tbuckley/cabot-search huggingface dataset:
Abstract P194: Gene-Environment Interactions and Blood Lipid levels: a Twin Study
Authors: Lindsey F Masson, Alistair M Cumming, Chuluuntulga Tuya, Kellie A Rance, Sharon Wood, Geraldine McNeill
Journal: Circulation (2012)

Genetic variation may affect blood lipid levels by directly determining levels (‘level genes’) and/or by influencing the response to environmental factors (‘variability genes’), i.e. gene-environment interaction. Previous dietary studies assessing variability gene effects have produced inconsistent results, perhaps due to a lack of statistical power, different dietary protocols, and/or differences in the age, sex, habitual diet, baseline lipid values and other genes of the participants. Monozygotic (MZ) twins can enhance our ability to identify variability genes because they are genetically identical and also share the same age, sex and aspects of their early environment. Therefore, all intrapair differences in blood lipid levels are due to environmental factors such as diet and lifestyle, and variation between genotypes in intrapair differences will indicate the existence of variability genes. We investigated the hypothesis that polymorphisms within the genes for apoB, apoE and lipoprotein lipase influence the blood lipid response to environmental factors. The subjects studied were 64 MZ male and female twin pairs aged 18-75 years who had been recruited for a study of coronary heart disease risk factors in twins. Blood samples already taken for analysis of fasting lipid levels were used for DNA extraction. Genotypes were determined for the polymorphisms apoB signal peptide insertion/deletion (I/D), apoB Xba I, apoE, and lipoprotein lipase Pvu II, Hind III and S447X. Mean intrapair differences in lipid levels adjusted for mean twin pair lipid level were calculated for each genotype group. In MZ twins, carriers of the apoB signal peptide D allele had smaller intrapair differences in total cholesterol (p=0.044) but larger intrapair differences in apoAI (p=0.035) than I/I twins, and apoE ε4 carriers had smaller intrapair differences in HDL-cholesterol than E3/3 and E3/2 twins (p=0.024). MZ twins with the Pvu II P-P- genotype had significantly greater intrapair differences in apoB than P-P+ or P+P+ twins. The Xba I, Hind III and S447X polymorphisms did not influence intrapair differences in lipid levels. In conclusion, the apoB signal peptide I/D, apoE and lipoprotein lipase Pvu II polymorphisms may act as variability genes and influence the susceptibility of blood lipid levels to dietary and pharmacological interventions for dyslipidaemia. The approach of using MZ twins to identify variability genes can be applied to other phenotypes, prior to determining the environmental factors that interact with the genes to influence the phenotype.
Systemic modulatory effects of the treatment with IL-2 of lung metastasis
Authors: D. Diaz, L. Chara, J. Chevarria, V. Navas, E. Esteban, J. Carballido, A. Muñoz, Z. Torregrosa, M. Arroyo, M. Alvarez-Mon
Journal: Journal of Clinical Oncology (2006)

2560 Background: IL-2 is a drug that is employed in the treatment of several tumors due to its capacity of restore or increase the regulatory and effector function of the immune system. These effects have been demonstrated with the administration of the drug by intravenous and subcutaneous ways. Recently, it has been observed that the inhaled IL-2 administration is effective in the treatment of lung and renal cell carcinoma metastasis. However, it is unknown if this therapeutic effect is accompanied of systemic and local modulatory effects. Objectives: To compare spontaneous and mitogen-induced apoptosis in lymphocytes of renal carcinoma patients before and after treatment with inhaled IL-2. Methods: Peripheral blood mononuclear cells were purified from 7 patients with renal carcinoma before and after treatment with inhaled IL-2. The cells were characterized in a FACScalibur analyzer using fluorocrome-labeled monoclonal antibodies. The AI (or percentage of apoptotic cells, AI x 100) was calculated for T-cells expressing CD3, CD4, CD8, CD56, HLA-DR, CD25 and CD45RO/CD45RA antigens and NK-cells (CD3-CD56+ or CD3-CD16+). These AI were determined after 24 hours of culture under two conditions: without exogenous apoptosis inducers and in the presence of phytohemagglutinin. Comparisons between patients were carried out using the Wilcoxon test and were considered significant when p &lt; 0.05. Results: A significant decrease in spontaneous ex vivo apoptosis was found in peripheral blood lymphocytes from renal carcinoma patients after treatment with inhaled IL-2 with respect to pretreatment values. This decrease occurred in T-cells and also in CD45RO expressing cells from both CD4+ and CD8+ subsets. A decrease of apoptosis was also observed in CD25+ expressing cells from CD3+, CD4+ and CD8+ subsets. A decrease in AI was found in mitogen induced apoptosis of CD25+ cells from CD3+, CD4+ and CD8+ subsets. Conclusions: The treatment with inhaled IL-2 has immunomodulatory effects that are observed at systemic level reducing the apoptosis of cells from several memory and activated T-cell subsets. No significant financial relationships to disclose.
Estimating residual kidney function in dialysis patients without urine collection
Authors: Tariq Shafi, Wieneke M. Michels, Andrew S. Levey, Lesley A. Inker, Friedo W. Dekker, Raymond T. Krediet, Tiny Hoekstra, George J. Schwartz, John H. Eckfeldt, Josef Coresh
Journal: Kidney International (2016)
Deletion polymorphism of the GSTM1 gene in lung cancer patients from the Lake District in Turkey
Authors: F. Coskun Ari, G. Bosgelmez, H. S. Coskun, M. Polat, N. Kisioglu, I. Ergurhan Ilhan
Journal: Journal of Clinical Oncology (2006)

20089 Background: Association of glutathione-S-transferase M1 (GSTM1) polymorphisms and cancer has been demonstrated. Especially the deletion polymorphism of GSTM1 has been related to risk for lung cancer in some studies. We thus investigated the frequency of GSTM1-null genotype in lung cancer patients and healthy individuals from the Lake District in Turkey. Methods: Cases were recruited among patients with clinically and histologically confirmed diagnosis of lung cancer patients from the Lake District. Controls were selected among the nonsmoking healthy blood donors applied to hospital in same region. DNA samples were extracted from whole blood using proteinaz K (20 mg/mL) digestion in lysis buffer (10 mM Tris-HCl, 400 mM NaCl, 2 mM EDTA, % 10 SDS). Homozygous deletion of the GSTM1 gene was determined by PCR using the primers E4F: 5′-CTGCCCTACTTGATTGATGGG-3′, E5R: 5′-CTGGATTGTAGCAGATCATGC-3′, corresponding to exons 4 and 5 of the GSTM1 gene. PCR products were analyzed by 1% agarose gel electrophoresis and UV transilluminator was then used to evaluate the product content. Individuals carrying the GSTM1 gene were identified by the presence of a 273 bp DNA fragment. Results: The study comprised 30 patients and 30 controls. The frequency of GSTM1-null genotype was found to be (n = 14) 46.7% in lung cancer patients and (n = 5) 16.6% in controls. The difference was statistically significant (Fisher’s chi square test: 4.80, P: 0.0251). Conclusion: We found an increased incidence of GSTM1-null genotype among lung cancer patients, indicating that the GSTM1 absence is associated with a slightly increased lung cancer risk in people from the Lake District in Turkey. No significant financial relationships to disclose.
ITCC phase II study of imatinib mesylate in children with solid tumors expressing imatinib-sensitive tyrosine kinase receptors
Authors: G. Vassal, B. Geoerger, M. Le Deley, F. Doz, F. Pichon, D. Frappaz, J. Gentet, J. Landman-Parker, P. Berthaud, B. Morland
Journal: Journal of Clinical Oncology (2006)

9003 Background: Imatinib mesylate inhibits selectively specific activations of the platelet-derived growth factor receptor (PDGFR), c-KIT and BCR/ABL tyrosine kinases and is approved for the treatment of chronic myeloid leukemia and gastro-intestinal stromal tumors (GIST). This study evaluated efficacy of imatinib in solid childhood tumors. Methods: Phase II study of imatinib as single agent in children and adolescents with refractory or relapsing solid tumor expressing at least one of the receptors. Patients were to be treated at 340 mg/m 2 , a dose escalation allowed to 440 mg/m 2 after 2 months in case of insignificant improvement. C-KIT, PDGFRα and β expression was determined on archive tissue sections by immunohistochemistry prior to study entry. Gene mutations, pharmacokinetics, pharmacogenetics, and positron emission tomography imaging were assessed. Results: 36 patients, 21 boys, median age 13.7 years (2.2–22.5 y), 12 with brain tumors, 6 fibromatosis, 8 mesenchymal/bone tumors, and 10 other solid tumors, including 1 GIST and 3 chordoma, were treated at 340 mg/m 2 daily during a total of 168 months (median 1.9 month/patient, range 0.5–19). 18/36 expressed c-KIT, 10 PDGFRα, 21 PDGRβ; 12 expressed more than one receptor. Ten patients were escalated to 440 mg/m 2 due to lack of efficacy. During the 1st month, 17 patients experienced mild toxicity (grade 1 and 2) related to study treatment: gastro-intestinal (n=22), face edema (n=7), asthenia (n=5), tumor induration (n=2), skin toxicity (n=2), thrombocytopenia (n=1). No partial or complete response was observed; 5 patients (2 fibromatosis, 1 GIST, 1 medulloblastoma, 1 pseudo-inflammatory tumor) experiencing durable stable disease have been under treatment for more than 12 months. Interesting tumor stabilization during 10 and 7 months, respectively, was achieved in a brain stem glioma and a renal carcinoma. Glucose uptake on 18 FDG PET scan was reduced in a chordoma, although the child progressed and died due to disease. Pharmacokinetic and genetic data are currently evaluated. Conclusions: Imatinib as single agent was well tolerated, but—as used in our study —failed to show measurable anti-tumor effects according the standard criteria in the pediatric malignancies studied. No significant financial relationships to disclose.
Can the Vulnerable Elders Survey-13 and/or the G8 adequately identify elderly patients with head and neck cancer in need of a comprehensive geriatric assessment?
Authors: P. R. Debruyne, T. Boterberg, H. Pottel, L. Goethals, N. Van den Noortgate, F. Duprez, W. De Neve, S. Rottey, K. Geldhof, K. Van Eygen, K. Kargar-Samani, V. Ghekiere, F. Cornelis, S. G. Mohile, L. Pottel
Journal: Journal of Clinical Oncology (2011)

e19670 Background: The comprehensive geriatric assessment (CGA) has been proposed by the National Comprehensive Cancer Network as a key component in the treatment approach of elderly cancer patients. However, it is neither feasible nor useful for every patient. In this study, we tested the validity of two proposed screening tools, the Vulnerable Elders Survey-13 (VES-13) and the G8, for identifying impairments in elderly head and neck (H&N) cancer patients. Methods: All patients aged ≥ 65 years with primary H&N cancer, who were referred for curative treatment to the radiotherapy departments of the General Hospital Groeninge or the Ghent University Hospital, were consecutively asked consent for assessment of VES-13, G8 and CGA. Receiver operating characteristics (ROC)-analysis was used to determine diagnostic performance of both screening instruments. Results: Fifty-one of 60 eligible patients with a median age of 72 were recruited. 68.6% of H&N cancer patients were defined vulnerable, exhibiting impairments in two or more domains within the CGA. The area under the ROC-curves (AUC±SE) of VES-13 (0.889±0.084) and G8 (0.852±0.095) did not significantly differ (p=0.709). At the cut-off scores proposed in literature, a sensitivity and specificity of respectively 57.1% and 100% for VES-13 (cut-off ≥ 3) and 85.7% and 75.0% for G8 (cut-off ≤ 14) was obtained. The combined score of VES-13 + (maximum-G8) shows an AUC of 0.971±0.039, superior to G8 (p=0.040) and VES-13 (p=0.078). The most optimal cut-off score of 5 for the combined test resulted in a sensitivity of 91.4% and a specificity of 93.8%. Conclusions: Both proposed screening tools (VES-13 and G8) were found to have a good diagnostic performance, based on the AUC. However, at the cut-off scores proposed in literature, our data suggest the G8 as the most optimal screening tool in the H&N population, considering its lower percentage of false negatives. Moreover, the combined test was found to have the highest predictive capacity of detecting risk of vulnerability and could therefore represent an interesting alternative that warrants further exploration in large prospective trials.
LBA-10 MODUL – A Multicentre Randomised Clinical Trial of Biomarker-Driven Therapy for the 1st-Line Maintenance Treatment of Metastatic Colorectal Cancer (mCRC): A Highly Adaptable Signal-Seeking Approach
Authors: D. Arnold, H-J. Schmoll, A. de Gramont, M. Ducreux, A. Grothey, P. O'Dwyer, J. Tabernero, F. Hermann, B. Bendahmane, C. Mancao, E. Van Cutsem
Journal: Annals of Oncology (2015)
Broad Therapeutic Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis
Authors: Athol U. Wells, Ivan O. Rosas
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Idiopathic pulmonary fibrosis (IPF) is a variably progressive disease that carries a poor prognosis. Recent international multicenter phase III clinical trials testing the efficacy of nintedanib (1) and pirfenidone (2) have shown that medical therapy, specifically antifibrotic agents, can reduce the rate of lung function decline in patients with IPF. In the United States, these groundbreaking findings were quickly followed by U.S. Food and Drug Administration fast-track priority review, orphan product designation, and drug approval for both pirfenidone and nintedanib (3). Nintedanib, a small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor, was tested in two simultaneous phase III trials (INPULSIS-1 and INPULSIS-2) (1). Compared with placebo, nintedanib consistently slowed disease progression by significantly reducing the annual rate of decline in forced vital capacity (FVC) in both INPULSIS trials (1). Comparable reductions in disease progression were reported for pirfenidone, raising the possibility that overlapping mechanisms mediate these remarkably similar antifibrotic effects.
Large Intestinal Carcinogenesis. III. Studies in Low-Incidence (Japanese) Patients&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Abulkalam M. Shamsuddin, M.D., Ph.D., Yo Kato, M.D., Haruo Sugano, M.D.
Journal: JNCI Journal of the National Cancer Institute (1984)

Recent studies have demonstrated that at the early stages of carcinogenesis of the large intestine(s) (LI), severely dilated crypt(s) (SDC) appear followed by atypical and/or neoplastic crypt(s) (ANC) and, subsequently, carcinomas. Thus both SDC and ANC appear to be premalignant changes and are probably initiated foci. Since the Japanese in Japan (JIJ) show a much lower rate of large intestinal carcinomas (LIC) compared to people in the Western Hemisphere, a study was designed to answer the question: Is the difference between the rates due to a difference in initiation or promotion? If the difference is due to less initiation, large intestinal epithelium of JIJ should contain fewer initiated foci. For testing this hypothesis, a retrospective histopathologic study was conducted on 100 LI of JIJ resected at the Cancer Institute, Tokyo, Japan, between 1977 and 1978, and mucosae remote from carcinomas were examined for SDC and ANC. In sharp contrast to a 100% incidence of SDC in the cases in the United States, only 1 of 100 LI of patients with LIC at the Cancer Institute demonstrated the presence of SDC. However, ANC was seen in 10 of 100 LI (10%), a figure comparable to that in the United States (7%). The extreme rarity of SDC in JIJ represents lesser initiation of that type. The presence of a comparable number of ANC in JIJ indicates that ANC is the predominant morphologic type of initiated foci in JIJ. This study suggests that not only promotional agents but also different initiating factors may be responsible for the difference in incidence and prevalence of LIC in the two populations. Comparative studies of parallel experimental animal models with the use of high and low doses of azoxymethane support this conclusion.
Phase II study of erlotinib for acquired resistance to gefitinib in patients with advanced non-small cell lung cancer.
Authors: A. Horiike, N. Yamamoto, H. Tanaka, N. Yanagitani, K. Kudo, F. Ohyanagi, T. Naito, H. Murakami, T. Horai, M. Nishio
Journal: Journal of Clinical Oncology (2010)

7573 Background: Gefitinib and erlotinib are two orally active epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) used in the treatment of advanced non-small cell lung cancer (NSCLC). Gefitinib is usually used as a first-line EGFR-TKI in Japan, but there are no effective treatment options after gefitinib failure. Several small studies showed that erlotinib may have some efficacy in patients (pts) with resistant tumors that had previously responded to gefitinib. In this phase II study, we evaluated the efficacy of erlotinib against acquired resistance to gefitinib. Methods: The study included advanced NSCLC pts who had received 1 or more chemotherapy regimens and gefitinib monotherapy. Only pts who obtained a partial response (PR) or stable disease (SD) with gefitinib monotherapy were eligible. Erlotinib (150 mg) was given until disease progression or unacceptable toxicity. Results: From January 2008 to September 2009, 50 pts were enrolled. Pt characteristics were as follows: male/female: 39/11; median age: 65 yr (36-81); histology, adeno/sq/large: 46/2/2; PS, 0/1/2: 24/19/7; smoking status, never/former/current: 33/15/2. Prior responses to gefitinib were PR/SD: 36/14. The median duration of prior gefitinib therapy was 419 days (63-1,540). The median interval from gefitinib was 29 days (13-1,198). PR and SD with erlotinib were observed in 5 and 29 of 48 pts, respectively (response rate, 10.4% and disease control rate [DCR], 70.8%). The DCR in pts who continued gefitinib treatment more than 1 year was significantly higher than in pts who stopped gefitinib treatment before 1 year (81.5% vs 57.1%, p = 0.018), but DCR was not associated with prior responses to gefitinib or interval from gefitinib. The median times to treatment failure and overall survival were 100 days (95% CI, 90-110 days) and 342 days (95% CI, 242-442 days), respectively. The most common toxicities were rash (78%) and diarrhea (68%). Grade 5 pneumonitis occurred in 1 pt (2%). Conclusions: After acquired resistance to gefitinib, a change to erlotinib may prolong the efficacy of EGFR-TKI treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharma
Cytogenetic and early-response characteristics of adolescents and young adults with acute lymphoblastic leukemia (ALL): A Children's Oncology Group (COG) study.
Authors: E. A. Raetz, M. Devidas, A. J. Carroll, N. A. Heerema, M. J. Borowitz, B. L. Wood, J. M. Gastier-Foster, C. L. Willman, M. L. Loh, E. C. Larsen
Journal: Journal of Clinical Oncology (2010)

9509 Background: Outcomes foradolescents and young adults (AYA) with ALL are inferior to those for younger children, raising the question of whether there are differences in the underlying biology of the disease or host. Methods: Blast cytogenetic features, clinical and early disease response characteristics for two cohorts of patients (ages 1-15 vs. 16-30 years) enrolled on the current COG AALL0232 therapeutic trial for NCI high risk B-precursor ALL were compared. All patients were required to have blast cytogenetic studies for prognostically significant chromosome translocations and ploidy as well as measurements of marrow minimal residual disease (MRD) by flow cytometry at end-induction in COG Reference Laboratories. The AALL0232 trial includes a standard 4-drug induction with a randomization to dexamethasone (10 mg/m2/day) for 14 days or prednisone (60 mg/m2/day) for 28 days. These analyses are confined to patients randomized to receive prednisone during induction therapy, as the results for the steroid randomization remain blinded. Results: 1379 eligible/evaluable patients were analyzed; 1113 patients ages 1-15 and 266 patients ages 16-30 years (AYA). AYA ALL was characterized by a male predominance (69% vs. 54%, p<0.0001) and a lower initial median white blood cell count (9 vs. 33 × 109/L, p<0.0001). Fewer AYA patients had the ETV6-RUNX1 fusion (3.7% vs. 14.4%, p<0.0001); however, simultaneous trisomies of chromosomes 4, 10, 17 were more common in AYA ALL (16.0% vs. 10.2%, p=0.02). There were no significant differences in the presence of very high risk features including the BCR-ABL1 fusion, MLL translocations, or hypodiploidy among the two age cohorts. End-induction MRD was negative (<0.01%) in 59% of AYA patients compared to 74% of younger patients (p<0.0001) and only 67% of AYA vs. 80% of younger patients (p=0.0015) achieved an M1 marrow (< 5% blasts) on day 15 of induction. Conclusions: AYA patients with ALL have similar very high risk cytogenetic profiles when compared to younger patients, but display slower initial responses to induction therapy, suggesting that additional biologic features in AYA ALL have yet to be discovered. No significant financial relationships to disclose.
First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc).
Authors: W. R. Schelman, S. K. Sandhu, V. Moreno Garcia, G. Wilding, L. Sun, C. Toniatti, M. Stroh, N. Kreischer, C. L. Carpenter, L. R. Molife, S. B. Kaye, J. S. De Bono, R. M. Wenham
Journal: Journal of Clinical Oncology (2011)

3102 Background: MK4827 is an orally active, PARP 1/2 inhibitor with nanomolar potency. It induces selective synthetic lethality in homologous recombination (HR) repair deficient tumors with BRCA1/2 loss and in tumor cell lines with non-BRCA-related HR defects, supporting broad clinical application. A phase I study was undertaken to determine the toxicity and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and preliminary anti-tumor activity. Methods: Patients (p) with advanced solid tumors enriched for BRCA-mutation carriers (BRCA-MC) and non-BRCA HR defects received once daily, escalating doses of MK4827 in cohorts of 3-6 p. Dose escalation was guided by toxicity, PK and PD data. Results: 60 p (M13, F47; median age 56 yr; 21 BRCA-MC) were treated at 10 dose levels from 30mg to 400mg on days 1-21 of a 28 day cycle (C) in C1, followed by continuous dosing. 20 additional p with soc were enrolled at the MTD. Prior systemic treatments were ≤2 (23p), ≥3 (17p), and ≥4 (40p). Overall, DLT was observed in 4p: grade (G) 3 fatigue in 1/6p at 30mg, reversible G3 pneumonitis in 1/6p at 60mg, and reversible G4 thrombocytopenia in 2/6p treated at 400mg. The MTD was established at 300mg. Other MK4827 related G1-2 reversible adverse events included fatigue, anorexia, nausea and myelosuppression. Dose proportional PK was observed with a mean t1/2 of 40 hours (range 37-42 hr). PD studies confirmed PARP inhibition in peripheral blood mononuclear cells at doses of ≥80 mg. Antitumor activity was observed in both sporadic and BRCA-MC cancers. In total, there have been 12p with partial responses (PR) (10 ovarian [7 BRCA-MC; 3 soc], 2 breast, 10/12 BRCA-MC cancers, 4/12 with ongoing treatment), and 8p with stable disease (SD) (4 ovarian [2 BRMC-MC], 2 NSCLC, 2/4 BRCA-MC) ≥120 days. PRs have ranged from 86(+)-483 days and SD from 18(+)-354 days. Conclusions: MK-4827 was well tolerated, had linear PKs, evidence of target modulation, and promising antitumor activity in both BRCA-MC and sporadic cancer. Specific cohort expansions in other nonhereditary tumors enriched for HR defects is ongoing. Updated safety and response data will be provided.