tbuckley/cabot-search huggingface dataset:
Two-fraction carbon ion radiotherapy for hepatocellular carcinoma
Authors: H. Kato, S. Yasuda, S. Yamada, R. Hara, M. Kano, T. Kamada, J. Mizoe, H. Tsujii
Journal: Journal of Clinical Oncology (2007)

15134 Background: In Japan, most patients with Hepatocellular Carcinoma (HCC) have liver cirrhosis, an advanced hepatic disorder, and they often require repeated therapies owing to the multicentric nature of carcinogenesis in the cirrhotic liver. Therefore, both radical effect and minimal invasiveness are essential for the treatment of HCC. However, there were no therapies satisfying both of these essential requirements for every-sized HCC. The purpose of this trial was to evaluate the safety and efficacy of two-fraction carbon ion radiotherapy (CIRT) for HCC. Methods: Eligibility criteria for this study were as follows: biopsy-proven HCC; recurrent or residual tumor after other ineffective treatments or no indication for any other treatment; no prior radiotherapy for target tumors; hepatic disorder of Child-Pugh grade A or B; Karnofsky performance status of 60–100; no other active cancer; and digestive tract not in contact with clinical target volume. CIRT was administered within dose escalation study of 32.0 to 38.8 cobalt gray equivalent (GyE) in 2 fractions for 2 days. Results: Between April 2004 and August 2006, 40 patients were totally enrolled. All patients had chronic liver diseases of Child-Pugh grade A in 37, B in 3. The median tumor size was 4.7 cm in diameter (2.0 to 6.7 cm). During a median follow-up of 32 months (range, 5–45 months), no hepatic failure resulting from the therapy and no treatment-related death occurred. Incidence of grade 3 early hepatic toxicity according to NCI-CTC ver.2 in the essential valuables concerning hepatic function was 0% in serum-GPT, ALB, prothrombin activity (PT%) and ALP, and 3% in T.BIL. No grade 4 toxicity has occurred. In 94% and 86% out of the patients, Child-Pugh score did not increase by more than 1 point in the early and late phases, respectively. In the lower-dose group (32.0, 33.6, 35.2 GyE: n=18), 2-year local control rate and overall survival rate were 71% and 83%, respectively. In the higher-dose group (37.0, 38.8 GyE: n=22), they were 100% and 90%, respectively. Conclusions: Although 2-fraction carbon ion radiotherapy seems to be safe and effective, and to have a promising potential as a new, radical, and minimally invasive therapeutic option for Hepatocellular Carcinoma, further careful follow-up is needed to confirm it’s clinical efficacy. No significant financial relationships to disclose.
Endometrial stromal sarcomas: A retrospective analysis of 28 patients, single center experience for 20 years
Authors: J. Kim, E. Nam, Y. Kim, J. Kim, S. Kim, S. Kim, B. Yoon
Journal: Journal of Clinical Oncology (2007)

16053 Background: Little is known about the pathogenesis, risk factors, optimal therapy or outcomes of endometrial stromal sarcoma (ESS). The aim of this study is to evaluate the behavior of ESS in relation to its clinical and pathogenic features and to find the better treatment strategy. Methods: A retrospective analysis was performed of 28 patients with histologically proven ESS treated at our institution between 1987 and 2006. Results: The median follow-up time was 54.7±63.1 months and 5-year survival rate was 82.0%. 16 (57.1%) patients were referred to our institution from private clinics for further treatment of the ESS. They were previously undergone either hysterectomy, myomectomy, or hysteroscopy for presumed benign gynecological conditions. 22 patients (81.5%) showed low grade and 5 patients (18.5%) showed high grade disease. A univariate analysis revealed that histologic grade according to mitotic count is associated with longer survival (p=0.004). However, among those with low grade tumor, 5/20 patients (25%) had recurrence and 2/21 (9.5%) had distant metastasis during the follow-up period. Except for 2 cases, 26 patients with ESS had hysterectomy for their primary treatment. Adjuvant treatment after surgery was performed in 14/26 cases (53.8%). Hormone therapy by progesterone, chemotherapy and/or radiotherapy individually did not influence the overall survival of the patients. However, postoperative adjuvant therapy group regardless of the treatment modality was associated with relatively increased overall survival when compared to the surgery only group (p=0.054). Conclusions: Differential diagnosis of ESS from other benign gynecologic diseases before surgery is a difficult problem. Furthermore, it is advised that postoperative adjuvant therapy should be performed after hysterectomy to prevent recurrence or distant metastasis. No significant financial relationships to disclose.
Topoisomerase-2alpha (T-2a), Ki67, Her-2 and response to neoadjuvant anthracycline-containing chemotherapy in breast cancer. A prospective, correlation study
Authors: M. Bari, D. Sartori, P. Zambenedetti, G. Tacchetti, U. Sicari, F. Rosetti, A. Iop, G. L. Pappagallo, O. Vinante
Journal: Journal of Clinical Oncology (2007)

21094 Background: T-2a creates a reversible double-strand DNA break allowing DNA doubling. Anthracyclines (A) stabilize the DNA double-strand breaks, and T-2a is probably the primary molecular target of A. Due to the close location of T-2a and Her-2 genes on chromosome 17, T-2a gene aberrations are mainly associated with Her-2 gene amplification; while a correlation exists between Her-2 amplification and protein overexpression this is not true for T-2a. A linear correlation between T-2a and Ki67 labeling indices was found, suggesting that both essentially reflect cellular proliferation. The correlation between T-2a overexpression and both Her-2 and Ki67 was investigated in a series of consecutive patients undergone neoadjuvant A-containing chemotherapy for locally-advanced breast cancer. Material and Methods: T-2a expression was measured by means of monoclonal antibody Ki-S1; thresholds (ts) for immunopositivity were tested at 10%, 15% and 20%, respectively. Both the anti-c-erb-B2 primary antibody (clone CB11) and the Dako test were employed to recognize c-erb-B2 protein. Ki67 was measured using the MIB-1 antibody, with ts for positivity at 10%. Patients were required to have a cT&gt;2cm breast cancer. The neoadjuvant chemotherapy included Adriamycin 60mg/m2 or Epirubicin 75mg/m2, in combination with Paclitaxel (175 mg/m2), every 3 weeks for 4 cycles. Bivariate correlations were performed according to Pearson. Results: 38 patients were enrolled until August, 2006. A significant correlation between T-2a and Ki67 was found (r=.598; P&lt;.000); the T-2a positivity rate within Ki67 positive patients was of 90% (10% ts), 86% (15% ts), and 67% (20% ts). No correlation appeared between T-2a and Her-2 labeling indices (r=.150; P=.391); the T-2a positivity rate within Dako +++ patients was 75% (for both 10% and 15% ts) and 50% (for 20% ts). The overall response rate by T-2a overexpression was 61% (10% ts), 70% (15% ts), and 72% (20% ts). Conclusions: We provide a further evidence of the correlation between T-2a and Ki67. We can also generate the hypothesis that a 20% ts for T-2a correlate with a better prediction of response to A-containing chemotherapy; at the same ts, no correlation with Her-2 status was found. No significant financial relationships to disclose.
Abstract ES12-2: Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer
Authors: T Helleday
Journal: Cancer Research (2020)

Abstract DNA damaging agents, i.e., radio- and chemotherapy, constitute the backbone for treatment of a wide variety of cancers and may result in complete cure from the disease. Our strategy is to exploit endogenous DNA damage caused by cancer vulnerabilities, by DNA repair inhibitors using a synthetic lethal strategy. Our early work on PARP inhibitors in BRCA mutated cancers is establishing in breast cancer and here I will describe novel DNA repair targets and how these can be integrated into treatment of breast cancer. Here, I will also describe a novel link between PARP and hormone dependent cancers. Interestingly, we show that the PARP related protein NUDT5 activity is critical to elicit nuclear ATP production following hormone stimulation and a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. The NUDT5 protein is critical for 3D organoid growth of breast cancer cells. Here, we confirm the involvement of NUDT5 in ADP-ribose metabolism and identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can effectively block growth of 3D breast cancer organoids. Citation Format: T Helleday. Targeted DNA repair in cancer and new NUDT5 inhibitors to block hormone signalling to target breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES12-2.
Abstract P107: Serum Urate Trajectories in Young Adulthood and Incident Cardiovascular Disease Events By Middle Age; The Coronary Artery Risk Development in Young Adults (cardia) Study
Authors: Nagisa Morikawa, Michael P. Bancks, Yuichiro Yano, Masanori Kuwabara, Angelo L. Gaffo, Daniel A. Duprez, Myron D. Gross, David R. Jacobs
Journal: Circulation (2020)

Introduction: Higher levels of serum urate (UA) obtained on a single occasion have been shown to be associated with a higher risk of cardiovascular disease (CVD) events among middle-aged or older adults. However, little is known regarding UA trajectory patterns during young adulthood and their associations with CVD outcomes by middle age. Hypothesis: We hypothesize that higher UA trajectory is associated with a higher risk for CVD events compared to lower UA trajectories. Methods: We included data from 4845 CARDIA Study participants (mean age at the Year 20 exam 44.8±3.7 (37-55) years; 50.8% African American; 55.6% female). Sex-specific UA trajectories were assessed using group-based trajectory modeling (PROC TRAJ in SAS version 9.4) based on UA levels obtained at baseline (Year 0) and 10, 15, 20 years later. Covariates included age, sex, race, and clinical characteristics at Year 20 (body mass index, diabetes and creatinine). We estimated hazard ratios (HR) for CVD events (coronary heart disease, heart failure, and stroke) from Year 20 (2005-06) through 2017. Results: We identified 3 UA trajectories in men and 3 similar but lower UA trajectories in women, characterized by low-increasing (men: 30%; n=652, mean UA 5.1; women 43%, n=1191, mean UA 3.9), moderate-increasing (men: 52%; n=1290, mean UA 6.4; women 45%, n=1284, mean UA 5.0), and high-increasing UA (men: 17%; n=377, mean UA 8.0; women 12%, n=305, mean UA 6.4) (Figure 1). Sex-specific trajectories were pooled. Over a median follow-up of 10.9 years, 203 incident CVD events occurred. The adjusted HRs for CVD events were 0.98 (95%CI, 0.66-1.45) for the pooled moderate-increasing group and 1.77 (95%CI, 1.10-2.84) for the pooled high-increasing group compared to the pooled low-increasing group. Conclusions: High-increasing UA trajectory during young adulthood was associated with an greater risk of CVD events by middle age. Modeling UA trajectories may help identify young adults at higher risk for CVD events.
A Protease-Activated Fluorescent Probe Allows Rapid Visualization of Keratinocyte Carcinoma during Excision
Authors: Ethan Walker, Yiqiao Liu, InYoung Kim, Mark Biro, Sukanya Raj Iyer, Harib Ezaldein, Jeffrey Scott, Miesha Merati, Rachel Mistur, Bo Zhou, Brian Straight, Joshua J. Yim, Matthew Bogyo, Margaret Mann, David L. Wilson, James P. Basilion, Daniel L. Popkin
Journal: Cancer Research (2020)

Keratinocyte carcinomas, including basal and squamous cell carcinomas, are the most common human cancers worldwide. While 75% of all keratinocyte carcinoma (4 million annual cases in the United States) are treated with conventional excision, this surgical modality has much lower cure rates than Mohs micrographic surgery, likely due to the bread-loaf histopathologic assessment that visualizes <1% of the tissue margins. A quenched protease-activated fluorescent probe 6qcNIR, which produces a signal only in the protease-rich tumor microenvironment, was topically applied to 90 specimens ex vivo immediately following excision. "Puzzle-fit" analysis was used to correlate the fluorescent images with histology. Probe-dependent fluorescent images correlated with cancer determined by conventional histology. Point-of-care fluorescent detection of skin cancer had a clinically relevant sensitivity of 0.73 and corresponding specificity of 0.88. Importantly, clinicians were effectively trained to read fluorescent images within 15 minutes with reliability and confidence, resulting in sensitivities of 62%-78% and specificities of 92%-97%. Fluorescent imaging using 6qcNIR allows 100% tumor margin assessment by generating en face images that correlate with histology and may be used to overcome the limitations of conventional bread-loaf histology. The utility of 6qcNIR was validated in a busy real-world clinical setting, and clinicians were trained to effectively read fluorescent margins with a short guided instruction, highlighting clinical adaptability. When used in conventional excision, this approach may result in higher cure rates at a lower cost by allowing same-day reexcision when needed, reducing patient anxiety and improving compliance by expediting postsurgical specimen assessment. SIGNIFICANCE: A fluorescent-probe-tumor-visualization platform was developed and validated in human keratinocyte carcinoma excision specimens that may provide simple, rapid, and global assessment of margins during skin cancer excision, allowing same-day reexcision when needed.
Abstract P341: Development of Predictive Models for Cardiovascular Health to Support Its Use in Real-world Data
Authors: Hui Hu, Jiang Bian, Thomas A Pearson, Heather S Lipkind, Yi Zheng, Jinying Zhao
Journal: Circulation (2020)

Life’s Simple 7 (LS7) developed by the American Heart Association (AHA) is a new index of cardiovascular health (CVH). LS7 is comprised of 7 metrics, including 3 health factors (blood pressure [BP], total cholesterol, and glucose) and 4 health behaviors (body mass index [BMI], cigarette smoking, diet, and physical activity). To date, CVH estimates are mainly obtained from national surveys, clinical trials, and cohort studies. Real-world data (RWD) such as electronic health records (EHRs) and claims data and real-world evidence generated from these data are playing an increasing role. However, the lack of information on all 7 CVH metrics in RWD limits the use of the CVH concept in research and preventions based on RWD. Using data from the 1999-2016 National Health and Nutrition Examination Survey (NHANES), we developed predictive models for CVH among adults using 3 metrics (i.e. BP, BMI, and smoking) and sociodemographic factors (i.e. age, gender, race/ethnicity, education, and marital status) which are widely available in RWD. Each CVH metric was categorized into ideal (2 points), intermediate (1 point), or poor (0 point), and then weighted accordingly following LS7 to generate an overall CVH score (0-14 points) with a higher score indicating better CVH. Individuals with more than 4 ideal CVH metrics were determined as having ideal CVH. In addition, we also developed models using 4 CVH metrics (i.e. BP, BMI, and smoking + one of the other 4 metrics). The data were randomly divided into training (80%) and testing (20%) sets. Gradient boosting decision trees models were trained using the CatBoost library with hyper-parameters tuned by a grid search based on 5-fold cross validations. A total of 45,614 individuals aged 18 years and older in 1999-2016 NHANES were included. The models with 3 CVH metrics (i.e. BP, BMI, and smoking) as predictors achieved a test-AUC of 0.95 and a test-RMSE of 1.39. Including one of the other 4 CVH metrics (i.e. total cholesterol, glucose, diet, or physical activity) as a predictor in the models along with the previous 3 metrics (i.e. BP, BMI, and smoking) further improved the predictive performance (test-AUC&gt;0.96 and test-RMSE&lt;1.38). These findings suggested that the 3 CVH metrics (i.e. BP, BMI, and smoking) that are widely available in RWD can be used to accurately estimate CVH among adults in the United States.
Abstract P119: Non-exercise Cardiorespiratory Fitness Prediction Equations: Accuracy Over Time in Apparently Healthy Adults
Authors: James E Peterman, Matthew Harber, Mary Imboden, Mitchell Whaley, bradley fleenor, Leonard A Kaminsky
Journal: Circulation (2020)

Introduction: Mortality risk predictions are improved with routine assessment of cardiorespiratory fitness (CRF). Accordingly, an American Heart Association Scientific Statement suggests routine clinical assessment of CRF in apparently healthy adults minimally using non-exercise prediction equations, which can be calculated from common health metrics. However, no study has assessed the ability of non-exercise CRF prediction equations to accurately detect longitudinal changes. Hypothesis: Changes in estimated CRF (eCRF) would be related to directly-measured changes, yet appreciable misclassification would occur at the individual level. Methods: The sample included 987 apparently healthy adults (324 females; mean±SD age 43.1±10.4 years) who completed 2 cardiopulmonary exercise tests (CPX) at least 3 months apart (3.2±5.4 years follow-up). The change in eCRF from 27 distinct non-exercise prediction equations was compared to the change in directly-measured CRF determined from CPX. A change of ≥5% was used to classify participants as having a directional increase or decrease in CRF. Analysis included Pearson product moment correlations, standard error of estimate (SEE) values, the Benjamini-Hochberg procedure to compare eCRF with directly-measured CRF, and chi-squared tests to examine the impact of follow-up time on the percentage of participants correctly identified as having a directional increase or decrease in CRF. Results: The change in eCRF from each equation was correlated to the change in directly-measured CRF ( P &lt;0.001) with R 2 values ranging from 0.06-0.43 and SEE values ranging from 0.9-5.9 ml·kg -1 ·min -1 . For 16 of the 27 equations, the change in eCRF was significantly different from the change in directly-measured CRF. When classifying directional changes, the prediction equations correctly categorized an average of 54% of individuals as having increased, decreased, or no change in CRF. When examining the influence of follow-up time, the average percentage of individuals correctly classified as having a directional increase in CRF was greater when the time between tests was ≤8months (54%) compared to ≥2years (28%). In contrast, the average percentage correctly classified as having a directional decrease in CRF was lower with tests ≤8months apart (8%) compared to ≥2years (73%). Conclusions: As hypothesized, discernible variability was found in the accuracy between non-exercise prediction equations and the ability of equations to accurately assess changes in directly-measured CRF over time. Considering the appreciable error that prediction equations had with detecting even directional changes in CRF, these results suggest eCRF may have limited clinical utility.
Abstract P281: Examining Allostatic Load Among Marijuana Users In The United States: An Analysis Of The National Health And Nutrition Examination Surveys, 2007-2010
Authors: Amber J Johnson, Yendelela Cuffee, Denise Vidot, Lenette M Jones
Journal: Circulation (2020)

Introduction: Allostatic Load (AL) has been associated with cardiovascular risk and subsequent cardiovascular disease disparities. Recent studies have investigated pharmacological approaches to reduce and/or reverse AL. One particular area of interest lies in the utility of the cannabinoid system in regulating the physiological irregularities associated with AL. The purpose of this study was to describe AL among marijuana users vs. non-marijuana users in a United States sample. Hypothesis: We hypothesized that AL scores and AL prevalence would be lower among marijuana users compared to non-marijuana users. Methods: Data from adults (20-to-65 years) who completed the National Health and Nutrition Examination Surveys between 2007 and 2010 ( N =6,994) were examined. Marijuana use was defined via computer-assisted self-report of lifetime use (had ever smoked marijuana, yes/no) and current use (had used marijuana at least once in the past 30-days). AL scores were calculated using clinical cut-points for BMI, systolic blood pressure, diastolic blood pressure, pulse, C-reactive protein, high-density lipoprotein, total cholesterol, Glycohemoglobin, albumin, and creatinine clearance. An independent samples t-test was conducted to compare AL scores among lifetime and current marijuana users. Pearson Chi-square analysis was employed to determine whether the prevalence of AL (i.e., AL scores 4 or above) significantly differed between low and high frequency marijuana users. Results: Over half of the sample (58%) reported lifetime use of marijuana. Among current users of marijuana (17.0%), participants reported having used marijuana an average of 12 times in the last month. There was a significant difference in mean AL scores, such that means for those who had ever smoked marijuana (M= 1.67, SD= 1.49) were lower than those who had never smoked marijuana (M=1.84, SD= 1.54; p &lt; .001). Current marijuana users with low frequency of marijuana use in the last 30 days (i.e., less than 12 times) had a significantly higher AL score (M= 1.59, SD= 1.51) than those with high frequency of marijuana use (M=1.37, SD= 1.34; p = .01). The prevalence of AL was significantly higher among participants with low frequency of marijuana use (12.4%) versus those with high frequency (7.0%) ( p = .01). Conclusion: The findings of this analysis describe the relationship between marijuana use and allostatic load. Specifically, allostatic load was lower among individuals reporting lifetime marijuana use and those reporting a higher frequency of current marijuana use. Additional research is needed, in particular - longitudinal studies that examine diverse patterns of marijuana use and variations in allostatic load.
CoRESTed development of regulatory T cells
Authors: Luisa Morales-Nebreda, Kathryn A. Helmin, Benjamin D. Singer
Journal: Journal of Clinical Investigation (2020)

Tregs require specific epigenetic signatures to induce and maintain their suppressive function in the context of inflammation and cancer surveillance. In this issue of the JCI, Xiong and colleagues identify a critical role for the epigenetic repressor REST corepressor 1 (CoREST) in promoting Treg suppressive transcriptional and functional programs. Pharmacologic inhibition and genetic loss of CoREST in Tregs impaired organ allograft tolerance and unleashed antitumor immunity via epigenetic activation of effector T cell programs. We propose that exploiting epigenetic control mechanisms will further the translation of Treg-based therapeutics to target inflammatory and malignant disorders.