tbuckley/cabot-search huggingface dataset:
Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide.
Authors: Wolfgang Wick, Patrick Roth, Benedikt Wiestler, Christian Hartmann, Peter Hau, Makoto Nakamura, Florian Stockhammer, Michael Sabel, Susanne Koeppen, Ralf Ketter, Peter Vajkoczy, Ilker Eyupoglus, Stephen Kaendler, Rolf Kalff, Norbert Galldiks, Friederike Schmidt-Graf, Andreas von Deimling, Michael Platten, Guido Reifenberger, Michael Weller
Journal: Journal of Clinical Oncology (2015)

2001 Background: NOA-04 compared the efficacy and safety of radiotherapy versus (vs)chemotherapy in patients with newly-diagnosed, centrally assessed, supratentorial gliomas of WHO grade III and had not demonstrated a difference in efficacy parameters between arms. Here, long-term clinical follow-up for the intention-to-treat population (n = 274) and the biomarker group (n = 207) are presented. Methods: Patients with anaplastic astrocytoma (52.6%) and anaplastic oligodendroglial tumors (47.4%) were randomized 2:1:1 (A:B1:B2) to receive radiotherapy to 54-60 Gy or four 6-week cycles of procarbazine, CCNU and vincristine (PCV) or eight 4-week cycles of temozolomide. The primary endpoint was time-to-treatment-failure (TTF) defined as progression after radiotherapy and one chemotherapy in either sequence, or any time before if no further therapy could be administered. Exploratory analyses of the correlation between molecular status and TTF, progression-free (PFS) and overall survival (OS) were part of the study. Results: With a median observation period of 11.8 years (ys) median TTF [4.6 (3.4-5.1) ys vs 4.4 (3.3-5.3) ys], PFS [2.5 (1.3-3.5) ys vs 2.7 (1.9-3.2) ys], and OS [8 (5.5-10.3) ys vs 6.5 (5.4-8.3) ys] were not different between arms (A vs B1/B2). Oligodendroglial vs astrocytic histology, but more so subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status revealed a strong prognostic value of CIMPpos with (CIMP-codel) versus without 1p/19 co-deletion (CIMP-non-codel) vs CIMPneg., but no differential efficacy of radio- and chemotherapy for any of the observed endpoints (PFS CIMP-codel: 8.8 (4-11.2) ys for A versus 7.6 (4.1-9.5) ys for B). In CIMPneg. mainly astrocytic tumors hypermethylation of the O6-methyl-guanyl-DNA methyltransferasepromoter (MGMT) provided a large risk reduction for PFS in arms B1/B2, but not arm A. Conclusions: NOA-04 long-term data do not support a differential efficacy of primary temozolomide monotherapy or PCV polychemotherapy vs radiotherapy in any of the histological or molecular subgroups of anaplastic glioma. Molecular diagnosis is superior to histology. MGMT is predictive in CIMPneg. gliomas. Clinical trial information: NCT00717210.
Meta-analysis of breast cancer expression data using published gene signatures to reveal key cellular processes implicated in chemosensitivity and resistance.
Authors: Daniel G. Stover, Laura M Selfors, Jonathan L Coloff, Joan S Brugge, Eric P. Winer
Journal: Journal of Clinical Oncology (2015)

509 Background: Although many pathways and cell states are implicated in therapeutic resistance, predicting response to chemotherapy remains a challenge. Methods: We assembled expression data and pathologic complete response (pCR) versus residual disease (RD) status for 1,507 breast cancer samples collected prior to neoadjuvant chemotherapy. For each sample, we evaluated 118 published gene signatures including signaling, lineage, cell state, immune, and microenvironmental processes. Results: Among all signatures, the strongest predictors of pCR vs. RD were proliferation-related. Microarray data from a breast epithelial cell morphogenesis assay demonstrated that five separate proliferation signatures correlated with in vitro proliferation. To assess how proliferation contributes to chemosensitivity, we evaluated genes differentially expressed in patients with pCR versus RD (FDR-adjusted p < 0.05, limma) before and after normalizing data for proliferation using two distinct proliferation signatures. Among ER+ breast cancer and ER+ subsets Luminal A and B, > 95% of differentially expressed genes were proliferation-associated, suggesting that proliferation differences account for most of the variation in ER+ chemosensitivity. In comparison, among triple-negative breast cancers (TNBCs) and the basal-like subset, only 72.0% and 35.4% of differentially expressed genes, respectively, were proliferation-associated. For TNBCs, signatures associated with chemotherapy response clustered into five key areas: proliferation, mesenchymal phenotype, TGF-beta signaling/stromal features, cyclin and Src activation, and ER signaling (possibly low-level not detected by IHC). Stratifying 175 TNBCs with zero (N0) or few positive lymph nodes (N1) by high versus low activity of three signatures—proliferation, epithelial-to-mesenchymal transition, and Src signaling—was highly predictive of failure to achieve pCR (negative-predictive value 0.965; 95% CI 0.912-0.990). Conclusions: Interrogating multiple signatures in a large expression data set allows insights into key processes associated with chemoresistance and sensitivity in breast cancer.
Clinical outcomes in Caucasian (C), African American (AA) and Asian men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Susan Halabi, Sandipan Dutta, Kim N. Chi, Catherine M. Tangen, Daniel Peter Petrylak, John C. Araujo, Karim Fizazi, David I. Quinn, Celestia S. Higano, Ian Tannock, Eric Jay Small, William Kevin Kelly
Journal: Journal of Clinical Oncology (2019)

186 Background: We have previously shown in multivariable analysis that African American (AA) men had 19% lower risk of death than Caucasian (C) men with metastatic castration resistant prostate cancer (mCRPC) treated with a docetaxel (D) prednisone (P) based regimen. The primary goal of this analysis was to compare progression-free survival (PFS) and PSA PFS in C men, AA men, and Asian men with mCRPC treated with a DP based regimen. Methods: Individual patient data from 8,820 mCRPC men randomized on nine phase III trials to a DP containing regimen were combined. Race used in the analysis was based on self-report. The endpoints were PFS and PSA PFS. Per protocol definition of PFS was used in the analysis while PSA PFS was defined per PCWG3 criteria. The proportional hazards model was used to assess the prognostic importance of race in predicting PFS and PSA PFS, adjusting for treatment arm and prognostic factors that were common across the trials (performance status, and sites of metastases). Results: Of 8,820 patients, 7,528 (85%) were C, 500 (6%) were AA, 424 (5%) were Asian and 368 (4%) had race unspecified. Men with race unspecified were excluded from the analysis, leaving 8,452 men. Median PFS was 8.3 months (m) (95% CI = 8.1-8.5), 8.2 m (95% CI = 7.4-8.8), and 8.3 m (95% CI = 7.6-8.8) in C, AA and Asian men, respectively. In multivariable analysis adjusting for risk factors, the pooled hazard ratios for AA vs. C was 1.04 (95% CI = 0.94-1.15, p-value = 0.461) and 1.08 (95% CI = 0.96-1.21, p-value = 0.192) for Asian vs. C. PSA data were available for 6,685 (89%) C, 456 (91%) AA and 412 (97%) Asian men. Median PSA PFS were 9.7 m (95% CI = 9.4-10), 8.5 m (95% CI = 7.6-10) and 10.0 m (95% CI = 9.5-11.8) in C, AA and Asian, respectively. In multivariable analysis, the pooled hazard ratios were 1.05 (95% CI = 0.94-1.16, p-value = 0.408) for AA vs. C and 1.00 (95% CI = 0.82-1.22, p-value = 0.996) for Asian vs. C. Conclusions: There were no differences in PFS and PSA PFS outcomes in C, AA, or Asian men with mCRPC enrolled on these phase III clinical trials with DP. Clinical trial information: NCT00004001.
Novel Combination Therapy Targeting rDNA Transcription and Histone Deacetylation Provides Effective Treatment for Multiple Myeloma, and Synergises in Bortezomib-Resistant MM
Authors: Kylee H Maclachlan, Andrew Cuddihy, Nadine Hein, Carleen Cullinane, Simon J. Harrison, Ross Hannan, Gretchen Poortinga
Journal: Blood (2018)
Ramucirumab (RAM) exposure-response (ER) relationship in RANGE: A randomized phase III trial of RAM plus docetaxel (DOC) versus placebo (P) plus DOC in advanced platinum-refractory urothelial carcinoma (UC) patients (pts).
Authors: Ronald De Wit, Thomas Powles, Daniel E. Castellano, Andrea Necchi, Jae-Lyun Lee, Michiel Simon Van Der Heijden, Nobuaki Matsubara, Aristotelis Bamias, Aude Flechon, Cora N. Sternberg, Alexandra Drakaki, Evan Y. Yu, Oday Hamid, Annamaria H. Zimmermann, Ling Gao, Amanda Long, Richard A. Walgren, Katherine M Bell-McGuinn, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2019)

353 Background: Recent RANGE results showed significant improvement in PFS, a non-significant positive trend in OS, increased ORR and acceptable safety with RAM+DOC vs P+DOC in UC pts (Petrylak et al. Lancet 2017; Petrylak et al. ESMO 2018, abstr 865PD). RAM ER-OS relationships in RANGE are reported here. Methods: Pts received RAM (10 mg/kg) + DOC or P + DOC (Day 1 of a 21 day cycle) until discontinuation criteria were met. Population pharmacokinetic analysis predicted RAM minimum concentrations after first dose (RAM C min, 1 ). Multivariate Cox regression &amp; matched case control (MCC) analyses using exposure treated as a continuous covariate, or grouped as quartiles, evaluated the ER-OS relationship. Results: Several poor prognostic factors, including Bellmunt risk factors, appeared to be more frequent in the lower exposure quartiles, suggesting a possible disease-PK interaction. Increasing RAM exposure as a continuous covariate in an ER population of n=246 pts significantly ( p=0.01) associated with improvements in OS. Higher exposure quartiles trended toward longer survival &amp; smaller HRs compared to P (Table, Q1=lowest). Conclusions: OS and ORR benefits favored Q4, a group which was associated with more favorable prognostic features and higher exposure. The observed disease-PK interaction may confound the interpretation of the ER results and warrants further exploration. Clinical trial information: NCT02426125. [Table: see text]
Effect of the dose of radiation (RT) to the anal sphincter on the sphincter function of patients with locally advanced rectal cancer (LARC) treated with preoperative chemoradiotherapy followed by low anterior resection (LAR) with total mesorectum excision (TME).
Authors: Fernando Arias, Clara Eito, Itxaso Mora, Koldo Cambra, Fernando Mañeru, Berta Ibañez, Leire Arbea, Antonio Viudez, Marta Errasti, Marta Barrado, Miguel Ciga, Gemma Asin
Journal: Journal of Clinical Oncology (2015)

e14595 Background: The objectives of the study is to determine the correlations between the variables of dose and sphincter function (SF) in patients with LARC treated with preoperative capecitabine/radiotherapy followed by LAR with with TME. Methods: We have retrospectively reviewed 92 consecutive patients with LARC treated at our center with LAR from 2006 and more than 1 year free of local or distant relapse at the time of the study. We re-contoured all the anal sphincters (AS) of patients in the CT planning with the help of the radiologist. SF was assessed by Werner´s test (0 to 20 points, being punctuation inversely proportional to sphincter function). All questionnaires were filled between January 2010 and December 2012. The dosimetric parameters over the sphincter that have been studied include: V20 (sphincter percentage receiving over 20Gy), V30, V40, V50, median dose (Dmean), mínimum dose (Dmin), D90 (dose to the 90% sphincter) and D98 The study was approved by de Ethical Committee of Navarre and all patient signed the IC before entering the study. Statistical analysis: the correlations between the variables of dose and SF were studied by the Spearman correlation coefficient. Differences in SF related to maximum doses to the sphincter were assesd by Mann-Whitney test. Results: Dmean had the most statically significant relation with SF measured by Werner´s test, with a Spearman correlation coefficient r = 0,19 (p = 0.036). Patients receiving doses of radiation to the SA under 20 Gy showed a significantly better SF (p = 0.008). Conclusions: In order to improve the SF, the maximum dose of radiation to the AS should be limited, when possible, to < 20 Gy
Burden of Cardiovascular Diseases in China, 1990-2016
Authors: Shiwei Liu, Yichong Li, Xinying Zeng, Haidong Wang, Peng Yin, Lijun Wang, Yunning Liu, Jiangmei Liu, Jinlei Qi, Sha Ran, Shiya Yang, Maigeng Zhou
Journal: JAMA Cardiology (2019)

<h3>Importance</h3> Cardiovascular disease (CVD) remains the top cause of death in China. To our knowledge, no consistent and comparable assessments of CVD burden have been produced at subnational levels, and little is understood about the spatial patterns and temporal trends of CVD in China. <h3>Objective</h3> To determine the national and province-level burden of CVD from 1990 to 2016 in China. <h3>Design, Setting, and Participants</h3> Following the methodology framework and analytical strategies used in the 2016 Global Burden of Disease study, the mortality, prevalence, and disability-adjusted life-years (DALYs) of CVD in the Chinese population were examined by age, sex, and year and according to 10 subcategories. Estimates were produced for all province-level administrative units of mainland China, Hong Kong, and Macao. <h3>Exposures</h3> Residence in China. <h3>Main Outcomes and Measures</h3> Mortality, prevalence, and DALYs of CVD. <h3>Results</h3> The annual number of deaths owing to CVD increased from 2.51 million to 3.97 million between 1990 and 2016; the age-standardized mortality rate fell by 28.7%, from 431.6 per 100 000 persons in 1990 to 307.9 per 100 000 in 2016. Prevalent cases of CVD doubled since 1990, reaching nearly 94 million in 2016. The age-standardized prevalence rate of CVD overall increased significantly from 1990 to 2016 by 14.7%, as did rates for ischemic heart disease (19.1%), ischemic stroke (36.6%), cardiomyopathy and myocarditis (23.1%), and endocarditis (26.7%). Substantial reduction in the CVD burden, as measured by age-standardized DALY rate, was observed from 1990 to 2016 nationally, with a greater reduction in women (43.7%) than men (24.7%). There were marked differences in the spatial patterns of mortality, prevalence, and DALYs of CVD overall as well as its main subcategories, including ischemic heart disease, hemorrhagic stroke, and ischemic stroke. The CVD burden appeared to be lower in coastal provinces with higher economic development. The between-province gap in relative burden of CVD increased from 1990 to 2016, with faster decline in economically developed provinces. <h3>Conclusions and Relevance</h3> Substantial discrepancies in the total CVD burden and burdens of CVD subcategories have persisted between provinces in China despite a relative decrease in the CVD burden. Geographically targeted considerations are needed to tailor future strategies to enhance CVD health throughout China and in specific provinces.
Impact of treatment sequence in metastatic castration-resistant prostate cancer (mCRPC) on outcome in a prospective cohort study.
Authors: Rebeca Lozano, Elena Castro, Josep M. Piulats, Ana Medina, Jose Carlos Villa Guzman, Iciar Garcia Carbonero, Rosa Villatoro, Jose Angel Arranz, Jose Luis Perez-Gracia, Javier Garde, Aranzazu Gonzalez del Alba, A. Montesa, Raquel Luque, Pablo Borrega, Sergio Vázquez, Esther Martinez, Belen Gonzalez Gragera, Nuria Romero-Laorden, David Olmos, David Lorente
Journal: Journal of Clinical Oncology (2019)

264 Background: Abiraterone (Abi), enzalutamide (Enza) and docetaxel (Doc) are all valid first-line (1L) mCRPC treatment options. Evidence suggests a degree of cross-resistance between agents, which may impact the efficacy of subsequent lines of therapy. Evidence on the optimal treatment sequence is lacking. Methods: We evaluated the outcome of patients (pts) treated with 1L Doc, Abi or Enza in the prospective PROREPAIR-B cohort study. We assessed the impact of 1L treatment option (Doc vs Abi/Enza) on overall survival (OS), progression-free survival (PFS) to 1L-therapy (PCWG2) and PFS2 (time from initiation of 1L-therapy to progression on second-line [2L] therapy). Uni- (UV) and multivariable (MV) cox-regression models were used. MV model covariates included age (≥75 years), local therapy, Gleason Score, metastases at diagnosis, visceral metastases, ALP (≥ULN), LDH (≥ULN), haemoglobin (≤LNL), albumin (≤LNL) and ECOG PS. Results: 406 pts received 1L-Doce (N=188) or Abi/Enza (N=218). Pts receiving Doc were younger (p=0.002), had higher rates of visceral metastases (17.6 vs 8.7%; p=0.008), ALP (52.1% vs 40.4%; p=0.018), LDH (48.1% vs 31.2%; p&lt;0.001) and lower Hb (7.4 vs 2.8%; p=0.029) and albumin (11.3 vs 4.6%). PFS was higher in pts receiving 1L-Abi/Enza (10.8 vs 8.3 months; HR:0.5; p&lt;0.001). Pts receiving 1L Abi/Enza had higher rates of radiographic progression (88.4 vs 80%; p=0.032). 123/188 pts treated with 1L-Doc received 2L-Abi/Enza: 30 received other 2L and 35 had not started 2L. 111/216 pts treated with 1L-Abi/Enza received 2L-Doc, 26 were started on other 2L and 79 had not initiated 2L. A significant difference between pts treated with initial Abi/Enza vs Doc was observed in PFS2 (20.6 vs 16.6m; HR:0.78; p=0.006) but not OS (31.3 vs 29.9 m; HR:1.05; p=0.725). Choice of first-line agent was not associated with OS in the MV model. Conclusions: Despite longer PFS to 1L and PFS2 in pts treated with initial Abi/Enza, no differences in OS were observed between treatment sequences starting with Doc vs Abi/Enza. Pts treated with 1L-Doc had worse baseline prognostic features. Molecular stratification may enable biomarker-driven patient selection to optimize benefit in pts. (NCT03075735).
Predicting individualized post-operative survival for colorectal cancer using a new mobile application derived from the National Cancer Database.
Authors: Emmanuel M. Gabriel, Pragatheeshwar Thirunavukarasu, Eisar Al-Sukhni, Kristopher Attwood, Steven J. Nurkin
Journal: Journal of Clinical Oncology (2015)

3556 Background: For patients treated with surgery for colorectal cancer, prediction calculators can estimate post-operative survival and assist in the decision making process for adjuvant treatment. Methods: We queried the National Cancer Database (NCDB) from 1998-2006 for patients with either colon or rectal cancer who had surgical resection. Within each subset, patients were randomized to a test cohort (nt) comprising 90% of the dataset and a validation cohort (nv) comprising the remaining 10%. Multivariate logistic regression of nt identified independent predictors of the 5-year overall survival (OS), which were used to build prediction models. Model performance was validated and calibrated using nv. Correlation of observed to predicted OS using nv was expressed as area under receiver operating characteristic curve (AUC). Prediction models were translated into a mobile application. Results: A total of 402,844 patients and 106,037 patients were identified from the colon and rectum datasets, respectively. Independent predictors of OS included patient specific characteristics (age, gender, race, Charlson Deyo comorbidity index, pre-operative CEA level), pathologic factors (site of tumor, size, grade, pathologic TNM stage, margin status, number of nodes examined) and treatment options (type of surgery, neoadjuvant or adjuvant chemoradiation). Length of post-operative stay and unplanned readmission rates were also associated with OS. Our prediction models showed that the predicted OS rates were accurate compared to the actual OS rates (colon AUC = 0.714, rectum AUC = 0.735). These models were translated into mobile application software for a point-of-care, user-friendly medium. Conclusions: We developed accurate, individualized post-operative survival calculators for colon and rectal cancer integrated into a mobile-based application platform. Unique to existing calculators, our prediction models utilize nationwide “big data”, culminating in highly comprehensive and statistically robust survival calculators.
Calcium Buffering in the Heart in Health and Disease
Authors: Godfrey L. Smith, David A. Eisner
Journal: Circulation (2019)

Changes of intracellular Ca2+ concentration regulate many aspects of cardiac myocyte function. About 99% of the cytoplasmic calcium in cardiac myocytes is bound to buffers, and their properties will therefore have a major influence on Ca2+ signaling. This article considers the fundamental properties and identities of the buffers and how to measure them. It reviews the effects of buffering on the systolic Ca2+ transient and how this may change physiologically, and in heart failure and both atrial and ventricular arrhythmias, as well. It is concluded that the consequences of this strong buffering may be more significant than currently appreciated, and a fuller understanding is needed for proper understanding of cardiac calcium cycling and contractility.
Abstract P177: Hypertension is Considerably More Prevalent, Yet Decreasing Over Time According to the New Guidelines
Authors: Joyce E Rudy, Randi E Foraker, Randall E Harris, Julie K Bower
Journal: Circulation (2019)

Introduction: New High Blood Pressure (BP) Guidelines released by the American Heart Association (AHA) and the American College of Cardiology redefined hypertension, imparting implications for monitoring cardiovascular health (CVH). The impact on reclassification of patients according to electronic health record (EHR) data as a result of changes in criteria for BP cut points has not yet been described. Hypothesis: We hypothesized that more stringent cut points for hypertension would increase the prevalence of United States (US) adults with poor CVH for BP. Methods: We analyzed outpatient visit data recorded in The Guideline Advantage©, a repository of EHRs of patients from eight diverse healthcare systems in the US from 2012-2015. For each year, the first non-missing BP measurement for each patient was categorized into poor (hypertensive), intermediate (pre-hypertensive), and ideal (normotensive) for CVH, first in accordance with AHA’s Life Simple 7 guidelines, and then in accordance with the new guidelines. We compared overall trends with trends stratified by race and sex, in distributions of poor and intermediate categories, and in the proportion eligible for pharmacological treatment (BP ≥ 130/80). Results: A total of 172,209 unique patients contributed 348,933 BP measurements, and most were female (58.63%) and white (75.09%). Although the prevalence of poor CVH for BP was consistently 3-fold higher under the new guidelines and the difference in prevalence was significant (p&lt;0.0001), it decreased over time for the both the old (9.4% to 8.7%) and new (27.8% to 26.4%) guidelines. Over time, the proportion classified as hypertensive decreased (12.4% to 10.4 vs. 33.9% to 30.3%) for males and increased for non-whites (10.2% to 13.9% vs. 27.1% to 35.3%) from the old and new guidelines, respectively, but remained stable for females and whites. Similarly, the annual difference in the proportion of intermediate CVH for BP was significant (p&lt;0.0001); however, pre-hypertension prevalence slightly increased under the old (57.9% to 58.5%) and new (39.5% to 40.7%) guidelines. Among untreated adults eligible for pharmacological intervention, the proportion remained relatively unchanged over time; in 2015, patients lacking treatment yet meeting treatment criteria was 23% and 7.3% under the new and old guidelines, respectively, resulting in a difference of 15.7% (p&lt;0.0001). Whites (66.8%) and females (50.6%), compared with non-whites and males, respectively, comprised the majority. Conclusions: Prevalence of poor CVH for BP among US adults substantially increases in the outpatient setting when categorizing measures with the new guidelines. Active participation by clinicians and public health practitioners are needed to address the higher prevalence of and disparities in both hypertension and treatment prescription identified with the old versus new guidelines.