tbuckley/cabot-search huggingface dataset:
A meta-analysis of potential contribution of genetic polymorphisms in drug-metabolizing enzymes/transporters to axitinib pharmacokinetic (PK) variability in healthy volunteers.
Authors: J. A. Williams, M. Brennan, Y. Chen, M. A. Tortorici, Y. K. Pithavala, Y. C. Liu
Journal: Journal of Clinical Oncology (2011)

e13033 Background: Axitinib (AG-013736) is an oral, potent, and selective inhibitor of VEGF receptors 1, 2, and 3 with clinical efficacy in various human solid tumors, including advanced renal cell carcinoma. Axitinib is primarily metabolized by cytochrome P450 (CYP) 3A4/5 but also is a substrate for CYP1A2, CYP2C19, and UDP-glucoronosyltransferase (UGT) 1A1 enzymes, and the drug transporters P-glycoprotein (encoded by the ABCB1 gene), and OATP1B1 (SLC01B1). This analysis explored whether single-nucleotide polymorphisms (SNPs) in genes encoding these enzymes and transporters could contribute to the observed variability in axitinib PK in healthy volunteers. Methods: A meta-analysis of pooled data from 11 healthy volunteer studies of axitinib was performed. Axitinib plasma exposure (area under the concentration–time curve) was estimated using noncompartmental methods, and major SNPs for CYP2C19, CYP3A4, CYP3A5, UGT1A1, and drug transporters were assayed; based on the detected genotype, the phenotype for each enzyme was inferred. The potential genetic effect on PK was fitted through a statistical model using age, gender, fasting/fed status, and body mass index as covariates. Since none of the study-by-genetic-effect interactions were statistically significant, a fixed effects meta-analysis model was selected for every genetic polymorphism instead of a random effects meta-analysis model. The genetic effect was estimated using two contrasts (or log ratios) of axitinib plasma AUC: homozygous variant genotypes vs homozygous wild-type genotypes, and heterozygous genotypes vs homozygous wild-type genotypes. Results: Up to 315 healthy volunteers per SNP were assayed. After multiplicity adjustment using the fixed effects meta-analysis model, no statistically significant associations were seen between the genetic polymorphisms evaluated and axitinib PK variability. Axitinib PK variability attributed to gene polymorphisms was below 5%. Conclusions: None of the genetic polymorphisms analyzed was a statistically significant predictor of axitinib PK variability.
Magnetic resonance lymphography to localise pelvic lymph nodes for intensity-modulated radiotherapy in gynaecological cancer
Authors: A. Taylor, A. G. Rockall, M. E. B. Powell
Journal: Journal of Clinical Oncology (2004)

5070 Background: Intensity-modulated radiotherapy (IMRT) for gynaecological tumours requires accurate target volume delineation. Pelvic lymph nodes are poorly visualised on CT and MRI. Blood vessels with a 1–2cm margin are currently used as surrogate targets. A significant volume of small bowel is potentially irradiaited due to uncertainty about the exact lymph node position. Ultrasmall superparamagnetic iron oxide (USPIO), a novel MR contrast agent, localises in macrophages causing normal lymph nodes to appear black on MR images. This study used USPIO to determine the position of pelvic lymph nodes in relation to anatomic structures and develop guidelines for nodal irradiation. Methods: 15 patients with endometrial or cervical cancer had a diagnostic MRI (4mm slices) with subsequent USPIO administration and a repeat scan after 24 hours. All common iliac, presacral, external iliac, internal iliac and obturator nodes were outlined. On 10 scans, vessels were expanded by a margin of 15mm, 10mm, 7mm, 5mm and 3mm. The obturator and upper sacral regions were included with a corresponding margin. Nodal contours were overlaid on each expanded volume and analysed for coverage. Small bowel within each planning target volume (PTV) was measured. The resulting nodal irradiation guidelines were applied to the next 5 patients. Results: 836 nodal contours were evaluated. The mean number per patient was 56 (range 29–106). Contours covered by 15mm, 10mm, 7mm, 5mm and 3mm expansion were 99%, 96%, 90%, 77% and 63% respectively. The mean PTV bowel volume was 284, 204, 159, 130 and 102cm3. From these results, volume guidelines using an adjusted 7mm margin were applied to a further 5 patients resulting in 97% nodal coverage. Conclusions: MR lymphography with USPIO is an innovative technique to locate pelvic lymph nodes. Guidelines have been developed from these data for pelvic nodal irradiation with IMRT and conformal radiotherapy. A modified 7mm margin around vessels is recommended. This reduction in the margin reduces the small bowel volume within the PTV by 22% without compromising tumour coverage. No significant financial relationships to disclose.
Prevention of Symptomatic Skeletal Events with Denosumab Administered Every 4 Weeks Versus Every 12 Weeks–A Non-Inferiority Phase III Trial: Sakk 96/12 - Reduse
Authors: A.J. Templeton, L. Stalder, L. Albiges Sauvin, J. Bernhard, P. Brauchli, S. Gillessen, S. Hayoz, D. Klingbiel, K. Matter-Walstra, B. Thürlimann, R. von Moos
Journal: Annals of Oncology (2014)
Agglutination of &lt;italic&gt;In Vitro&lt;/italic&gt; Cultured Neoplastic and Non-Neoplastic Cell Lines by a Wheat Germ Agglutinin
Authors: R. Raymond Gantt, John R. Martin, Virginia J. Evans
Journal: JNCI Journal of the National Cancer Institute (1969)

A glycoprotein, present as a contaminant in a wheat germ lipase extract, has been reported to be a specific agglutinin for neoplastic cells. This agglutinin was tested on six established cell lines cultured in vitro, five neoplastic and one non-neoplastic. The results indicate that in our in vitro system there is no general correlation between ability to agglutinate and ability to cause tumors when the cells are injected into syngeneic animals. Two of the five neoplastic lines tested demonstrated essentially the same degree of agglutination as the non-neoplastic line examined.
Sequence variations in small-subunit ribosomal RNAs of Hartmannella vermiformis and their phylogenetic implications.
Authors: P H Weekers, R J Gast, P A Fuerst, T J Byers
Journal: Molecular Biology and Evolution (1994)

Evidence of associations between free-living amoebas and human disease has been increasing in recent years. Knowledge about phylogenetic relationships that may be important for the understanding of pathogenicity in the genera involved is very limited at present. Consequently, we have begun to study these relationships and report here on the phylogeny of Hartmannella vermiformis, a free-living amoeba that can harbor the etiologic agent of Legionnaires' disease. Our analysis is based on studies of small-subunit ribosomal RNA genes (srDNA). Nucleotide sequences were determined for nuclear srDNA from three strains of H. vermiformis isolated from the United Kingdom, Germany, and the United States. These sequences then were compared with a sequence previously obtained for a North American isolate by J. H. Gunderson and M. L. Sogin. The four genes are 1,840 bp long, with an average GC content of 49.6%. Sequence differences among the strains range are 0.38%-0.76%. Variation occurs at 19 positions and includes 2 single-base indels plus 14 monotypic and 3 ditypic single-base substitutions. Variation is limited to eight helix/loop structures according to a current model for srRNA secondary structure. Parsimony, distance, and bootstrap analyses used to examine phylogenetic relationships between the srDNA sequences of H. vermiformis and other eukaryotes indicated that Hartmannella sequences were most closely related to those of Acanthamoeba and the alga Cryptomonas. All ditypic sites were consistent with a separation between European and North American strains of Hartmannella, but results of other tests of this relationship were statistically inconclusive.
A phase II study of oxaliplatin and pemetrexed plus bevacizumab in advanced non-squamous non-small cell lung cancer
Authors: J. M. Waples, M. Auerbach, R. Boccia, R. G. Wiggans, R. Steis
Journal: Journal of Clinical Oncology (2007)

18025 Background: As single agents, oxaliplatin and pemetrexed have shown activity in patients with non-small cell lung cancer (NSCLC) and pemetrexed has demonstrated synergistic effectiveness when combined with platinum-based drugs. Moreover, bevacizumab has an additive effect on many chemotherapy agents in several tumor types, including NSCLC. The purpose of this phase II, open-label, non- randomized study is to evaluate the efficacy and safety of the combination of bevacizumab, oxaliplatin, and pemetrexed as first-line treatment for NSCLC. This report presents preliminary safety information demonstrating the safety and tolerability of this combination. Methods: Patients = 18 years with histologically/pathologically confirmed Stage IIIB/IV non-squamous NSCLC received 6 cycles of oxaliplatin (120 mg/m 2 ), pemetrexed (500 mg/m 2 ), and bevacizumab (15 mg/kg) on Day 1 of each 21-day cycle. Following 6 cycles, patients received bevacizumab alone every 21 days until disease progression or unacceptable toxicity. Results: At the time of analysis, 53 subjects received study medication and are evaluable for safety. Patient characteristics include: gender male/female/unknown, 16/34/3; median age 62.0 years (range 43–86); and ECOG performance status 0/1/unknown, 24/25/4. The median number of cycles administered is 4 (range 1–11). Fifty patients are still on study. The most common Grade 3 toxicities were neutropenia (10.4%), dyspnea (6.0%), fatigue (4.5%), thrombocytopenia (4.5%), hyperglycemia (4.5%), nausea (3.0%), and vomiting (3.0%). Grade 4 toxicities were dyspnea (1.5%), hyperglycemia (1.5%), asthenia (1.5%), thrombocytopenia (3.0%), neutropenia (3.0%), and pulmonary embolism (1.5%). Three patients died; 2 of progressive disease and 1 of hypoxia (not likely related to study drugs). Conclusions: These preliminary results suggest that the combination of oxaliplatin, pemetrexed, and bevacizumab demonstrates an acceptable safety profile for first-line treatment of stage IIIB/IV NSCLC. Conclusions concerning the efficacy of this combination await further treatment information. Supported by Genentech, Inc., Sanofi-Aventis, and Eli Lilly and Company. [Table: see text]
Association of extensive delayed overmethylation influenced by advanced atrophy with risk for gastric cancer.
Authors: Jung Hwan Oh, Sung Hoon Jung, DaeYoung Cheung, Mun Gan Rhyu, Seung Jin Hong
Journal: Journal of Clinical Oncology (2015)

13 Background: Helicobacter pylori (HP) infection facilitates overmethylation of CpG-island genes, which can be delayed by advanced mucosal atrophy. Delayed overmethylation results in unstable cell phenotypes responsible for gastric cancer. To delineate cancer risk period, the overmethylation period from HP infection to severe atrophy was traced in the gastric cancer and dysplasia. Methods: A pair of normal-appearing mucosal specimens was obtained from the antrum and body of 110 HP-positive and 95 HP-negative controls, 99 cancer patients, and 118 dysplasia patients. Gastric mucosal atrophy was assessed using the endoscopic atrophic border score. Eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, TRAPPC2L) and LTR retroelements (MMP2, CDKN2A, RUNX2, RUNX3) and the TFF3 gene lacking CpG island were chosen. The methylation-variable sites in gene-control regions were analyzed using radioisotope-labeling methylation-specific PCR. Results: The antrum-specific TFF3 gene on the antrum tended to be overmethylated earlier than Alu-type CpG-island genes on the body in the HP-positive controls with mild mucosal atrophy (mean age; 50 years vs. 52 years). In moderate atrophic cases, the antrum-site TFF3 overmethylation was delayed four years compared with the whole cases (58 years vs. 54 years) and the Alu-type overmethylation on the body was early detected (49 years). Gastric cancer patients with moderate atrophy induced a late overmethylation on both the antrum and body site (56 and 58 years) and increased LTR-type slow overmethylation (OD, 5.3; 95% CI, 2.0-14.1). Dysplasia patients (65 years) older than gastric cancer sustained an early Alu-type overmethylation on the body site. Conclusions: Moderate atrophy of the gastric mucosa can delay overmethylation of CpG-island genes, which leads to unstable cancer period and subsequent stable dysplasia period.
Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study
Authors: S.D. Fossä, G. Martinelli, U. Otto, G. Schneider, H. Wander, F. Oberling, H.W. Bauer, U. Achtnicht, E.E. Holdener
Journal: Annals of Oncology (1992)
Abstract 231: Relationship Between Early Lactate Clearance With Improved Mortality in Cardiac Arrest Patients With Cardiopulmonary Bypass
Authors: Kei Hayashida, Masaru Suzuki, Akio Kawamura, Yuichiro Maekawa, Akiko Shiroshita-Takeshita, Yukio Satoh, Shingo Hori
Journal: Circulation (2010)

Objective: Early lactate clearance has been reported to be associated with improved mortality in patients with post cardiac arrest syndrome. It seems that hypoperfusion plays in an important role i...
Adjuvant chemotherapy with uracil-tegafur (UFT) for serosa negative advanced gastric cancer: Results of a randomized trial by national surgical adjuvant study of gastric cancer
Authors: T. Kinoshita, T. Nakajima, Y. Ohashi
Journal: Journal of Clinical Oncology (2005)

4021 Background: To evaluate the survival benefit of adjuvant chemotherapy with UFT after curative resection in AGC patients (pts) with t2 and n1–2, a multi-center phase III clinical trial was conducted by 31 participating centers in Japan. Methods: Eligibility included pts with curative gastrectomy with D2 or greater lymph node dissection also with t2 and n1–2 AGC; PS:0–2; no prior chemotherapy. Patients were randomized in a 1:1 ratio to adjuvant chemotherapy or surgery alone. The treatment arm consisted of oral UFT 360mg/m2 (400–600mg/body)/day 6 weeks after surgery for the following 16 months. The primary endpoint was overall survival. Relapse-free survival and the site of recurrence were secondary endpoints. Assuming 244 eligible pts in each arm, the study had 0.8 power to detect 8.8% difference in 5-year survival rate. However this study was closed at an accrual of 190 pts because of slow recruitment and necessity to start adjuvant trial with more promising anticancer drug, S-1. All p-values reported are two-sided. Results: Between 06/1997 to 03/2001, 188 pts were randomized to chemotherapy arm (93 pts) or surgery alone arm (95 pts) excluding two pts with early gastric cancer. There was no treatment-related death. Although grade 3 adverse events were observed in 33% of pts (neutropenia (13.3%), increase in serum total bilirubin (9.0%), etc), grade 4 adverse effects (diarrhea) appeared in only one patient (1.1%) in the chemotherapy arm. A planned interim analysis using the Lan & DeMets stopping rule at 3.8-year of a median follow up showed significant difference in overall and relapse-free survival between the arms (4-year survival 86.3% chemotherapy vs. 73.6% surgery alone; P=.0176 and 4-year relapse-free survival 84.5% chemotherapy vs. 68.1% surgery alone; P=.0040 respectively). Fourteen pts in chemotherapy arm and 31 pts in surgery alone arm were confirmed to have cancer recurrence. Conclusions: There was definitive benefit in overall and relapse-free survival with this adjuvant chemotherapy. We recommend adjuvant chemotherapy with this regimen for this population in clinical practice, although the planned sample size was not attained. No significant financial relationships to disclose.
Abstract 12847: A New Assay of Measuring Platelet Reactivity Using Monoclonal Antibody Against Activated Platelet Glycoprotein IIb/IIIa in a Whole Blood
Authors: Seung-Jae Joo, Joon-Hyouk Choi, Song-Yi Kim, Ki-Seok Kim, Young-Ree Kim
Journal: Circulation (2014)

Introduction:  Clopidogrel binds to P2Y12 ADP receptors of platelets to inhibit aggregation. However, in some patients with coronary artery diseases, platelet aggregation is not inhibited despite taking clopidogrel. Although VerifyNow P2Y12 assay is commonly used to measure residual platelet reactivity, it is a kind of light transmission aggregometry. Activation and prothrombin binding of platelet glycoprotein (GP) IIb/IIIa is a final common pathway of platelets aggregation. If the reactivity of platelet GP IIb/IIIa is directly measured, that will be a more accurate assay to evaluate residual platelet reactivity.   Hypothesis:  PAC1, a monoclonal antibody against activated platelet GP IIb/IIIa, and flow cytometric analysis would be used to measure platelet reactivity.   Methods:  Twenty seven patients with coronary artery disease who were taking clopidogrel were enrolled in this study. Whole blood was withdrawn into a sodium citrate coated tube. FITC-conjugated PAC1 15 μL (3 μg) was incubated for 15 minutes with 5 μL of whole blood in a mixture, consisted of 5 μL of ADP, and 25 μL of isotonic HEPES buffer (total volume 50 μL). Final concentrations of ADP were 1, 10, or 20 μM. After fixation with 1% paraformaldehyde, flow cytometric analysis was performed with BD FACSCalibur. Mean fluorescence intensity (MFI) and % positive platelets (PP) were measured and binding index (BI: MFI x %PP/100) was calculated. P2Y12 reaction unit (PRU) and %inhibition of VerifyNow assay were also measured in a usual manner.   Results:  PRU of VerifyNow assay correlated significantly with MFI, %PP, and BI at 10 μM (r=0.59, 0.73, and 0.60, all p   Conclusions:  Direct measurements of the reactivity of platelet GP IIb/IIIa were feasible using PAC1 and flow cytometry. Cut-off values of this assay to define residual platelet reactivity are needed to be determined in the clinical study.
Response to Letters Regarding Article, “Efficacy of Long-Term β-Blocker Therapy for Secondary Prevention of Long-Term Outcomes After Coronary Artery Bypass Grafting Surgery”
Authors: Zhe Zheng, Heng Zhang, Xin Yuan, Haibo Zhang, Sipeng Chen, Yan Zhao, Kun Hua, Chenfei Rao, Wei Wang, Hansong Sun, Shengshou Hu
Journal: Circulation (2016)
<i>MLT/MALT1</i> involving translocations and amplifications are important mechanisms in the pathogenesis of non-Hodgkin’s lymphoma
Authors: E. M. Murga Penas, W. Lampe, K. Hinz, T. Zivković, K. Röser, C. Copie-Bergmann, P. Gaulard, T. Löning, R. Parwaresch, D. K. Hossfeld, J. Dierlamm
Journal: Journal of Clinical Oncology (2005)

6582 Background: The t(11;18)(q21;q21) and the t(14;18)(q32;q21) involving the MLT/MALT1 gene are the main structural abnormalities in extranodal marginal zone lymphoma (MZL). In addition, amplification of MLT/MALT1 has been proposed as a pathogenetic mechanism in NHL. Amplifications in 18q21 frequently involve the BCL2 gene, which lies about 5Mb telomeric to MLT/MALT1. However, a recent study described amplification of MLT/MALT1 without BCL2 coamplification, suggesting that MLT/MALT1 and BCL2 are independent targets of amplification in NHL. Methods: In order to screen for translocations and amplifications of MLT/MALT1, we have analyzed 214 NHL with a novel FISH assay using probes flanking the MLT/MALT1 gene (PACs 117B5 and 59N7). The assay was applied to 91 MALT lymphomas, 19 splenic MZL, 17 nodal MZL, 17 follicular lymphomas (FL), 8 mantle cell lymphomas (MCL), 15 chronic lymphocytic leukemias (CLL), 3 B-cell prolymphocytic leukemias (PLL), 9 Burkitt’s lymphomas (BL), 30 diffuse large B-cell lymphomas (DLBCL), 5 T-cell NHL, and 10 cell lines (7 BL, 1 transformed MCL, 1 transformed FL, and 1 MZL). Results: In 20 MALT lymphomas (22% of MALT lymphomas) a translocation involving MLT/MALT1 was detected. FISH analyses with API2 and IGH specific probes revealed the t(11;18) in 13 cases and the t(14;18) in 7 cases. Amplification of MLT/MALT1 was observed in 2 DLBCL, the MZL cell line SSK41, and the BL cell line NAMALWA. Further FISH analyses showed a concomitant amplification of BCL2 in the 2 DLBCL but in SSK41 and NAMALWA an amplification of MLT/MALT1 without BCL2 involvement was found. Trisomy or polysomy of the chromosomal region 18q21 was found in 13 MZL, 9 DLBCL, 8 FL, 1 MCL, 1 CLL, and the transformed MCL cell line Granta-519. In addition, a heterozygous deletion of MLT/MALT1 was detected in two MALT lymphomas of the stomach. Conclusions: 1) MLT/MALT1 associated translocations occur exclusively in extranodal MALT lymphomas and represent either the t(11;18) or the t(14;18); 2) true amplifications of MLT/MALT1 occur in some aggressive NHL and some transformed cell lines; and 3) trisomy or polysomy of 18q21 are seen in different subtypes of B-cell NHL and cell lines. No significant financial relationships to disclose.
Correlation between FLT-PET and Ki-67 change in breast cancer during neoadjuvant chemotherapy.
Authors: S. C. Blackman, R. A. Railkar, R. Fox, L. George, R. Iannone, D. A. Bergstrom, P. D. Mozley
Journal: Journal of Clinical Oncology (2010)

TPS182 Background: [18F]-fluorothymidine (FLT) PET is an emerging imaging modality that measures change in cellular uptake of a radiolabeled thymidine analogue and may provide a more direct assessment of alterations in cell proliferation than changes in tumor size or glucose utilization. FLT-PET may be a useful tool in early clinical development for new oncology therapeutics. A high correlation between pre-treatment FLT uptake and Ki-67 expression in breast and lung cancer has been shown in small studies, but there have been no studies examining the correlation between change in FLT uptake and change in tissue-based measures of proliferation. The goal of this study is to determine whether a change in breast tumor FLT-PET standardized uptake value (SUV), pre- and post-treatment, correlates with the change in tumor Ki-67 labeling index (LI) during the same period. In addition, the correlation between change in tumor volume and the change in FLT uptake, Ki-67 LI, or a gene signature of cell proliferation will be assessed. Methods: A single-arm, open-label, multicenter study of 30 patients (ages 35-75) with stage II-III locally advanced breast cancer (tumor size > 2 cm) undergoing standard-of-care neoadjuvant chemotherapy has been initiated. Treatment regimens are selected by the treating physician, but must include a cytotoxic agent. The key endpoints to be measured are FLT (SUVmax and SUVmean), Ki-67 staining (as quantified by LI), tumor response (assessed by 2D and 3D MRI), and changes in a transcriptional proliferation signature. Patients will undergo chest [18F]FLT-PET/CT imaging at baseline, at the end of cycle 1 of chemotherapy (week 2-3), and at the end of neoadjuvant treatment (week 12-16). In parallel, core needle biopsies will be obtained at each time point. Analysis of Ki-67 LI, mitotic index (pHH3), as well as geminin and Mcm2 expression will be performed by IHC. Samples will undergo transcriptional profiling and analysis of a prespecified 50-gene signature reflective of cell proliferation. Finally, patients will undergo breast MRI for assessment of tumor anatomy (two-dimensional), tumor volume (three-dimensional), and apparent diffusion coefficient (ADC). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck Merck