tbuckley/cabot-search huggingface dataset:
Patterns of hepatic impairment in phase I clinical trials.
Authors: Aaron Scott Mansfield, Diana Vulih, Gary L. Smith, Pamela Jo Harris, S. Percy Ivy
Journal: Journal of Clinical Oncology (2015)

2567 Background: Liver impairment confounds dosing of anti-neoplastic agents. The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) sponsors standard phase I clinical trials (P1CT) to determine the safety of novel agents and combinations, and hepatic dysfunction phase I clinical trials (HDCT) to determine safe doses for patients with varying degrees of liver dysfunction. We sought to compare patterns of liver injury, number of cycles administered, and reasons for discontinuation between HDCTs and P1CTs in a meta-analysis. Methods: The records of participants of 51 NCI-sponsored phase I clinical trials conducted between 1994 and 2014 were reviewed. The NCI’s Organ Dysfunction Working Group’s definitions of liver impairment were used to classify subjects. Peak liver test results were used to classify patterns of liver impairment using the US Food and Drug Administration’s (FDA) R ratio and modified Hy’s law (aminotransferase ≥ 3xULN, total bilirubin > 2xULN without elevated serum alkaline phosphatase & no other explanation for abnormalities). The Kruskal-Wallis one way analysis of variance was used to compare groups and the Pearson test was used for contingency analyses. Results: There were 513 subjects treated on HDCTs and 1328 subjects treated on P1CTs with a median age of 58.6 years [51-66 interquartile range (IQR)] and 59 years (49-67 IQR) respectively. 55.6% and 49.9% were male, on P1CTs and HDCTs respectively. Subjects received a median of 2 cycles of treatment on HDCTs and P1CTs. Cholestatic peak patterns of liver impairment by the FDA R ratio were more frequent in HDCTs than P1CTs (p < 0.0001). Criteria for Hy’s Law were met in eleven patients on P1CTs. Disease progression was the most common reason for treatment discontinuation, followed by adverse events in HDCTs and P1CTs. Subjects with severe liver function abnormalities on HDCTs typically received one cycle of treatment, and 9.9% died on study compared to those with less severe hepatic dysfunction (range of 3.0-3.7% p < 0.0001). Conclusions: Subjects on HDCTs are more likely to experience cholestatic peak patterns of liver function abnormalities, but receive a similar number of cycles of therapy, and discontinue from trial participation for similar reasons as those on P1CTs.
The efficacy and safety analysis of sunitinib plus temozolomide therapy in patients with metastatic mucosal melanoma.
Authors: Bixia Tang, Zhihong Chi, Chuanliang Cui, Lu Si, Xi Nan Sheng, Yan Kong, Li Li Mao, BIN LIAN, Si Ming Li, Xuan Wang, Xieqiao Yan, Jun Guo
Journal: Journal of Clinical Oncology (2015)

e20043 Background: Mucosal melanoma (MM) is a special subtype melanoma with poor prognosis, and no standard therapeutic options exist for metastatic MM patients. Temozolomide (TMZ) is still the fir...
Long-term survival in patients with pancreatic cancer: Relevant factors in CONKO-001.
Authors: Marianne Sinn, Bruno Valentin Sinn, Jana Kaethe Striefler, Jens Stieler, Marco Niedergethmann, Klaus Gellert, Peter Neuhaus, Bernd Dörken, Carsten Denkert, Hanno Riess, Helmut Oettle
Journal: Journal of Clinical Oncology (2012)

4020 Background: Long-term survival (LTS) in patients with pancreatic cancer is still rare, even in resectable and potentially curative stages. Few prospective data are available to identify predictive factors. The CONKO-001 study establishing adjuvant gemcitabine (GEM) may provide data to answer this question. Methods: CONKO-001 patients (pts) with an overall survival &gt; 5 years were included in this analysis and compared to those with &lt; 5 years. Central re-evaluation of the primary histology was done to confirm the diagnosis of pancreatic adenocarcinoma. Univariate analysis with the x²-test identified qualifying factors (p&lt;0.10). Logistic regression with a stepwise selection process was used to investigate the influence of these covariates on LTS. Results: Of the 354 pts included in the intention-to-treat analysis of CONKO-001, 53 (15%) pts with an overall survival of more than 5 years could be identified, for 39 (74%) tumor specimens could be obtained. In 38 (97% of pts with LTS) the diagnosis of adenocarcinoma was confirmed, 1 showed a high-grade neuroendocrine tumor. Relevant factors for all 53 pts with LTS compared to remaining 301 non-LTS pts in univariate analysis were active treatment (GEM) (68% in LTS pts vs 48% in non-LTS pts; p=0.006), tumor grading (G1 17% vs 3%, G2 64% vs 55%, G3 17% vs 40%; p=0.000), tumor-size (T2 15% vs 9%, T3 74% vs 84%; p=0.004) and lymph nodes (N0 47% vs 25% N1 53% vs 74%; p=0.003. Significance could not be demonstrated for resection margin (R0 vs R1), sex, age, Karnofsky performance status (&lt;80% vs 80% vs &gt;80%) and CA 19-9 (40-100 U/ml vs &lt;40 U/ml) at study entry. In the multivariate analysis tumor grading (gr) (odds ratio gr 3 vs gr 1=0.07; gr 3 vs gr 2= 0.38; p=0.017) and active treatment (odds ratio GEM vs observation=0.38; p=0.004) were the only independent prognostic factors. Conclusions: Long-term survival can be achieved in adenocarcinoma of the pancreas. In pts with completely resected pancreatic cancer, tumor grading and active treatment with GEM were the only predictive factor for LTS.
Sequential monitoring of androgen receptor expression and copy number variation in castration-resistant prostate cancer (CRPC).
Authors: Mitchell E. Gross, David B. Agus, Tanya B. Dorff, Jacek K. Pinski, David I. Quinn, Angel E Dago, Asya Stepansky, Anders Carlsson, Natalie Felch, Madelyn Luttgen, Anand Kolatkar, James B Hicks, Peter Kuhn
Journal: Journal of Clinical Oncology (2013)

11047 Background: The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to identify and characterize CTCs. Here, we utilized the HD-CTC assay to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential samples obtained from patients with CRPC treated with abiraterone acetate (AA). Methods: Patients were approached for participation in a study to provide peripheral blood at baseline, at 2-5 weeks, and at 9-12 weeks (or at progression). In each sample, 10 6 cells (defined with a DAPI-intact nucleus) were quantitatively examined for the presence of cytokeratin and AR (CTCs) and CD45 (leukocytes). Initial results are available from 9 subjects treated with AA as standard of care. Results: At baseline, the median (range) CTC was 7.8 (1.1-57.2) cells/ml. Using a definition of AR positive (AR+) as &gt;6 standard deviations over mean signal observed in leukocytes, the median (range) of AR+ and total CTCs observed at baseline were 3.1(0-33.8) and 7.8 (1.1-57.2) cells/ml, respectively. Detailed single-nucleus CNV analysis was performed in sequential samples in a single subject (Table). Complex genomic rearrangements were observed including AR amplification and 8p deletion in both AR+ and AR- negative (AR-) cells at baseline. During AA treatment, the frequency of AR+ CTCs decreased along with changes in the CNV pattern including loss of AR amplification. At 10 weeks, disease progression occurred coincident with re-emergence of an AR+ CTC population exhibiting AR amplification and a novel CNV pattern only distantly related to that of the baseline CTCs. While multiple complex abnormalities were noted, MYC amplification was observed at higher frequency in cells present at progression. Conclusions: Overall, our results demonstrate the feasibility of monitoring of CTCs for treatment emergent changes in protein which may be used to better monitoring and predict therapeutic responses in patients with metastatic cancer. [Table: see text]
Estimation of polio infection prevalence from environmental surveillance data
Authors: Yakir Berchenko, Yossi Manor, Laurence S. Freedman, Ehud Kaliner, Itamar Grotto, Ella Mendelson, Amit Huppert
Journal: Science Translational Medicine (2017)

A major obstacle to eradicating polio is that poliovirus from endemic countries can be reintroduced to polio-free countries. Environmental surveillance (ES) can detect poliovirus from sewage or wastewaters samples, even in the absence of patients with paralysis. ES is underused, in part because its sensitivity is unknown. We used two unique data sets collected during a natural experiment provided by the 2013 polio outbreak in Israel: ES data from different locations and records of supplemental immunization with the live vaccine. Data from the intersecting population between the two data sets (covering more than 63,000 people) yielded a dose-dependent relationship between the number of poliovirus shedders and the amount of poliovirus in sewage. Using a mixed-effects linear regression analysis of these data, we developed several quantitative tools, such as (i) ascertainment of the number of infected individuals from ES data for application during future epidemics elsewhere, (ii) evaluation of the sensitivity of ES, and (iii) determination of the confidence level of the termination of poliovirus circulation after an outbreak. These results will be valuable in monitoring future outbreaks with ES, and this approach could be used to certify poliovirus elimination or to validate the need for more containment efforts.
Efficacy and safety of eribulin monotherapy in patients with heavily pretreated metastatic breast cancer.
Authors: Ozturk Ates, Taner Babacan, Furkan Sarici, Neyran Kertmen, Alma Cenoli, Serkan Akin, Yusuf Karakas, Saadettin Kilickap, Sercan Aksoy, Yavuz Yasin Ozisik, Kadri Altundag
Journal: Journal of Clinical Oncology (2015)

e12036 Background: Eribulin is a non-taxane microtubule inhibitor, which can be used after antracycline and taxane treatment in patients with metastatic breast cancer (MBC). The purpose of this study was to investigate the efficacy and safety of eribulin monotherapy in patients with heavily pretreated MBC patients. Methods: In this single center trial, a total of 65 MBC patients who received eribuline monotherapy in Hacettepe University Cancer Institute between 2013 and 2014 were retrospectively analyzed.Kaplan Meier survival analysis was carried out for progression free survival (PFS) and for overall survival (OS). Two-sided p values of < 0.05 were considered as statistically significant. Results: Sixty five patients who received at least one cycle of eribulin were identified. Most patients were heavily pretreated with a median of 3 (1-8) previous chemotherapy lines prior to eribulin. Median patient age was 50 years (28-67). Most of patients treated with eribuline at fourth and fifth line ( 40% and 20%). Brain metastases were present in 17(27%) patients at the time of initial eribulin administration. Median PFS was 4 months (CI: 2.5-5.4) and median OS was 11 months. Fourteen patients (21.5%) responded to treatment with partial remission and 37 (56,9%) patients had stabile disease. No hypersensitivity reactions and no toxic deaths were observed. Three (4%) patients experienced grade 4 neurotoxicity. G-CSF was used in 14 (21,5%) patients developing grade 3-4 neutropenia Conclusions: Eribulin monotherapy is an effective and safe regime for heavily pretreated MBC patients. This agent a preferable option for both physicians and patients because of its low toxicity and ease in its intravenous administration profile.
The impact of race, age, and sex in follicular lymphoma (FL): A comprehensive SEER analysis in the pre- and post-rituximab (R) eras.
Authors: Chadi Nabhan, Briseis Aschebrook-Kilfoy, Brian C-H Chiu, Kimberly R. Kruczek, Angelo Clemenzi-allen, Anand Patel, Sonali M. Smith, Andrew M. Evens
Journal: Journal of Clinical Oncology (2012)

8072 Background: While racial disparity has been well documented in a number of cancers, the impact of race in FL outcomes is not well defined. Further, the importance of gender in FL has not been fully explored. Methods: We examined population-based FL overall survival (OS) data from SEER 13 (1993-2008) regarding race, sex, age, and socioeconomic status (SES) over two consecutive 8-year (yr) periods: Era 1 (1993-2000, n=7,409) and Era 2 (2001–2008, n=9,083). Results: We identified16,492 FL patients (pts) (white (W): n=13,441; Hispanic (H): n=1,417; Asian/Pacific Islander (A/PI): n=887; and Black (B): n=747). Median ages at diagnosis differed significantly according to: (in yrs, W: 62.1, H: 57.3, A/PI: 60.5, B: 56.6; P&lt;0.01 for each race vs. W). For all pts, OS was superior in Era 2 vs. Era 1 (5-yr OS: 77% vs. 68%, respectively, P&lt;0.0001). Further, OS was significantly improved for all age groups (&lt;50, 50-59, 60-69, and 70-79 yrs) as well as for males (P=0.0019) and females (P&lt;0.0001) across eras. Interestingly, females had superior OS compared with males in Era 1 (P=0.004), but not in Era 2 (P=0.83). We subsequently compared OS within and across races (Table). All races, except A/PI, had improved 5-yr OS rates (age adjusted) from Era 1 to Era 2 (W: &lt;0.001, H: 0.049, A/PI: 0.15, B: 0.003). Notably, A/PIs had the highest OS in Era 1, while H had the poorest OS in Era 2. These differences were more evident in males compared with females within each race. Finally, pts with higher SES had better OS in both eras, although OS was improved across eras for lower and higher SES populations. Conclusions: Collectively, we identified improved OS across eras, which was apparent for all ages, both sexes, and all races. We did not find superior outcome for females in the modern era as has been recently noted. However, several racial disparities persist, including inferior OS for H and superior OS A/PIs in the contemporary era. The disproportionate improvement in outcomes for some, but not all races, warrants continued study of racial disparities in FL. [Table: see text]
A phase II study of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low- to intermediate-grade, unresectable, recurrent, or metastatic pancreatic, or GI neuroendocrine tumors/carcinoid (GI-NETs/PNETs) with elevated biomarkers.
Authors: Steven K. Libutti, Lowell Brian Anthony, David J. Chaplin, Julie Ann Sosa
Journal: Journal of Clinical Oncology (2017)

432 Background: GI-NETs/PNETs are highly vascular tumors. CA4P, a vascular disrupting agent (VDA), occludes tumor vasculature resulting in ischemic necrosis. Pre-clinical studies of CA4P have shown activity in GI-NETs/PNETs. Methods: OX4218s is a phase II, single-arm, open-label study (NCT02132468) of CA4P in patients (pts) with GI-NETs/PNETs with elevated biomarkers who relapsed during or after standard-of-care treatment. Pts received CA4P 60 mg/m 2 IV on days 1, 8, and 15 of a 21-day cycle for 3 cycles. Primary endpoint was change in biomarkers from baseline. Secondary endpoints were safety, tolerability, symptoms, and QOL. Exploratory endpoints were ORR (RECIST 1.1). Pts achieving biomarker or symptom response were eligible for a rollover study. Results: 18 pts were enrolled; 7 subsequently entered the rollover study. Pts were on average aged 58 years, white (89%), male (50%) with ECOG status of 0-1. The majority (94%) had well-differentiated disease (GI-NETS 78%) and received prior Tx (94%). There were no meaningful changes in biomarkers. Eleven (61%) pts had stable disease (SD) and 1 (6%) had a partial response (PR). In the rollover study, 5 (71%) had SD, and 1 had SD for 14 cycles prior to progression (PD). 77% of pts had treatment-related AEs. Key grade 3-5 AEs (&gt; 10%): anemia, abdominal pain, fatigue, hypertension, ALT and AST increases, with 1 grade 5 carcinoid syndrome. Conclusions: The primary endpoint was not met. However, the number of pts entering the rollover study and ORR suggest that CA4P conferred some activity and was generally safe and well tolerated. These findings suggest that due to their inherent variability, tumor biomarkers may not be an ideal endpoint for this population. Clinical trial information: NCT02132468. [Table: see text]
Renovascular safety of sunitinib in prostate cancer: The prognostic value of hypertension and proteinuria.
Authors: Vincent Launay-Vacher, Nicolas Janus, Florian Scotte, Isabelle Laure Ray-Coquard, Philippe Beuzeboc, Catherine Daniel, Joseph Gligorov, Frédéric Selle, Francois Goldwasser, Olivier Mir, Jean-Philippe Spano, Jean Christophe Thery, Jean-Baptiste Rey, Christelle Jouannaud, Jean F. Morere, Reza-Thierry Elaidi, Richard Dorent, Gilbert Deray, Stephane Oudard
Journal: Journal of Clinical Oncology (2015)

e16056 Background: MARS is a prospective multicentric study conducted to assess the renovascular tolerance of anti-VEGF drugs (AVD) in the clinical setting in France, in different tumor types. Methods: Patients (pts) from 8 centres were included when they were 1) naïve of any AVD and 2) about to start treatment with an AVD, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr) and MDRD eGFR, HTN, hematuria (Hu) and dipstick Proteinuria (Pu), at baseline and at each visit during f/u. This sub-group analysis presents the results for metastatic castration-resistant prostate cancer (mCRPC) pts receiving sunitinib. Univariate (UA) and multivariate analyses (MA) tested the associations of HTN and Pu, at baseline or de novo, with overall survival (OS) (pre-planned). Results: In our cohort of 1124 pts, 47 had mCRPC and received sunitinib. Median age: 70.0 years. Visceral, bone metastasis frequencies were 21.3 and 97.3%, respectively. At inclusion, HTN prevalence was 53.2%. Baseline renal assessment retrieved: Pu 27.5%, Hu 10.0%, mean MDRD 77.7 ml/min/1.73m2. Both incidences of de novo Pu and HTN during f/u were 65.5% (Table). 72.7% of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 57.9% afterwards improved/normalized. No thrombotic micro-angiopathy (TMA) was reported. De novo Pu, de novo HTN and HTN at inclusion were not associated with OS in both UA and MA. Pu at inclusion was the only criteria statistically associated with OS, and prognostic of reduced OS in both UA (p = 0.03) and MA (Hazard-Ratio = 2.655; [1.001-7.040]; p = 0.0497). Conclusions: Pu at inclusion was prognostic of poorer OS in our prospective cohort of 47 mCRPC patients treated with sunitinib. Further studies are mandatory to confirm and detail the mechanisms of such an association. If confirmed, this criterion should be considered in future clinical trials. Renovascular effects in mCRPC patients. Renovascular effects Prevalence at inclusion Incidence during f/u Pu* All G G1 G2 G3 27.5% 17.5% 10.0% 0.0% 65.5% 62.1% 0.0% 3.4% HTN 53.2% 65.5% Hu All Hu Traces/+ ++ +++ 10.0% 5.0% 2.5% 2.5% 30.6% 13.9% 11.1% 5.6% *NCI-CTC v4; G: Grade
Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis
Authors: Unnur Styrkarsdottir, Hannes Helgason, Asgeir Sigurdsson, Gudmundur L Norddahl, Arna B Agustsdottir, Louise N Reynard, Amanda Villalvilla, Gisli H Halldorsson, Aslaug Jonasdottir, Audur Magnusdottir, Asmundur Oddson, Gerald Sulem, Florian Zink, Gardar Sveinbjornsson, Agnar Helgason, Hrefna S Johannsdottir, Anna Helgadottir, Hreinn Stefansson, Solveig Gretarsdottir, Thorunn Rafnar, Ina S Almdahl, Anne Brækhus, Tormod Fladby, Geir Selbæk, Farhad Hosseinpanah, Fereidoun Azizi, Jung Min Koh, Nelson L S Tang, Maryam S Daneshpour, Jose I Mayordomo, Corrine Welt, Peter S Braund, Nilesh J Samani, Lambertus A Kiemeney, L Stefan Lohmander, Claus Christiansen, Ole A Andreassen, Olafur Magnusson, Gisli Masson, Augustine Kong, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Helgi Jonsson, John Loughlin, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir, Kari Stefansson
Journal: Nature Genetics (2017)
The relationship between tumor location, tumor microenvironment, systemic inflammation, and cancer-specific survival in patients undergoing surgery for colon cancer.
Authors: Meera Patel, James Hugh Park, Hester Catharina van Wyk, Joanne Edwards, Paul G. Horgan, Donald C McMillan
Journal: Journal of Clinical Oncology (2017)

689 Background: Evidence from clinical trials and cohort studies suggest primary tumour location is a prognostic factor in patients with advanced colorectal cancer and that right and left colonic tumours should be considered as distinct clinical and biological entities. The aim of the present study was to examine the relationship between tumour location, tumour microenvironment, systemic inflammatory response (SIR), and cancer-specific survival (CSS) in patients undergoing surgery for colon cancer. Methods: Clinicopathological characteristics were extracted from a prospective database of patients who underwent potentially curative surgery for colon cancer between 1997 and 2016, at a single centre. The tumour microenvironment was assessed retrospectively using routine H&amp;E pathological sections. Results: 722 patients were included. The majority of patients were over the age of 65 years (69%), were male (52%), had right-sided (RS) tumour location (63%), had TNM stage I/II disease (64%) and 25% received adjuvant chemotherapy. RS location was associated with poor tumour differentiation ( p =&lt; 0.001) and high venous invasion ( p =0.003) but not with TNM stage (p= 0.310), perineural invasion ( p= 0.286), tumour budding ( p= 0.568), margin involvement ( p= 0.424), peritoneal involvement ( p= 0.689), tumour necrosis ( p= 0.423) or tumour cell proliferation ( p= 0.605). RS location was not associated with tumour inflammatory cell infiltrate at the margin (CD3 + p= 0.103, CD8 + p= 0.620) or in the tumour (CD3 + p= 0.540, CD8 + p= 0.713) or with tumour stroma percentage ( p= 0.843). RS location was associated with high mGPS ( p =0.007) and neutrophil:platelet score ( p =0.001) but not NLR ( p= 0.387). Finally, there was no difference between RS and left sided tumour location in the administration of adjuvant chemotherapy (p= 0.901) or CSS ( p= 0.951). Conclusions: Few clinicopathological features were associated with tumour location in patients undergoing surgery for colon cancer. However, RS tumour location was consistently associated with a higher SIR. This may account for the poor prognosis associated with RS tumours in patients with advanced colon cancer.
Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study
Authors: Peter C Thuss-Patience, Manish A Shah, Atsushi Ohtsu, Eric Van Cutsem, Jaffer A Ajani, Hugo Castro, Wasat Mansoor, Hyun Cheol Chung, Gyorgy Bodoky, Kohei Shitara, Gail D Lewis Phillips, Tina van der Horst, Marie-Laurence Harle-Yge, Betsy L Althaus, Yoon-Koo Kang
Journal: The Lancet Oncology (2017)
A close consideration of effect sizes reviewed by Jussim (2012)
Authors: David Trafimow, Yogesh J Raut
Journal: Behavioral and Brain Sciences (2017)

Abstract This commentary on Jussim (2012) makes two points: (1) Effect sizes often reflect artifacts of experimental design rather than real-world relevance, and (2) any argument dependent on effect sizes must correct for attenuation due to instrument reliabilities. A formula for making this correction is presented, and its ramifications on the debate over accuracy in person perception are discussed.