tbuckley/cabot-search huggingface dataset:
Phase II trial of dovitinib in recurrent glioblastoma.
Authors: Manmeet Singh Ahluwalia, Nikolaos Papadantonakis, Vyshak Alva Venur, Cathy Schilero, David M. Peereboom, Glen Stevens, Steven Rosenfeld, Michael A. Vogelbaum, Paul Elson, Andrew B. Nixon, Keith McCrae
Journal: Journal of Clinical Oncology (2015)

2050 Background: Glioblastoma (GBM) is a vascular tumor and bevacizumab (a monoclonal antibody against VEGF-A) is FDA-approved in recurrence. Mechanisms of resistance to anti VEGF therapy include up-regulated FGF signaling and increased PDGF-mediated pericyte coverage. Dovitinibis an oral, small-molecule tyrosine kinase inhibitor of FGFR 1-3, PDGFR β, and VEGFR 1-3. Methods: This was a phase II trial in adults with GBM, stratified by prior anti-angiogenic therapy (naive – arm A, refractory – arm B). Arm A's primary endpoint (PE) was PFS6 with a 2-stage accrual design to test the hypothesis that PFS6 was 36% vs. 55%. Arm B's PE was time to progression (TTP) and a one-stage design to test the hypothesis that median TTP could be increased from 1.5 to 3 months. Type I and II error was 10% and 20%, respectively in both arms. Extracellular vesicles (EV) were measured at study enrollment, at the end of cycle 1 (day 28), and at progression (PD) to evaluate response to therapy. Results: Nineteen patients enrolled in Arm A and 14 in Arm B. Accrual in arm A was stopped after the first stage due to futility. Overall 64% (21/33) of patients were male, median age at on-study was 57 years (range 26-68), and median KPS was 80 (range 60-90). In Arm A, PFS6 was 5% (1/19), median PFS was 1.8 months (95% C.I. 1.3-2.8) and median OS was 7.9 months (95% C.I. 3.6-11.7). In arm B, median TTP was 1.8 months (95% C.I. 1.0-1.8); median PFS was 1.8 months (95% C.I. 0.7-1.8) and median OS was 3.0 months (95% C.I. 0.8-4.7). In arm A, patients with PD had significantly higher levels of CD14+ EV (median 83289 vs 27500, p = 0.027) and CD142+ EV (median 38855 vs. 4675 , p = 0.042) compared to stable disease at end of cycle 1. Overall 5 patients (15%) reported grade 4 toxicities and 22 (67%) reported grade 3 reactions, primarily elevated lipids/lipase (42%), fatigue (21%), thromboembolic events (18%), hypertension (9%), and lymphopenia (9%). Other toxicity seen were grade 4 appendicitis/colitis (n = 1), oral pain and proteinuria (n = 1), and delirium (n = 1). Conclusions: Dovitinib is not active in recurrent GBM, regardless of prior anti-angiogenic therapy. In arm A, elevated pre-treatment levels of CD14+ and CD142+ EV were associated with PD, suggesting their potential role as a predictor of poor response to Dovitinib. Clinical trial information: NCT01753713.
Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure
Authors: Ravi V. Shah, Amanda Anderson, Jingzhong Ding, Matthew Budoff, Oliver Rider, Steffen E. Petersen, Majken Karoline Jensen, Manja Koch, Matthew Allison, Nadine Kawel-Boehm, Jessica Wisocky, Michael Jerosch-Herold, Kenneth Mukamal, João A.C. Lima, Venkatesh L. Murthy
Journal: JACC. Cardiovascular imaging (2017)
Vorinostat (V) intratumoral levels and biomarker response in a window of opportunity trial in patients with resectable aerodigestive tract cancer.
Authors: Konstantin H. Dragnev, Jan Hendrik Beumer, Bean Anyang, Tian Ma, Fabrizio Galimberti, Cherie Parungo Erkmen, William Nugent, James R. Rigas, Kathryn Abraham, David Johnstone, Vincent Memoli, Ethan Dmitrovsky
Journal: Journal of Clinical Oncology (2012)

7022 Background: Aerodigestive tract cancer (ADT) is the leading cause of cancer-related death in the US. New effective treatments are needed. Among a panel of drugs causing growth inhibition of lung cancer cells and repression of cyclin D1, the histone deacetylase inhibitor V was found most potent. To translate studies into the clinic, a window of opportunity trial of V was conducted. Methods: Pts with resectable ADT received 400 mg V once daily orally for 7 days prior to surgical resection. Serum samples were obtained before the last V dose and at the time of biopsy. Tumor tissue was immediately snap-frozen in liquid nitrogen, stored at -70°C, homogenized in three parts PBS (1:3g/v). V was quantitated with a LC-MS/MS assay. Post- versus pre-treatment tumor biopsies were scored for necrosis, acute and chronic inflammation, and immunohistochemical changes in Ki-67, cyclin E, cyclin D1, EGFR, phospho-EGFR, p21, p27 and caspase. Results: 15 pts enrolled, 9 pts took V for a median of 7 days (3-9), underwent resection and had adequate pretreatment samples. Median age 66, 4 women, 4 former, 5 current smokers, 1 squamous cell lung carcinoma, 8 adenocarcinoma (1 esophageal). PK analyses confirmed plasma (8pts) and tumor (7pts) concentrations above the detection limits. There was considerable interindividual variation in plasma V concentrations (7.3-192.4 ng/ml; CV 95%), at 178-500 min from last V dose, and in intratumoral V levels (15.0-80.3 ng/g; CV 59%). All pts had wild-type EGFR, 4 pts had KRAS codon 12 mutations, 78% showed reduced Ki-67 expression, 50% had decreased cyclin E, 78% exhibited necrosis, chronic or acute inflammation in the post-treatment biopsies. Most cases with KRAS mutations had biomarker responses. Changes in multiple biomarkers were observed across the range of intratumoral V levels. Conclusions: This is the first report of V concentrations in human tumors. Preoperative treatment with V achieved intratumoral concentrations comparable to serum with evidence of necrosis, decreased Ki-67 and cyclin E, and other biomarker responses in resected ADT. The results demonstrate the value of window of opportunity trials in the investigation of novel cancer therapeutics.
Comprehensive analysis of <i>KRAS</i> and <i>NRAS</i> mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408).
Authors: Scott D. Patterson, Marc Peeters, Salvatore Siena, Eric Van Cutsem, Yves Humblet, Jean-Luc Van Laethem, Thierry Andre, Ying Tian, Roger Sidhu, Kelly S. Oliner
Journal: Journal of Clinical Oncology (2013)

3617 Background: An exploratory biomarker analysis of the randomized, phase 3 monotherapy 20020408 study of pmab vs best supportive care (BSC) demonstrated that mutations in KRAS exon 3 and NRAS exons 2 and 3 appeared to be predictive of pmab response (Peeters et al, 2013). We expanded these results to determine whether mutations in exon 4 of the KRAS and NRAS genes are predictive for pmab treatment and to determine the treatment effect in the overall wild-type (WT) KRAS and NRAS population. Methods: Using a combination of Next Generation Sequencing, Sanger Sequencing, and WAVE-based SURVEYOR Scan Kits from Transgenomic, archival patient tumors were examined for mutations in KRAS and NRAS exon 4. These data were combined with previously presented data from KRAS and NRAS exon 2 and 3 analyses for evaluation of the comprehensive WT KRAS and NRAS subgroup. Results: 9/243 (3.7%) and 2/243 (0.8%) patient tumors with WT KRAS exon 2 status harbored a mutation in KRAS or NRAS exon 4, respectively. One tumor had mutations in both KRAS and NRAS exon 4. In the pmab arm, patients with WT KRAS and WT NRAS tumor status had an objective response rate (ORR) of 15% (11/72) whereas patients with mutant (MT) KRAS or MT NRAS tumor status had an ORR of 1% (1/95; 1 patient with MT KRAS exon 4 had a partial response). There were no responses in the BSC arm regardless of the tumor status. In this analysis set, the treatment hazard ratio (HR; pmab:BSC) for progression-free survival (PFS) in the WT KRAS and WT NRAS subgroup was 0.38 (95% CI: 0.27 - 0.56), and in the MT KRAS or MT NRAS subgroup was 0.98 (95% CI: 0.73 - 1.31). The original WT KRAS exon 2 subgroup PFS HR was 0.45 (95% CI: 0.34 - 0.59) (Amado et al, 2007). Conclusions: This exploratory analysis suggests that mutations in KRAS and NRAS exon 4 occur in a small, but meaningful percentage of patients with mCRC. Extending previous findings from this study in patients with MT KRAS and/or MT NRAS exon 2 and/or 3 tumors, patients with MT KRAS and/or MT NRAS exon 4 tumors do not appear to benefit from pmab therapy. Clinical trial information: NCT00113763.
Predictors of response to platinum (Pt)-based chemotherapy in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Deepak Kilari, Kathryn A. Bylow, Kathryn E. K. Berlin
Journal: Journal of Clinical Oncology (2017)

e575 Background: Aggressive variant PC (AVPC) is a well-described subtype of PC which portends a poor prognosis. Studies have shown an increase in progression-free survival(PFS) when Pt is added to taxane-based treatment in AVPC. Clinical features including visceral metastasis, lytic bone lesions, low PSA, short responses to androgen suppression and high Gleason score at diagnosis predict response to upfront docetaxel (D) and Pt (Aparicio et. al. Clin Cancer Res 2013). Our objective was to study the effect of baseline characteristics on PFS with D+Pt in D-pretreated CRPC. Methods: A retrospective review of D-pretreated mCRPC men who received D (60-75 mg/m2) and carboplatin (C, AUC 4-5) at our institution between 2008- 2015 were included in this analysis. All patients had metastatic CRPC, were heavily pre- treated (median treatments = 4) and received at least one cycle of D+C. Numerical data was analyzed using Student’s T-test; binary data was analyzed with Z-proportions test. Results: 28 patients were identified. The median age was 60 yrs(48-73); median PSA at diagnosis was 21ng/dl(0.3-5000); median PSA at the start of D+C was 115.32 ng/dl( 0.65-1395). The response rate was 60.7% and the median time to response was 1 mo. The median reduction in PSA was 48.13%. The median PFS was 6 mo, and median OS was 10 mo. Common treatment – related side effects included grade 1 fatigue (82.14%), pancytopenia (42.86%), and febrile neutropenia (10.71%). Correlation of baseline characteristics to PFS was evaluated. Short response to ADT &lt; 1 yr (p &lt; 0.05), prior response to D (PFS &gt; 6 months) ( p = 0.037), and presence of visceral mets (p &lt; 0.05) predicted better response to D+C. Age (p = 0.27), Gleason score at diagnosis (p = 0.08), performance status at start of therapy (p = 0.27), PSA at diagnosis (p = 0.35), and PSA at start of D+C (p = 0.420) did not predict response. Conclusions: D+C is effective and safe in D pretreated CRPC. Response to prior D, short response to ADT, and the presence of visceral metastasis predicted response to D+C. These are features of AVPC. Prospective studies to validate our findings and identify molecular characteristics of Pt responders are needed in this heavily pre-treated “real world” patient population.
Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways
Authors: Jingkun Zhao, Baochi Ou, Dingpei Han, Puxiongzhi Wang, Yaping Zong, Congcong Zhu, Di Liu, Minhua Zheng, Jing Sun, Hao Feng, Aiguo Lu
Journal: Molecular Cancer (2017)

Metastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood.Herein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo.We found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3β/β-catenin pathway in a CXCR2-dependent manner. The silencing of Snail and β-catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model.In conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients.
Carboplatin dosing in the treatment of epithelial ovarian cancer (EOC): A Gynecologic Oncology Group (GOG) study.
Authors: Roisin Eilish O'Cearbhaill, Austin Miller, Franco Muggia, Judith A. Smith, Michael A. Bookman, Paul Sabbatini
Journal: Journal of Clinical Oncology (2012)

5041 Background: Optimal carboplatin dosing (CPRx) for patients (pts) with renal dysfunction or low creatinine (Cr) values in the setting of malnutrition and ascites is unknown. Multiple methods have been utilized to estimate Cr clearance (CrCl) but these perform differently in pts with abnormal Cr values. We sought to determine 1) the relationship between adverse events (AE) and baseline CrCl used for CPRx; 2) the effect on CPRx of using Cockcroft-Gault (CG) +/- the NCI/CTEP recommended limits (CGL), Modification of diet in renal disease (MDRD) or Jelliffe Formula (J) renal function estimates. Methods: Retrospective data were drawn from pts treated on GOG 182, a phase III trial of carboplatin doublet vs triplet or sequential doublet combinations in stage III/IV EOC. For patient safety, the protocol was amended to assign the lower limit of Cr at 0.6mg/dl for CPRx. Area under the receiver operating characteristic curve (AUC) was used to describe associations between CrCl J and various AE. Sensitivity and positive predictive values (PPV) described the AE rate in pts with CrCl J &lt;60ml/min. CPRx for each pt was calculated using J, CG, CGL and MDRD. Results: 3830 evaluable pts had a mean age 58.7yrs, mean BMI 26.8kg/m 2 and mean baseline CrCl J 81.9ml/min (range 23.4-239). The AUC statistics (range 0.52-0.64) show that the log(CrCl J ) was not a good predictor of grade ≥3 AE (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). A cutoff value of CrCl J &lt;60 ml/min would have deemed 15% of pts treated on GOG182 ineligible. The range of PPV for the above AEs in pts with CrCl J &lt;60 ml/min was 1.8-15%. Using CG, CGL, MDRD instead of J for CPRx would have resulted in &gt;10% decrease in CPRx in 21%, 32% and 12% of pts, respectively. Using CG, CGL, MDRD instead of J for CPRx would have resulted in &gt;10% increase in CPRx in 45%, 9.6% and 5.2% of pts, respectively. Conclusions: Our data do not support excluding patients with CrCl J &lt;60ml/min from clinical trials. The new GOG guidelines replacing J with CGL affect CPRx. The clinical significance of this change with regards to toxicity, particularly in pts with abnormally low Cr values, is yet to be determined.
SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST)
Authors: G. D. Demetri, J. Desai, J. A. Fletcher, J. A. Morgan, C. D. M. Fletcher, A. Kazanovicz, A. Van Den Abbeele, C. Baum, R. Maki, M. C. Heinrich
Journal: Journal of Clinical Oncology (2004)

3001 Background: Resistance to Imatinib mesylate (IM) following initial tumor regression and disease control in GIST is increasingly recognized as an unmet medical need. IM resistance can be correlated with the appearance of secondary mutations in the KIT or PDGFRA tyrosine kinases in GIST lesions refractory to IM; activation of alternative signaling pathways and different structural biology of the new mutant kinases contribute to emergence of IM-resistant GIST clones. Methods: Phase I/II clinical trial of SU11248 in pts with progressing IM-resistant GIST. Tumor biopsies were obtained to define the mutational status of the KIT and PDGFRA kinases by dHPLC and sequencing assays. Results: 98 pts with progressive GIST have been enrolled in this ongoing study; with tumor response data available in 48 pts and GIST genotype determined in 41. The phase II regimen chosen was SU11248 50 mg orally once daily for 4 weeks, followed by a 2 week period off drug in each 6 wk cycle. SU11248 therapy induced clinical benefit (defined by objective response or stable disease for ≥ 6 months) in 26/48 (54%) of these previously progressing pts, with 6/48 (13%) confirmed partial responses (PR). KIT exon 9 mutants had fewer secondary mutations than Exon 11 GIST. Conclusions: SU11248 therapy can induce objective responses and control progressive disease in pts with several mutational variants of GIST with different genomic mechanisms of resistance to IM. These data are the basis for a phase III trial to define further the activity of SU11248 in pts with IM-resistant GIST. Understanding the efficacy of SU11248 in IM-resistant GIST should help to elucidate the structural biology of PDGFRA, KIT and other aberrant signaling pathways in the pathogenesis of GIST and may have relevance to molecularly targeted therapies for other malignancies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Novartis; Pfizer Pfizer Novartis; Pfizer Pfizer Oncology
Feasibility of computer-based self-administered cancer-specific geriatric assessment (SA-CSGA) in older pts with gastrointestinal malignancy (GIM).
Authors: Nadine Jackson McCleary, Devin Wigler, Donna Lynn Berry, Kaori Sato, Arti Hurria, Kimmie Ng, Thomas Adam Abrams, Jennifer A. Chan, Peter C. Enzinger, Charles S. Fuchs, Brian M. Wolpin, Deborah Schrag, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2012)

e19586 Feasibility of computer-based self-administered cancer-specific geriatric assessment (SA-CSGA) in older pts w/ gastrointestinal malignancy (GIM) Background: The CSGA (Hurria, JCO 2011) is a brief geriatric assessment consisting of validated measures primarily self-administered using paper format. We developed &amp; tested feasibility of a computer-based SA-CSGA in pts ≥70 yrs w/ GIM. Methods: From 12/2009 - 6/2011, pts ≥70 yrs receiving treatment (rx) for GIM at Dana-Farber Cancer Institute were consented to complete SA-CSGA at baseline (T 1 = new or change rx) &amp; follow-up (T 2 = w/in 4 wks of completing rx). Feasibility endpts are (1) proportion of eligible pts consenting; (2) proportion completing SA-CSGA at T 1 &amp; T 2 ; (3) time to completion of SA-CSGA; (4) proportion of MDs reporting change in clinical decision-making due to SA-CSGA. Results: Of the 49 eligible pts, 38 consented (55% female, 89% White, 76% enrolling prior to new rx). Mean age was 77yrs (range 70-89), 38% completed college, 49% married, 27% live alone, and 78% retired. 50% were diagnosed w/ colorectal cancer (ca). Mean MD-rated Karnofsky Performance Status was 87.5 at T 1 (range 60-100), 83.5 at T 2 (range 70-100). At T 1 , 92% used a touch screen computer; 97% completed the SA-CSGA (51% independently). At T 2 , all pts used a touch screen computer; 71% completed the SA-CSGA (41% independently). Reasons for not completing SA-CSGA were withdrawal of consent (n=1 at T 1 &amp; T 2 ), transfer of care (n=3; T 2 ) or death (n=7; T 2 ). The dominant reason for needing assistance was lack of computer familiarity (n=17 T 1 , n=14 T 2 ). Mean time to completion was 23min at T 1 (range 15-58); 20min at T 2 (range 13-35). Among the 8 MDs who consented to participate, SA-CSGA added information to clinical assessment for 75% at T 1 (n=27) and 65% at T 2 (n=17) but did not alter immediate clinical decision-making. Conclusions: The computer-assisted SA-CSGA feasibility endpt was met for older pts w/ GIM although approximately half required assistance. While the SA-CSGA added information to clinical assessment, results did not impact clinical decision-making. Reasons for this may include relatively high-functioning patients enrolled in this study.
Evaluation of Automated Molecular Testing Rollout for Tuberculosis Diagnosis Using Routinely Collected Surveillance Data — Uganda, 2012–2015
Authors: Colleen Scott, Simon Walusimbi, Bruce Kirenga, Moses Joloba, Muttamba Winters, Nyombi Abdunoor, Rommel Bain, Heather Alexander, Tom Shinnick, Sean Toney, Rosemary Odeke, Christine Mwangi, Estella Birabwa, Seyoum Dejene, Frank Mugabe, Mukadi YaDiul, J. Sean Cavanaugh
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

In 2012, Uganda introduced the use of GeneXpert MTB/RIF (Cepheid, Sunnyvale CA), a sensitive, automated, real-time polymerase chain reaction-based platform for tuberculosis (TB) diagnosis, for programmatic use among children, adults with presumptive human immunodeficiency virus (HIV)-associated TB, and symptomatic persons at risk for rifampicin (RIF)-resistant TB. The effect of using the platform's Xpert MTB/RIF assay on TB care and control was assessed using routinely collected programmatic data; in addition, a retrospective review of district quarterly summaries using abstracted TB register data from purposively selected facilities in the capital city of Kampala was conducted. Case notification rates were calculated and nonparametric statistical methods were used for analysis. No statistically significant differences were observed in case notification rates before and after the Xpert MTB/RIF assay became available, although four of 10 districts demonstrated a statistically significant difference in bacteriologically confirmed TB. Once the GeneXpert MTB/RIF platform is established and refined, a more comprehensive evaluation should be conducted.