tbuckley/cabot-search huggingface dataset:
Development of a statin risk communication tool for use in cancer survivors: A pilot.
Authors: Nirupa Jaya Raghunathan, Deborah Korenstein, Nassim Anderson, Roberto Adsuar, Emily S. Tonorezos, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2017)

87 Background: There are currently over a million survivors of childhood, adolescent, and young adult (CAYA) cancer in the US, many of whom were treated with radiation therapy. Chest radiation with fields including the coronary arteries is a risk factor for cardiovascular disease (CVD). Of note, survivors are often unaware of this increased CVD risk or, if they are aware, do not know how to mitigate the risk. Visual aids and communicating risk in terms of absolute risk reductions are shown to improve patients’ understanding. The Institute of Medicine recommends use of decision aids to optimize patient discussions of benefits and harms of therapies. Our goal is to develop and pilot test a statin therapy risk communication tool for use in high-risk cancer survivors to improve shared decision making and patient knowledge of coronary artery disease risk. Methods: The Statin Risk Communication Tool, modeled after the validated Statin Choice decision aid, presents a pictorial representation of absolute risk of coronary heart disease risk in survivors of CAYA cancer treated with radiation to the chest. The intervention also presents data depicting absolute risk reduction of myocardial infarction with use of statins in similar risk populations (≥7.5% baseline risk). This pilot study compares the statin risk communication tool to usual care. The post-visit assessment uses Likert-like scales to explore patient perceptions of statin use, knowledge questions to assess patient understanding of the risks and benefits of using statins and the validated 16-item Decisional Conflict Scale to measure decisional satisfaction. We will also survey participants three months after introduction of the tool to ascertain statin use and attitudes towards the discussion of statins. Results: The timeline for data collection anticipates analyzable results by August 2017. Conclusions: This risk communication tool will be assessed for acceptability, knowledge enhancement, and decisional conflict. Additionally, we will gather qualitative data regarding usual care. With this information, a future randomized controlled trial across institutions could provide information on how CAYA survivors approach shared decision making with risk communication tools. Clinical trial information: NCT02895880.
Characterization of circulating tumor cells in patients with localized high risk prostate cancer, post-prostatectomy.
Authors: Terence W. Friedlander, Archana Anantharaman, Christopher Welty, Kreshnik Zejnullahu, Jeffrey Hough, Matthew Edwards, Adam Jendrisak, Jerry Lee, Stephanie Greene, Priscilla Ontiveros, Ryon Graf, Angel Rodriguez, Mahipal Suraneni, Yipeng Wang, Mark Andrew Landers, Matthew R. Cooperberg, Peter Carroll, Ryan Vance Dittamore, Pamela Paris
Journal: Journal of Clinical Oncology (2017)

110 Background: Approximately 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features, many of these patients will recur despite definitive therapy. Better predictive biomarkers could allow for earlier detection of recurrence and change surveillance paradigms. The role of circulating tumor cells (CTCs) as biomarkers in this context is not well defined. Here, we evaluate the ability to detect CTCs from men with high risk, localized PCa after radical prostatectomy (RP) and correlate their presence with prospective clinical data. Methods: Blood samples from 31 patients with high risk, localized PCa were obtained 2-4 months post RP and sent to Epic Sciences on an IRB approved protocol. Nucleated cells were subjected to immunofluorescent (IF) staining for cytokeratin (CK), CD45, and AR N-terminus. CTCs were identified by fluorescent scanners using algorithmic analysis. Cytokeratin expressing (CK + ) CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number variation (CNV) and large scale transitions (LST, a surrogate of genomic instability). Patients were followed prospectively for biochemical recurrence, defined as detectable PSA. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 87.1% (27/31) samples with an average of 5.6 CTCs/ml (range: 0 – 22.87) detected per patient. AR expression was detected in 12.9% (4/31) of patients. Ninety-nine CTCs from 14 patients were amenable to LST and CNV analyses. 10.1% (10/99) CTCs from 7 patients exhibited higher ( &gt; = 6) LSTs than control WBCs (95% WBCs had LST &lt; 6). Copy number alterations were detected in CTCs in commonly mutated genes in PCa, including AR, MYC, and TP53 amplification and deletions in PTEN and RB1. Patients with higher CTC burdens exhibited a trend toward shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p: 0.13). Conclusions: There was a high incidence of CTC detection after RP in this population using a novel platform. We observed a trend toward shorter PFS in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa.
First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors
Authors: Mark N. Stein, Joseph R. Bertino, Howard L. Kaufman, Tina Mayer, Rebecca Moss, Ann Silk, Nancy Chan, Jyoti Malhotra, Lorna Rodriguez, Joseph Aisner, Robert D. Aiken, Bruce G. Haffty, Robert S. DiPaola, Tracie Saunders, Andrew Zloza, Sherri Damare, Yasmeen Beckett, Bangning Yu, Saltanat Najmi, Christian Gabel, Siobhan Dickerson, Ling Zheng, Wafik S. El-Deiry, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Janice M. Mehnert
Journal: Clinical Cancer Research (2017)

Purpose: ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D).Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163-9. ©2017 AACR.
A new 5-gene signature predictive of risk of relapse in early breast cancer.
Authors: Giorgio Mustacchi, Luca Morandi, Mariapia Sormani, Alessandra Gennari, Fabrizio Zanconati, Daniela Bonifacio, Adriana Monzoni, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2013)

546 Background: The aim of this study was look for the "core-genes" of published Signatures in order to find a simpler one Methods: To select candidate genes we used data of NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) including 408 breast cancer cases. Raw intensity data of Affymetrix HU133A and HU133B arrays of the two datasets (GSE1456 and GSE3494) were preprocessed using R/Bioconductor and the supercomputer Michelangelo ( www.litbio.org ). The candidate genes were selected from the “70-gene signature” (van 't Veer, Nature 2002), the “21-gene recurrence score” (Paik, NEJM 2004), the “two-gene–ratio model” (Ma, Cancer Cell 2004) and the “15-gene Insuline Resistence” signature (Gennari , JCO, Vol 25, No 18S, 2007: 10597), for a total of 98 genes.The 20 mRNA more significantly related to DFS were evaluated by quantitative reverse transcriptase PCR on 261 consecutive breast cancer cases, from paraffin embedded sections, split into a training (n 137) and a validation set (n 124). Results: The signature was developed on the training set and a multivariate stepwise Cox analysis selected 5 genes independently associated with DFS: FGF18 (HR=1.13, p=0.05) , BCL2 (HR=0.57, p=0.001), PRC1 (HR=1.51, p=0.001), MMP9 (HR=1.11, p=0.08), SERF1a (HR=0.83, p=0.007). These 5 genes were combined into a linear score weighted according to the coefficients of the Cox model, (0.125 FGF18 - 0.560 BCL2 + 0.409 PRC1 + 0.104 MMP9 - 0.188 SERF1A). The linear score was highly associated with DFS (HR=2.7, 95%CI=1.9-4.0, p&lt;0.001). The signature was then evaluated on the validation set assessing the discrimination ability by a Kaplan Meier analysis, using the same cut offs classifying patients at low, medium or high risk of relapse as defined on the training set. The score resulted highly associated with DFS also in the validation set (p&lt;0.001). Conclusions: Overexpression of BCL2 and SERF1A are related to a higher probability of relapse; overexpression of FGF18, PRC1 and MMP9 to a higher probability of survival without recurrence. The signature has a good discriminating ability and a further clinical validation is planned.
Antisense oligonucleotide targeted to the transferrin receptor gene suppresses tumor growth and lung metastases in 4T1 mammary adenocarcinoma mouse model
Authors: X. Jiang, A. Israyeeyan, E. Boykin, L. Lomax, J. F. Head, R. L. Elliott
Journal: Journal of Clinical Oncology (2006)

10616 Iron is required for the activity of ribonucleotide reductase and synthesis of DNA. Cellular surface transferrin receptors (TfR) are the principal transport protein for iron into cells. It has been reported that inhibition of TfR gene expression leads to the suppression of tumor cell growth in cell culture. In the present study, an antisense oligonucleotide targeted to the transferrin receptor gene was used to treat 4T1 mammary adenocarinoma in cell culture and a mouse model. The cytotoxicity of a 24-mer TfR antisense oligonucleotide was determined by 3 [H]-thymidine incorporation in vitro. The sense and random sequence 24-mer oligonucleotides were used as controls. We found that TfR antisense inhibited mRNA expression of TfR and cell growth of the 4T1 cells in the dose-dependent manner. Mice bearing the 4T1 mammary adenocarcinoma were continuously treated for 14 days through subcutaneous implantation of Alzet osmotic mini-pumps. Tumor sizes were measured twice a week. Tumor necrosis and metastases were determined grossly at autopsy and by microscopy. Tumor metastases to lungs (all lung lobes) was scored by the following criteria: 0 = no metastasis, 1 = 1–2 foci/slide, 2 = 3–10 foci/slide, 3 = 11–20 foci/slide and 4 = &gt;20 foci/slide. At 4, 7 and 10 days post-treatment, tumor sizes of the TfR antisense-treated group were significant smaller than control mice (p &lt; 0.05, p &lt; 0.05 and p &lt; 0.05, respectively). At 14 days post-treatment, autopsy showed that 91.7% (11/12) of control mice had multiple metastatic foci on their lung surfaces, but only 16.7% (2/12) of TfR antisense-treated mice had metastatic tumor foci on their lung surfaces (p &lt; 0.001). Primary tumor did not have significant necrosis in either group. Mean lung metastasis scores of 3.25 ± 1.06 in control group vs. 1.75 ± 1.49 in TfR antisense-treated group (p &lt; 0.01) were determined by microscopy. In summary, TfR antisense inhibited cell growth in cell culture and primary tumor growth in mice, and reduced lung metastasis of the 4T1 mouse mammary adenocarcinoma. No significant financial relationships to disclose.
p53 phosphorylation in benzo(a)pyrene-induced cell death in MCF-7 cells
Authors: Marjo Tampio, Jarkko Loikkanen, Kirsi Vahakangas
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4263 

Carcinogenic benzo(a)pyrene (BP), after activation to BP-diolepoxide, forms DNA adducts. This is associated with a p53 response in human cells in vitro and mouse tissues in vivo. Activation of p53 through phosphorylation has a pivotal role for its cellular functions. BP has been shown to induce ser15 phosphorylation and induction of apoptosis in murine cells. BP-induced p53 phosphorylation and p53 dependent cell death have been studied largely in animal cell lines (murine, rat). MCF-7 and A549 cells of human origin harbour wild type p53 protein enabling studies on the role of wt p53 in BP-exposed human cells. We studied whether and in what positions p53 in these cells is phosphorylated by BP-induced DNA-damage. A549 lung carcinoma and MCF-7 breast adenocarcinoma cells were treated with different concentrations of BP (1, 5, 10, 20 and 40 μM) for 24, 48 and 72 hours. BP was activated to BP-diolepoxide DNA-adducts in both cell lines, as studied by synchronous fluorescence spectrophotometry. In accordance with our earlier studies, the number of adducts was about ten times higher in MCF-7 cells. Cell death was clearly induced in MCF-7 cells while A549 cells were very resistant to the effects of BP. In MCF-7 viability decreased the most with 5 µM BP and seemingly increased towards higher concentrations of BP (10, 20 and 40 µM) at 48 and 72 hours. However, the relative cell number also decreased with higher BP concentrations already at 24 h. In A549 cells BP did not affect cell viability or relative cell number. Anti-phospho-p53 antibodies against p53 protein phosphorylated at serines 6, 9, 15, 20, 37, 46 and 392, and immunoblotting were used to analyze p53 phosphorylation. While no phosphorylation of p53 in A549 cells could be detected, in MCF-7 cells several sites of p53 protein were phosphorylated after BP induced DNA-damage. Ser392 phosphorylation was clear already at 24 hours in association with an increase in p53 protein, while ser15 and ser20 phosphorylations appeared later. In conclusion, in human cells p53 phosphorylation at ser392, rather than at ser15, seems to be related to p53 response after BP diolepoxide-DNA-damage.
Impact of pretreatment thrombocytosis on blood-borne metastasis and prognosis of primary gastric cancer.
Authors: Kyung Min Kim, Jae-Ho Cheong, Seong-Geun Hwang, Yu Min Kim, Hyoung-Il Kim, Ji Yeong Ahn, Woo Jin Hyung, Sung Hoon Noh
Journal: Journal of Clinical Oncology (2012)

e14504 Background: Thrombocytosis has been associated with malignancies and poor prognostic implications in cancer patients. In the present study the prognostic significance of pretreatment platelet (PLT) level was assessed with regard to recurrence and survival in patients with primary gastric adenocarcinoma. Methods: The authors reviewed the prospective data of 1,593 gastric cancer patients who received curative gastrectomy with extended lymphadenectomy. The correlations of PLT level with recurrence and overall survival were evaluated by both univariate and multivariate analyses. Results: Thrombocytosis (≥ 40 x 10 4 /μL) was present in 6.4% of the patients prior to curative surgery. Thrombocytosis was more frequently associated with advanced T and N stage, larger tumor size, anemia, and old age (p&lt;0.05). The 5-year survival rate of patients with thrombocytosis was significantly worse than that of patients without thrombocytosis (56.9% vs. 65.5%; p=0.043). The recurrence rate was higher, mainly attributed to the frequent hematogenous spread, in patients with thrombocytosis than in those without thrombocytosis (51.0% vs. 34.5%; p&lt;0.001). Furthermore, thrombocytosis was an independent risk factor of recurrence (Odds ratio 1.649 [95% CI 1.074 – 2.531], p=0.022), along with serosa invasion and nodal metastasis. Conclusions: Pretreatment thrombocytosis correlated significantly with poor prognosis and can be used as an independent predictor of recurrence by blood-borne metastasis in gastric cancer.
A population-based analysis of urban-rural disparities in advanced pancreatic cancer (APC) management and outcomes.
Authors: Thomas Canale, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2017)

254 Background: Given the significant morbidity burden associated with APC, its management is complex and frequently requires multidisciplinary care. Because of potential geographical barriers to healthcare access, we aimed to determine the effect of rurality on management and outcomes of APC patients. Methods: Patients diagnosed with APC (locally advanced or metastatic disease) from 2008 to 2015 and received gemcitabine (gem), gem plus nab-paclitaxel (gem/nab), or FOLFIRINOX at any 1 of 6 British Columbia cancer centers across the province were reviewed. Using postal codes, the Google Maps Distance Matrix determined the distance from each patient’s residence to the closest cancer center. Rural and urban status were defined as patients living &gt;= 100 km and &lt; 100 km from the closest treatment site, respectively. Univariate and Cox regression analyses were applied to examine whether rurality resulted in variations in management and outcomes. Results: In total, we identified 667 patients: median age 68 years, 54.3% men, and 45.7% metastatic disease. Among them, 19.5% lived rurally and 80.5% resided in urban areas. For treatment, 67.8%, 9.4%, and 22.8% received gem, gem/nab, and FOLFIRINOX, respectively. However, there were no differences in baseline clinical characteristics between rural and urban patients (all p &gt; 0.05). Also, there were no significant variations in treatment patterns. For example, time from diagnosis to oncology appointment and time from appointment to treatment were 31.6 and 29.5 days for rural patients and 28.7 and 39.9 days for urban patients, respectively (all p &gt; 0.05). Use of gem/nab (9.8 vs 9.4%) and FOLFIRINOX (20.5 vs 23.3%) were similar regardless of rurality. In multivariate Cox regression, risk of death was similar between rural and urban groups (HR 1.34, 95% CI 0.95-1.87, p = 0.09). Conclusions: Our findings suggest that there is no correlation between rurality and outcomes in APC. The strategic and geographic allocation of cancer care delivery across the province of British Columbia may serve as a model for other jurisdictions that experience disparities in the outcomes of cancers that often require complex multidisciplinary care.
Final results of the AIO 0307 study: A controlled, randomized, double-blind phase II study of FOLFOX6 or FOLFIRI combined with sorafenib (S) versus placebo (P) in second-line metastatic colorectal carcinoma (mCRC) treatment.
Authors: Thomas Hoehler, Thomas Decker, Christoph Schimanski, Stephan H. Schmitz, Stephan Kanzler, Jacqueline Rauh, Ursula Vehling-Kaiser, Helga Bernhard, Thomas Hoffmann, Norbert Niederle, Ulla Von Verschuer, Goetz von Wichert, Thomas Wagner
Journal: Journal of Clinical Oncology (2013)

3586 Background: The oral multikinase inhibitor Sorafenib (S) inhibits angiogenesis and tumor growth in preclinical models of CRC. This study investigated the addition of S to standard 2 nd line chemotherapy (CTX). Methods: Patients (pts) with mCRC and progression after first-line therapy with an oxaliplatin- or irinotecan based fluoropyrimidine containing regimen ± Bevacizumab (Bev), were randomized to receive chemotherapy (CTX) (FOLFOX6 or FOLFIRI) + S (400 mg bid) or CTX + placebo (P). 240 pts were planned to be enrolled to ensure a power of 80% if median progression-free survival (PFS) with S is increased by 2 months compared to P. Results: Between 04/09 and 10/11, 101 pts were enrolled. Recruitment was stopped prematurely due to slow accrual. 97 pts were evaluable in the full analysis set. Median age was 65 years, 60 pts were male, 97% with ECOG 0 or 1. Median PFS was 5.2 months (mths) in S and 5.6 mths in P (HR 0.84, 90% CI 0.58, 1.22, p=0.439). Best response rate was 25.6% and 12.2% (p=0.106), respectively. Disease control rates were comparable. Median overall survival (OS) was 9.6 mths with S compared to 12.7 mths with P (HR 1.57, 90% CI 1.03, 2.41, p = 0.076). Difference in OS was even more pronounced in subgroup (n=41) with FOLFOX6 backbone (9.6 vs. 13.8 mths, HR 2.37, 90% CI 1.22, 4.60, p=0.026). In 69 Bev-pretreated pts OS was 8.4 vs. 14.9 mths (HR 2.30; 90% CI 1.36, 3.88, p=0.007) compared to 13.1 vs. 7.4 mths (HR=0.61; 90% CI 0.28, 1.36, p=0.308) in 28 pts without Bev pretreatment. Adverse events (AEs) were consistent with the known safety profiles. Most frequent grade 3/4 AEs affected the gastrointestinal tract (diarrhea, mucositis/stomatitis, nausea); other frequent severe AEs included neutropenia and leukopenia, fatigue, fever, sensory neuropathy, and thrombosis. Conclusions: No unexpected safety concerns occurred during the course of the study. S did not lead to improved PFS. There was a detrimental effect of S on OS in patients with Bev pretreatment. Clinical trial information: 2008-000803-26.
Overall survival (OS) prognostic factors in metastatic castrate-resistant prostate cancer (mCRPC) patients retreated with docetaxel (D).
Authors: Shilpa Rashmikant Shah, Costantine Albany, Noah M. Hahn
Journal: Journal of Clinical Oncology (2012)

e15213 Background: Until recently, few post-D treatment options existed for mCRPC patients (pts). In pts taken off of first-line D for reasons other than progressive disease (PD), retreatment with D at the time of PD was a commonly used strategy. While several prognostic nomograms have been developed for mCRPC patients, none have exclusively examined prognostic factors in D retreated patients. In the present study, we aimed to characterize baseline clinical factors associated with OS outcomes in D retreated mCRPC pts. Methods: Between 1/2007 and 10/2010, all mCRPC pts seen in the Indiana University Simon Cancer Center oncology clinics were approached for recruitment to the IRB approved biorepository protocol. Participants completed a demographic and clinical questionnaire and provided a blood sample. Only mCRPC pts retreated with D with confirmed dates for D first-line completion, D retreatment, and OS were included in this analysis. At D retreatment, patient age, Gleason Grade (GG), presence of pain, time to progression after first-line D therapy, visceral metastases, ECOG performance status, PSA, and PSA doubling time (PSAdt) were examined by Cox proportional hazards model for significant associations (p &lt; 0.05) with OS outcomes. Results: 30 mCRPC pts retreated with D were identified. Complete data were available on 22 pts which formed the analysis cohort. Demographics included: mean age – 69.1 yrs, Caucasian/African-American – 21/1, median GG 8, 55% pain present at baseline, median time from first-line D – 8.6 mo., 30% visceral mets, ECOG 0/1/2 – 3/17/2, mean baseline PSA – 536 ng/ml, mean baseline PSAdt – 2.7 mo. By Cox proportional hazards model, baseline PSA (p = 0.006) was significantly associated with D-retreatment OS with a trend toward significance in patients with pain at baseline (p = 0.059). No other significant associations were identified. Conclusions: Baseline PSA levels were significantly associated with OS outcomes in mCRPC pts retreated with D. Validation and examination of additional clinical variables is warranted in larger datasets.