tbuckley/cabot-search huggingface dataset:
Phase I clinical trial of gemcitabine (GEM) in combination with PF-00477736 (PF-736), a selective inhibitor of CHK1 kinase.
Authors: N. Brega, G. A. McArthur, C. Britten, S. G. Wong, E. Wang, K. D. Wilner, A. Blasina, G. K. Schwartz, J. Gallo, A. N. Tse
Journal: Journal of Clinical Oncology (2010)

3062 Background: The S-phase and G2-checkpoints are critical mediators of the cell cycle response to cytotoxic therapy. PF-736 is a selective inhibitor of the S/G2-checkpoint kinase CHK1, displaying >10-fold selectivity over CHK2. Preclinical studies show that PF-736 can enhance response to GEM that is associated with abrogation of the S/G2 checkpoint with cells entering mitosis prematurely. Methods: We undertook a phase I, dose escalation study to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of PF-736 in combination with GEM in sequential cohorts of 3 to 6 gemcitabine naive patients (Pts) with advanced solid tumors. Pts received IV PF-736 alone on days 1 and 8 in cycle 0 (C0) and then started the combination of GEM and PF-736 in C1, days 1 and 8 and 2 and 9 respectively, with PF-736 starting 20-24 hrs after completion of GEM, in 21-day cycles. C0 and C1 were considered for dose-limiting toxicity (DLT). Results: 36 Pts to date have been treated with GEM 750mg/m2 and escalating doses of PF-736. 17 Pts were treated in cohorts of 3-8 with PF-736 50-80 mg infused over 3 h. 19 Pts have been treated in cohorts of 3-7 with PF-736 80-340 mg infused over 24 h. AEs were infrequent in C0. DLT of thrombocytopenia, sudden death, mucositis, and elevated lipase were seen in C1. The MTD was 270mg of PF-736 with GEM 750mg/m2. One Pt treated at PF-736 80 mg was admitted with elevated liver function tests on C10D9 and died from hepatic veno-occlusive disease 3 weeks later. Common drug-related AEs occurring in >30% Pts were pyrexia, fatigue, neutropenia, nausea, vomiting, and diarrhea. 42% of Pts had dose delays due to G3 neutropenia making the days 1 and 8 schedule difficult to maintain. The exposure of PF-736 increased proportionally with increased dose from 50mg to 270mg. Mean T 1/2 ranged from 8 to 20 hrs. Three partial responses were observed in Pts with SCC of the skin, non-small cell lung cancer, and mesothelioma. Conclusions: The combination of PF-736 and GEM 750mg/m2 is clinically active, and can be safely given to Pts. Future studies will determine the MTD of PF-736 with GEM 1,000mg/m2 and examine biomarkers, including inhibition of the S/G2 checkpoint by serial tumor biopsies at the MTD. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer
Significance of <i>TP53</i> Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children's Oncology Group
Authors: Ariadne H.A.G. Ooms, Samantha Gadd, Daniela S. Gerhard, Malcolm A. Smith, Jaime M. Guidry Auvil, Daoud Meerzaman, Qing-Rong Chen, Chih Hao Hsu, Chunhua Yan, Cu Nguyen, Ying Hu, Yussanne Ma, Zusheng Zong, Andrew J. Mungall, Richard A. Moore, Marco A. Marra, Vicki Huff, Jeffrey S. Dome, Yueh-Yun Chi, Jing Tian, James I. Geller, Charles G. Mullighan, Jing Ma, David A. Wheeler, Oliver A. Hampton, Amy L. Walz, Marry M. van den Heuvel-Eibrink, Ronald R. de Krijger, Nicole Ross, Julie M. Gastier-Foster, Elizabeth J. Perlman
Journal: Clinical Cancer Research (2016)

Abstract Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. Conclusions: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582–91. ©2016 AACR.
Randomized placebo-controlled, double-blind trial of ketanserin in claudicants. Changes in claudication distance and ankle systolic pressure. PACK Claudication Substudy.
Journal: Circulation (1989)

The effect of ketanserin on intermittent claudication (measured by treadmill walking distance and ankle systolic pressure) was assessed in 594 patients, a subset of the 3,899 patients who composed a double-blind study of the effect of ketanserin on cardiovascular events. Complete data sets at the beginning and end of 1 year's treatment with ketanserin or placebo were available in 436 patients. There was no difference between the groups in the improvement in pain-free treadmill walking distance. The placebo effect on treadmill walking distance increased continuously for at least 1 year at the rate of about 15% every 6 months. There was no significant change in either group in the ankle systolic pressure at the end of the treatment period but in the group given ketanserin, brachial systolic pressure was decreased and the ankle to arm systolic pressure ratio therefore increased. There was only a very weak association between treadmill walking distance and ankle to arm systolic pressure ratio both at the beginning and in terms of change over 1 year. Therefore, this pressure ratio is probably not a useful way of assessing the effects of medical treatment of claudication.
Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study
Authors: Marjan de Vries, Dagmar C.M. van Rijckevorsel, Kris C.P. Vissers, Oliver H.G. Wilder-Smith, Harry van Goor
Journal: Clinical Gastroenterology and Hepatology (2016)
Phase II study of gefitinib treatment in advanced thymic malignancies
Authors: A. Kurup, M. Burns, S. Dropcho, W. Pao, P. J. Loehrer
Journal: Journal of Clinical Oncology (2005)

7068 Background: Thymomas and thymic carcinomas are rare epithelial tumors arising from the thymus gland. Malignant thymic tumors have shown to express the epidermal growth factor receptor (EGFR). This study evaluates the activity of gefitinib, an EGFR tyrosine kinase inhibitor, in patients (pts) with advanced thymoma/thymic carcinoma. Objectives: Primary objective was to determine the objective response rate of gefitinib in previously treated pts, with advanced thymoma or thymic carcinoma. Secondary objectives were to determine duration of remission and toxicity. Methods: Twenty-six (female = 15, male = 11) previously treated pts with metastatic thymoma (n = 19) or thymic carcinoma (n = 7), with ECOG performance status of 0 or 1, were enrolled from January 21, 2003 to June 14, 2004. Nineteen pts had prior radiation therapy. Median number of prior systemic therapies was 2.5 (range, 0 - 6). Pts received gefitinib orally at 250 mg daily. Each treatment cycle was 28 days. Pts obtaining a complete remission (CR), partial remission (PR), or stable disease (SD) for 2 treatment cycles, continued therapy until progression, or a maximum of 8 cycles of treatment. Genomic DNA was extracted from 5 paraffin-embedded tumor blocks and sequenced for mutations (EGFR exons 18 to 21, KRAS2 exon 2). Results: All 26 pts were evaluated for response and toxicity. There were 0 CRs, 1 PR (response duration = 5 months), and 14 SDs. Six pts had SD for > 4 months. Grade 3/4 adverse events noted were: dyspnea (grade 4, n = 1; grade 3, n = 2), fatigue (grade 4, n = 1), anemia/thrombocytopenia (grade 4, n = 1), and myocardial infarction (n = 1). After completing 3 cycles, the patient with a PR developed presumed gefitinib-induced Grade 2 pneumonitis, which resolved following steroids and discontinuation of treatment. Median time to progression (TTP) was 4 months (range, 1 - 17+). Twenty-five of the 26 pts remain alive. None of the 5 pts (including 1 PR), analyzed by DNA sequencing, had evidence of EGFR or KRAS mutations. Conclusions: With limited number of tumors analyzed in this study, EGFR mutations do not appear to be common in thymic malignancies. Gefitinib is well tolerated, with minimal activity in this heavily pretreated population. (Supported in part by AstraZeneca.) No significant financial relationships to disclose.
Steroid hormone status and HER2/neu expression in pregnancy-associated breast cancer
Authors: M. Litwiniuk, E. Breborowicz, D. Breborowicz, V. Filas, J. Breborowicz
Journal: Journal of Clinical Oncology (2007)

21115 Background: Breast cancer occurring during pregnancy or within the first year after delivery is considered to be a pregnancy-associated breast cancer. Some studies have shown a decreased estrogen receptor-positive and progesterone receptor-positive status in pregnant patients with breast cancer, others, however, have not. Moreover, little information is available about the expression of HER2/neu and about the other human estrogen receptor, estrogen receptor beta (ERbeta) in pregnancy-associated breast cancers. The aim of this work was to determine the extent of the expression of ER alpha and beta, progesterone receptor (PgR) and HER2/neu in pregnancy- associated breast cancer. Material and Methods: Formalin-fixed, paraffin embedded tissues from 16 patients with pregnancy- associated breast cancer were used in this study. Immunostaining for ERalpha, ERbeta and PgR was performed using monoclonal antibodies against ERalpha, PgR (DakoCytomation) and against ERbeta (CHEMICON). The EnVision detection system was applied. Tumors were considered to be expressing receptors if a positive reaction (regardless of intensity) could be identified in at least 10% of cells. The HER-2 status was analyzed using HercepTest TM (IHC), and IHC 2+ results were confirmed with FISH test. Results: 44% of the tumors (7/16) were ERalpha and PgR positive. The expression of ERbeta protein was observed in 94% of pregnancy-associated breast cancers. As many as 50% of ERbeta positive tumors showed no expression of ERalpha. Further, 31% (5 of 16) of breast cancers were HER2/neu positive. Conclusions: This frequent expression of ERbeta in pregnancy-associated breast cancer may result from their prodifferentiative functions which increase during pregnancy and lactation. No significant financial relationships to disclose.
Explanation of Errors in Abstract and Supplement and in the Reporting of Analyses
Authors: Dariush Mozaffarian
Journal: JAMA Internal Medicine (2016)

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Retrospective analysis of candidate predictive tumor biomarkers (BMs) for efficacy in the GOG-0218 trial evaluating front-line carboplatin–paclitaxel (CP) ± bevacizumab (BEV) for epithelial ovarian cancer (EOC).
Authors: Michael J. Birrer, YounJeong Choi, Mark F. Brady, Robert S. Mannel, Robert Allen Burger, WEI WEI, Amreen Husain, Carlos Bais
Journal: Journal of Clinical Oncology (2015)

5505 Background: In EOC, the double-blind placebo (PLA)-controlled randomized phase 3 GOG-0218 trial showed significantly improved progression-free survival (PFS) (but not overall survival [OS]) with BEV added to front-line CP and continued alone. Plasma BM correlative analyses identified no predictive BMs for efficacy. Tumor BM evaluation was an exploratory objective. Methods: Patients (pts) with stage III (incompletely resected) or IV OC were randomized to receive 6 cycles of CP with: PLA (CPP); BEV 15 mg/kg q3w → PLA (CPB15); or BEV for 15 mo (CPB15+). Five tumor BMs (CD31, tVEGF-A, VEGFR-2, NRP-1, MET) with a biologic rationale for evaluation were assessed by immunohistochemistry (IHC). The BM-evaluable population (BEP; all pts with an evaluable BM sample and ≥ 1 post-baseline efficacy assessment) was analyzed using 1st, 2nd and 3rd quartile (Q) expression levels for each BM as the cutoff for high vs low BM subgroups. Correlations between tumor BM levels and PFS and OS were analyzed. Results: The BEP, comprising 1455 (78%) of 1873 pts in the ITT population, had very similar baseline characteristics and efficacy to the ITT population. No prognostic or predictive association was seen for VEGFR-2, NRP-1 or MET. However, when comparing CPB15+ vs CPP (control), higher microvascular density (MVD) measured by CD31 IHC showed prognostic (not shown) and potential predictive value for PFS ( > Q3 MVD HR 0.38 [95% CI 0.25–0.58]; ≤ Q3 MVD HR = 0.68 [95% CI 0.54–0.86]; interaction p = 0.018) and OS ( > Q3 MVD HR 0.57 [95% CI 0.39–0.83]; ≤ Q3 MVD HR 1.03 [95% CI 0.83–1.27]; interaction p = 0.0069). tVEGF-A showed potential predictive value for OS (and PFS) for CPB15+ vs CPP with a Q3 cutoff ( > Q3 tVEGF-A OS HR 0.62 [95% CI 0.43–0.91]; ≤ Q3 tVEGF-A OS HR 1.01 [95% CI 0.82–1.25]; interaction p = 0.023). Conclusions: These retrospective tumor BM analyses suggest a positive correlation between expression levels of molecular (tVEGF-A) and cellular (endothelial cell) targets of anti-VEGF and magnitude of PFS and OS improvement from BEV in EOC. The predictive value of these candidate efficacy BMs requires validation in other relevant datasets. Clinical trial information: NCT00262847.
Correlation of an epigenetic mitotic clock with cancer risk
Authors: Zhen Yang, Andrew Wong, Diana Kuh, Dirk S. Paul, Vardhman K. Rakyan, R. David Leslie, Shijie C. Zheng, Martin Widschwendter, Stephan Beck, Andrew E. Teschendorff
Journal: Genome biology (2016)

Variation in cancer risk among somatic tissues has been attributed to variations in the underlying rate of stem cell division. For a given tissue type, variable cancer risk between individuals is thought to be influenced by extrinsic factors which modulate this rate of stem cell division. To date, no molecular mitotic clock has been developed to approximate the number of stem cell divisions in a tissue of an individual and which is correlated with cancer risk.Here, we integrate mathematical modeling with prior biological knowledge to construct a DNA methylation-based age-correlative model which approximates a mitotic clock in both normal and cancer tissue. By focusing on promoter CpG sites that localize to Polycomb group target genes that are unmethylated in 11 different fetal tissue types, we show that increases in DNA methylation at these sites defines a tick rate which correlates with the estimated rate of stem cell division in normal tissues. Using matched DNA methylation and RNA-seq data, we further show that it correlates with an expression-based mitotic index in cancer tissue. We demonstrate that this mitotic-like clock is universally accelerated in cancer, including pre-cancerous lesions, and that it is also accelerated in normal epithelial cells exposed to a major carcinogen.Unlike other epigenetic and mutational clocks or the telomere clock, the epigenetic clock proposed here provides a concrete example of a mitotic-like clock which is universally accelerated in cancer and precancerous lesions.
Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects With Type 2 Diabetes: The AMD Annals Initiative
Authors: Giuseppina T. Russo, Salvatore De Cosmo, Francesca Viazzi, Antonio Pacilli, Antonio Ceriello, Stefano Genovese, Pietro Guida, Carlo Giorda, Domenico Cucinotta, Roberto Pontremoli, Paola Fioretto
Journal: Diabetes Care (2016)

OBJECTIVE Despite the achievement of blood glucose, blood pressure, and LDL cholesterol (LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high among patients with type 2 diabetes. This observational retrospective study investigated whether diabetic dyslipidemia—that is, high triglyceride (TG) and/or low HDL cholesterol (HDL-C) levels—contributes to this high residual risk for DKD. RESEARCH DESIGN AND METHODS Among a total of 47,177 patients attending Italian diabetes centers, 15,362 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, normoalbuminuria, and LDL-C ≤130 mg/dL completing a 4-year follow-up were analyzed. The primary outcome was the incidence of DKD, defined as either low eGFR (&amp;lt;60 mL/min/1.73 m2) or an eGFR reduction &amp;gt;30% and/or albuminuria. RESULTS Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction &amp;gt;30%, 23.2% albuminuria, and 4% albuminuria and either eGFR &amp;lt;60 mL/min/1.73 m2 or an eGFR reduction &amp;gt;30%. TG ≥150 mg/dL increased the risk of low eGFR by 26%, of an eGFR reduction &amp;gt;30% by 29%, of albuminuria by 19%, and of developing one abnormality by 35%. HDL-C &amp;lt;40 mg/dL in men and &amp;lt;50 mg/dL in women were associated with a 27% higher risk of low eGFR and a 28% risk of an eGFR reduction &amp;gt;30%, with a 24% higher risk of developing albuminuria and a 44% risk of developing one abnormality. These associations remained significant when TG and HDL-C concentrations were examined as continuous variables and were only attenuated by multivariate adjustment for numerous confounders. CONCLUSIONS In a large population of outpatients with diabetes, low HDL-C and high TG levels were independent risk factors for the development of DKD over 4 years.
Deletion of the Tumor Suppressor Gene NF1 Is Found In 3.5% of 485 De Novo Adult Myeloid Leukemia and Is Correlated with Unfavourable Cytogenetic: On Behalf of the ALFA Group
Authors: Elise Labis, Catherine Roche-Lestienne, Olivier Nibourel, Nicolas Boissel, Christophe Roumier, Christine Terre, Christine Perot, Virginie Eclache, Nathalie Gachard, Isabelle Tigaud, Ghislaine Plessis, Wendy Cuccuini, Sandrine Geffroy, Nathalie Helevaut, Sabine Quief, Martin Figeac, Aline Renneville, Meyling Cheok, Bruno Quesnel, Herve Dombret, Claude Preudhomme
Journal: Blood (2010)
Associations with Retinal Pigment Epithelium Thickness Measures in a Large Cohort
Authors: Fang Ko, Paul J. Foster, Nicholas G. Strouthidis, Yusrah Shweikh, Qi Yang, Charles A. Reisman, Zaynah A. Muthy, Usha Chakravarthy, Andrew J. Lotery, Pearse A. Keane, Adnan Tufail, Carlota M. Grossi, Praveen J. Patel
Journal: Ophthalmology (2016)
Rapid, durable restoration of malignant ascites-derived antigen presenting cell immunogenicity by toll-like receptor agonists.
Authors: S. Jean, S. F. Adams, A. Facciabene, X. Peng, G. Coukos
Journal: Journal of Clinical Oncology (2010)

5094 Background: Ovarian cancer is an ideal target for immunotherapy. Women with evidence of spontaneous antitumor T cell response have significant survival advantage. However, the immunosuppressive tumor microenvironment impairs local antigen presentation resulting in T cell anergy. We have previously shown that T cell activating immune function of ascites-derived antigen presenting cells (aAPCs) can be rapidly restored ex vivo with toll-like receptor (TLR) agonists. The utility of these tumor antigen-primed cells is contingent on the durability of this effect once they are re-introduced into the peritoneal cavity. The aim of this study was to determine whether restored immunogenicity of aAPCs persists after re-exposure to malignant ascites. Methods: Ascites specimens were obtained at the time of primary debulking surgery for women with advanced epithelial ovarian cancer. CD14+ enriched aAPC populations were compared with whole ascites cell specimens. Each specimen was treated with the TLR agonists LPS and CPG, and a blocking antibody to the IL-10 receptor. The ability of each cell group to activate autologous ascites-derived T cells was then evaluated using IFN- g ELISA. These results were compared to T cell activation by these same treated specimens after subsequent re-exposure to autologous untreated ascites supernatant. Results: Both CD14+ aAPCs and whole ascites cells responded to TLR agonist stimulation by inducing T cells to produce high levels of IFN-g. This stimulatory effect was conserved in the aAPCs following re-exposure to malignant ascites supernatant, but diminished in the whole ascites samples. Conclusions: These results indicate that selective ex vivo treatment of CD14+ cells with TLR agonists results in restoration of their ability to stimulate a T cell response that can withstand re-exposure to the immunosuppressive tumor environment. The inability of treated whole ascites to maintain this T cell response further supports a sophisticated immunomodulatory tumor function that requires further study. These data are important in evaluating the peritoneal cavity as both a source for experienced immune cells and as a site to deliver antitumor immunotherapy. No significant financial relationships to disclose.