostate cancer patients between the tumor volume of the index lesion calculated from whole mount pathology after radical prostatectomy and biochemical recurrence (BCR). We aimed to evaluate whether the index lesion tumor volume (ILTV) measured on MRI would have similar predictive ability. Methods: Clinical and pathologic data from a prospectively maintained, single-institution database was analyzed for 501 patients who underwent RARP (without prior therapy) between 2007 and 2016. Patients were excluded if they were found to have metastatic disease on pathology or if postoperative PSA ≥ 0.2ng/ml after RARP. ILTV was calculated from T2W MRI by multiplying length by width by depth by 0.52. Tumor volume was stratified into two categories based on the cutoff of 2cm 3 . BCR was defined as 2 PSA values ≥ 0.2 ng/ml, 1 PSA value ≥ 0.4 ng/ml, or receipt of radiation therapy/hormonal therapy after RARP. Cox proportional hazard regression was used to assess associations of clinical, imaging, and histopathological variables with BCR. Results: The median age of our cohort was 60 years (IQR 10) and median PSA was 6.20 ng/ml (IQR 6). Of the 493 patients who met our inclusion criteria, 55 (11.2%) experienced BCR. Patients with ILTV &gt; 2cc had a higher incidence of BCR compared to those with ILTV &lt; 2cc (18.0% vs 8.8%, p = 0.008). On univariate analysis, age (HR 0.96, p = 0.026), PSA (HR 1.04, p &lt; 0.001), black race (HR 1.816, p = 0.047), Gleason 8-10 on biopsy (HR 3.725, p &lt; 0.001), and ILTV (HR 2.496, p = 0.002) were significant for prediction of BCR. Although age (HR 0.955, p = 0.021), PSA (HR 1.029, p = 0.013), and Gleason 8-10 on biopsy (HR3.367, p &lt; 0.001) were found to be independent predictors of BCR, tumor volume was not found to be an independent predictor (HR 0.960, p = 0.642). Conclusions: Although ILTV alone was predictive of BCR, ILTV was not found to be an independent predictor of BCR, indicating that at this time, MRI cannot yet measure ILTV with enough accuracy to predict oncologic outcomes. As imaging technology improves, ILVT may provide additional prognostic information.
Aromatase inhibitor pain syndromes: Classification and determination of specific risk factors—A prospective multicenter cohort study.
Authors: Paul H. Cottu, Francoise Laroche, Jean-Yves Pierga, J Coste, T Medkour, Jean-Pierre Lotz, Karine Beerblock, Christophe Tournigand, Laure Chauvenet, Xavier Decleves, D Boussahira, F Batteux, F Borderie, Serge Perrot
Journal: Journal of Clinical Oncology (2013)

569 Background: Pain is frequent during Aromatase Inhibitors (AIs) treatment for breast cancer and several pain syndromes have been reported but not precisely defined. We developed a prospective multicentre study aiming at classifying AIs-related pain syndromes, comparing their impact on daily life, and identifying their specific determinants for a more targeted prevention approach. Methods: A one-year multicenter cohort prospective study, with 5 pre-scheduled visits, was carried out in early stage breast cancer women, free of pain, starting an AI treatment, recruited from 4 oncology centres. At baseline, clinical data (demography and psychosocial, cancer characteristics and treatments, pain, sleep, rheumatologic examination, cancer-related quality of life), biological data (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunological and inflammatory markers), and genetic polymorphism for pain mechanisms (opioid and serotonin pathways) were recorded. Results: A cohort of 135 women was evaluated. Among them, 77 (57%) developed a pain syndrome along the study period, leading to AIs discontinuation in 12 cases. Five main different types of pain syndromes were identified: joint pain, in 48 women overall over the follow-up (36%), diffuse pain, in 30 women (22%), tendinitis, in 29 women (22%), and neuropathic pain, in 12 women (9%) and mixed types, which were frequent and often transient. Analyses demonstrated that risk factors for developing pain syndromes were baseline anxiety and impaired quality of life, while cancer features, genetic background, inflammation, immunological and sex hormone levels were not involved. Conclusions: In pain-free women with breast cancer starting an AI, risks for developing pain during the first year of treatment are slightly greater than 50%. We identified 5 main pain syndromes, joint and widespread pain being the most frequent. In all instances, initial psychological dimensions (personality, impaired quality of life and anxiety) are identified as major risk factors for pain development.
NSABP B-51/RTOG 1304: Randomized phase III clinical trial evaluating the role of postmastectomy chest wall and regional nodal XRT (CWRNRT) and post-lumpectomy RNRT in patients (pts) with documented positive axillary (Ax) nodes before neoadjuvant chemotherapy (NC) who convert to pathologically negative Ax nodes after NC.
Authors: Eleftherios P. Mamounas, Julia R. White, Hanna Bandos, Thomas B. Julian, Atif J. Kahn, Simona Flora Shaitelman, Mylin Ann Torres, Susan Ann McCloskey, Frank A. Vicini, Patricia A. Ganz, Soonmyung Paik, Nilendu Gupta, Joseph P. Costantino, Walter John Curran, Norman Wolmark
Journal: Journal of Clinical Oncology (2014)

TPS1141 Background: This phase III randomized post-NC trial will evaluate if CWRNRT after mastectomy (Mx) or whole breast irradiation (WBI) with RNRT after breast-conserving surgery (BCS) significantly reduces the rate of IBCR-FI in pts who present with histologically positive Ax nodes but become histologically negative Ax nodes →NC. Secondary aims are OS, LRR-FI, DRFI, DFS-DCIS, and second primary cancer. Correlative science will examine the effect of RT by tumor subtype, molecular predictors of outcome for pts with residual disease, and the development of predictors of degree of reduction in loco-regional recurrence. Methods: Eligible pts with clinical T1-3, N1 breast cancer with pathologic Ax nodes (positive FNA or core needle biopsy) must complete ≥12 wks of NC (anthracycline and/or taxane-based regimen). HER2-positive pts must receive neoadjuvant trastuzumab or other anti-HER2 therapy (tx). After NC either BCS or Mx will be performed. Ax nodes must be histologically cancer free on sentinel node biopsy with or without axillary dissection (AND) or AND alone. ER/PR and HER-2 neu status before NC is required. All pts will receive additional required systemic tx. Site radiation credentialing with a facility questionnaire and case benchmarking is required. Randomization for Mx pts will be to no CWRNRT or CWRNRT and for BCS pts to WBI or WBIRNRT. 1,636 pts will be enrolled over 5 yrs with definitive analysis at 7.5 yrs. The study is powered at 80% to test the main hypothesis that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-year cumulative rate of 4.6%. Analysis will be on intent-to-treat with 3 formal interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events. Current accrual is 10. 736 enrolled pts will be evaluated with targeted pt-reported outcome instruments focusing on the effect of RT. Pt assessments will be prior to randomization and then at 3, 6, 12, and 24 mos. Clinical trial information: NCT01872975.
Dnmt3a regulates T-cell development and suppresses T-ALL transformation
Authors: A C Kramer, A Kothari, W C Wilson, H Celik, J Nikitas, C Mallaney, E L Ostrander, E Eultgen, A Martens, M C Valentine, A L Young, T E Druley, M E Figueroa, B Zhang, G A Challen
Journal: Leukemia (2017)
Cardiotoxicity in Chinese cancer patients treated with 5-fluorouracil or capecitabine: A multicenter prospective observational study.
Authors: Gong Chen, Jianjun Peng, Chao Dong, Meng Qiu, Chang Wang, Hua wei Li, Hao Yu, Min Zhang, Qun Zhao, Bo Zhu, Jun Zhang, Wenliang Li, Fenghua Wang, Qiong Wu, Ying Yuan, Wen-hao Zhou
Journal: Journal of Clinical Oncology (2017)

553 Background: Although the cardiotoxicity associated with 5-Fluorouracil (5-FU) or capecitabine administration has been well addressed in literature, there is still a lack of data from prospective clinical trials in Chinese population. The aim of this study was to evaluate the incidence, manifestations and predisposing factors for the cardiotoxicity in Chinese cancer patients treated 5-FU or capecitabine. Methods: A multicenter prospective observational study was performed in 527 patients with various solid tumors from 12 cancer centers in china . Of these patients, 196 received 5-FU-based and 331 received oral capecitabine-based chemotherapy as either first-line or adjuvant therapy. Outcome measures including electrocardiogram(ECG), myocardial enzymes, cardiac troponin(cTn), BNP and echocardio- graphy(UCG) etc. Univariate analysis and the logistic regression were performed for subgroup analysis and identification of the significant independent variables that are associated with cardiotoxicity of both agents. Results: In total, 161 of 527 patients (30.55%) experienced cardiotoxicity. The incidence of cardiotoxicity was 33.84% (112 out of 331) in the capecitabine-treated population, significantly higher than 25 %( 49 out of 196) in the 5-FU treated population (P = 0.0042). 110 out of 527 patients (20.87%) suffered arrhythmia, 105/527 (19.92%) developed ischemic changes, while 20/527(3.80%) heart failure and 6/527 (1.14%) myocardial infarction only. Among the factors evaluated with univariate analysis and the logistic regression, a history of cardiac disease, chemotherapy agent, duration of treatment and hypertension were significant with cardiotoxicity occurrence. The odds ratio were 15.447(with a history of cardiac history vs without), 2.118 (Capecitabine group vs 5-FU group), 1.079(5-8 vs 1-4 cycles) and 1.698 (with hypertension vs without) respectively. Conclusions: Cardiotoxicity induced by fluoropyrimidines in Chinese population may be underestimated in clinical practice.Possible risk factors are duration of treatment, chemotherapy agents, preexisting cardiac disease and hypertension.
Randomized, phase III study of carboplatin plus paclitaxel for 8 cycles (CP8) versus carboplatin x 8 cycles plus paclitaxel x 4 cycles (C8P4) in advanced ovarian, fallopian, or primary peritoneal carcinoma.
Authors: Aristotelis Bamias, Eleni Timotheadou, Gerasimos Aravantinos, Dimitrios G. Pectasides, Christos A. Papadimitriou, George Klouvas, Ioannis Xanthakis, Anastasia G Eleftheraki, Nikolaos Soupos, Thomas Makatsoris, Alexandros Rodolakis, George Vlachos, George E. Pentheroudakis, Alexandros Papanikolaou, Marinos Tsiatas, Aris Antsaklis, George Fountzilas, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2012)

5033 Background: The combination of carboplatin/paclitaxel represents the standard 1st-line chemotherapy in advanced OC, FC, and PPC. The optimal duration of paclitaxel treatment has not been defined, while its use is associated with cumulative neurotoxicity in about 50% of patients, which becomes long-term in 15-20% of cases. We, therefore, designed a randomized study to investigate the effect of administering 4 instead of 8 cycles of paclitaxel in the combination carboplatin/paclitaxel on efficacy and tolerability of this treatment. Methods: Patients with FIGO stages IIC-IV OC, FC, PPC were included. Carboplatin AUC 6 and paclitaxel at 175 mg/m 2 were used. Both agents were administered for 8 cycles in the CP8 arm, while paclitaxel was administered only for 4 cycles in the C8P4. The study was powered to detect a ± 15% difference in survival rate to a baseline rate of 50 % at the 3-year time point. Results: 389 pts were randomized (2/2004-1/2008) and 380 were eligible for analysis (CP8: 192, C8P4:188). The distribution (CP8 vs C8P4) of baseline characteristics were: stage III: 78% vs. 76%; IV: 12% vs. 15%, residual disease 0 cm: 25% vs. 22%, ECOG PS 0: 68% vs. 64%, serous carcinomas: 79% vs. 68%, tumor grade III: 56% vs. 63%. During a median follow up of 72.3 months 231 patients (111 [58%] in CP8 arm and 120 [64%] in the C8P4 arm) have died. Median PFS was significantly shorter in the C8P4 arm (21.41 vs. 16.46 months, HR [95% CI]: 1.36 [1.07-1.71], Wald’s p=0.011), while OS was similar between the two arms (53.41 vs. 46.59 months, HR [95% CI]: 1.18 [0.91-1.53], Wald’s p=0.211). Lower grade 3 or 4 neurotoxicity (1.9% vs. 10.8%, p&lt; 0.001) but higher myelotoxicity (neutropenia 38.8% vs. 28.8%, p=0.031; thrombocytopenia 20% vs. 8.3%, p=0.004) was observed in the C8P4 arm. Conclusions: Lowering the total number of cycles of paclitaxel in 1st-line chemotherapy of advanced OC, FC, PPC resulted in similar OS but shorter median PFS and is not recommended in this setting. The reduction of neurotoxicity by limiting the total paclitaxel cycles to 4 is achieved at the expense of higher myelotoxicity.
Impact of prior docetaxel (D) on sipuleucel-T (sip-T) product parameters in PROCEED patients (pts).
Authors: Celestia S. Higano, Andrew J. Armstrong, Matthew R. Cooperberg, Philip W. Kantoff, James Bailen, Raoul S. Concepcion, Vahan Kassabian, Shaker R. Dakhil, Steven E. Finkelstein, Jeffrey L. Vacirca, Robert M. Rifkin, Andrew Sandler, Candice McCoy, James Boyd Whitmore, Robert Claude Tyler, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2013)

5034 Background: Sip-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The IMPACT trial excluded pts who received D ≤3 months prior to registration. PROCEED is an ongoing, phase IV registry, enrolling pts treated with commercial sip-T. Use of D prior to sip-T is not restricted, so prior D affect on sip-T immune manufacturing parameters can be evaluated. Methods: Pts treated with sip-T ≤ 6 mo were eligible to provide informed consent. Sip-T parameters assessed included: total nucleated cell (TNC) count, antigen presenting cell (APC) count (CD54 + large cells) and APC activation (upregulation of CD54). Results: By Nov. 2012, 108/761 (14%) received D prior to sip-T and had similar median cumulative APC counts (1.83 [Q1, Q3: 1.16, 2.71] vs. 1.82 [1.27, 2.70] x 10 9 ) and TNC counts (10.16 [7.30, 13.69] vs. 11.47 [8.56, 15.31] x 10 9 ) vs. D naïve, whereas median cumulative APC activation appeared slightly lower (32.39 [25.05, 41.02] vs. 34.84 [28.71, 42.83]), but was well above the release criterion for each infusion (2.6 fold). The group was then split by Eastern Cooperative Oncology Group Performance Status (ECOG PS) and Gleason scores (Table). Conclusions: Pts with D prior to sip-T appeared to have product parameters comparable to pts without prior D, albeit with a slightly lower APC activation. Further analysis showed that pts receiving D within 3 months of sip-T had higher Gleason and ECOG scores. The clinical significance of these findings is unclear, but suggests that APC activation is not impaired following docetaxel. Clinical trial information: NCT01306890. [Table: see text]
Risk factors for extended-spectrum β-lactamase-producing Escherichia coli urinary tract infection in the community in Denmark: a case–control study
Authors: M. Søgaard, U. Heide-Jørgensen, J.P. Vandenbroucke, H.C. Schønheyder, C.M.J.E. Vandenbroucke-Grauls
Journal: Clinical Microbiology and Infection (2017)
Orally administered CCR2 selective inhibitor CCX872-b clinical trial in pancreatic cancer.
Authors: Marcus Smith Noel, Aram F. Hezel, David Linehan, Andrea Wang-Gillam, Ferry Eskens, Stefan Sleijfer, Ingrid Desar, Frans Erdkamp, Johanna Wilmink, Janet Diehl, Antonia Potarca, Niky Zhao, Jun Deng, Lisa Lohr, Shichang Miao, Israel Charo, Rajinder Singh, Thomas J. Schall, Pirow Bekker
Journal: Journal of Clinical Oncology (2017)

276 Background: CCR2 inhibition decreases tumor-associated macrophages and Treg cells, and increases CD8+ and CD4+ T cells in pancreatic tumors. Single oral doses of 150 mg CCX872-B were well tolerated in patients with pancreatic cancer. The first stage results of the multiple dose part of this study are presented. Methods: Patients with locally advanced or metastatic pancreatic cancer, ECOG score ≤ 2 were studied. Patients received FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) q2weeks for up to 24 wks plus 150 mg CCX872-B once or twice daily until disease progression or intolerance to CCX872-B. The primary efficacy endpoint is progression-free survival (PFS) at 24 wks. Tumor control rate (TCR) and the objective response rate (ORR), a secondary endpoint, are presented. Results: Fifty patients were enrolled. Baseline: Mean ± SD age: 60 ± 8.6 years, male 52%; primary tumor location: head 57%, body/tail 41%, local recurrence 2%; metastatic disease 78%, ECOG score 0: 62%, ECOG score 1: 38%. Thirty five of 50 patients completed week 12. Most common reasons for early withdrawal were subject request (5 pts) and adverse events typically associated with FOLFIRINOX (4 pts). In the pre-specified analysis population, i.e., those with ≥ 1 post baseline CT scan, tumor control at wk 12 was achieved in 32 of 41 (78%) patients, with 15 of 41 (37%) partial responders, and 17 of 41 (41%) with stable disease. The ORR was 37% (all partial responders) in the primary analysis population (30% when all enrolled patients were included). Thirteen of 21 patients with available CT scan results at week 24 were progression-free. Mean trough CCX872 plasma level was ~8 μg/mL. CCR2 was covered 88% on average by CCX872-B based on receptor occupancy assays. CCX872-B appeared to be well tolerated and the incidence of ≥ Gr 3 AEs was not increased with CCX872-B plus FOLFIRINOX vs historical data with FOLFIRINOX alone. The complete set of PFS data will be available by the end of 2016. Conclusions: CCX872-B plus FOLFIRINOX resulted in a TCR of 78% and an ORR of 30 to 37% with no safety issues ascribed to CCX872-B use. Clinical trial information: NCT02345408.