tbuckley/cabot-search huggingface dataset:
The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer
Authors: Yufang Ma, Lihong Wang, Leif R. Neitzel, Sudan N. Loganathan, Nan Tang, Lili Qin, Emily E. Crispi, Yan Guo, Stefan Knapp, R. Daniel Beauchamp, Ethan Lee, Jialiang Wang
Journal: Clinical Cancer Research (2016)

Purpose: The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer.Experimental Design: Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches.Results: BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulation in vitro and in vivo A combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts.Conclusions: Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer. Clin Cancer Res; 23(8); 2027-37. ©2016 AACR.
Anti-tumor effects of dovitinib in patient-derived gastrointestinal stromal tumor (GIST) xenograft models.
Authors: Yemarshet Kelemework Gebreyohannes, Thomas Van Looy, Agnieszka Wozniak, Jasmien Wellens, Haifu Li, Jasmien Cornillie, Ulla Vanleeuw, Lise Vreys, Matthew Squires, Ana-Maria Rodriguez, Maria Debiec-Rychter, Raf Sciot, Patrick Schoffski
Journal: Journal of Clinical Oncology (2015)

10532 Background: Advanced GIST is treated with the tyrosine kinase inhibitors imatinib, sunitinib and regorafenib, but the majority of patients develop heterogeneous resistance to these agents. In an attempt to overcome such resistance, we tested the efficacy of dovitinib which acts against VEGFR, FGFR, FLT3, PDGFRB and KIT, using patient-derived GIST xenograft models. Methods: NMRI nu/nu mice (n = 47) were transplanted bilaterally with the human GIST xenografts UZLX-GIST2 (KIT p.A502_Y503dup) or -GIST9 (KIT p.P577del+p.W557LfsX5+p.D820G) and were treated in 4 cohorts: control (untreated), imatinib (50 mg/kg/bid p.o.), imatinib (100 mg/kg/bid p.o.) and dovitinib (30 mg/kg/qd p.o.). Efficacy was assessed by tumor volume measurement (3x/week), histopathology, immunohistochemistry [Ki67, phospho-Histone H3 (pHH3), cleaved PARP] and Western blotting analysis of KIT signaling. Histologic response (HR) was graded according to Antonescu et al. Clin Cancer Res 2005; 11:4182-90. Microvascular density (MVD) was assessed by counting CD31 positive vessels. Mann Whitney U test was used for statistical analysis. Results: After three weeks of treatment, dovitinib caused tumor volume reduction (to 37% of baseline) in UZLX-GIST2 and disease stabilization in -GIST9. It induced grade 2-3 HR in > 50% of tumors in both models. Compared to control, dovitinib reduced mitotic activity by 22.6 fold (p < 0.0001) in UZLX-GIST2, whereas no significant difference was observed in the other model. Results were confirmed by pHH3 and Ki67 stainings. Apoptotic activity was decreased in dovitinib treated UZLX-GIST2 tumors compared to control. MVD was reduced in both UZLX-GIST2 (1.6 fold; p < 0.05) and -GIST9 (1.3 fold; p = 0.059) under dovitinib. Furthermore, it partially inhibited KIT, AKT and 4EBP-1 phosphorylation in UZLX-GIST2. Conclusions: Dovitinib showed anti-tumor efficacy in GIST xenograft models, with more pronounced effects in KIT exon 9 mutant disease. The decrease in MVD in both models suggested that the anti-tumor effects were at least partially mediated by the anti-angiogenic capacity of dovitinib. These results support ongoing and planned GIST trials (NCT01478373, 02268435, 01440959 and 01831726).
Clinical benefit of trastuzumab (H) among patients with HER2-positive metastatic breast cancer (MBC) not achieving objective responses when treated with H plus chemotherapy (CT)
Authors: C. H. Yeon, D. Slamon, R. Patel, A. Cartmell, B. Leyland-Jones, P. Klein, W. Eiermann, J. Wolter, G. Lieberman, M. Pegram
Journal: Journal of Clinical Oncology (2004)

680 Background: Clinical benefit from cytotoxic CT is observed largely in those patients with objective clinical response (OCR). This may not be the case, however, for targeted biologic agents with cytostatic mechanisms of action. H elicits cell cycle arrest in HER2-amplified cells via perturbation of HER2 signal transduction. Such mechanisms of action of H may not result in OCR, but rather induce disease stabilization. Methods: To test this hypothesis, we performed a retrospective analysis of the subset of patients not achieving an OCR from the pivotal phase III clinical trial of CT (either anthracycline/cyclophosphamide [AC] or paclitaxel [T]) with or without H in women with MBC (Slamon DJ et al. N Engl J Med 344: 783–792, 2001). A total of 469 patients with HER2 overexpression (2+/3+) by immunohistochemistry (IHC) were enrolled. This analysis focused on time to progression (TTP) and overall survival (OS) for the patients who did not achieve an OCR in the cohort as well as the fluorescence in situ hybridization (FISH) positive and negative subgroups. Results: Of 277 non-responders, patients who received CT+H had a longer median TTP than those who received CT alone (4.1 vs. 2.8 months, p=0.0017). This difference was also seen in the T+H vs. T subgroup (n=134, 3.9 vs. 2.1 months, p=0.0007) but not in the AC+H vs. AC subgroup (n=143, 4.4 vs. 4.3 months, p=0.3452). Statistically significant differences in TTP in the CT+H vs. CT (4.1 vs. 3.0 months, p=0.0102) and the T+H vs. T (3.9 vs. 2.0 months, p=0.0141) subgroups were observed for the FISH-positive (n=198) patients but not in FISH-negative (n=66) patients. OS for the FISH-positive non-responders who received CT+H vs. CT was 16.4 vs. 13.9 months (p=0.3777). Conclusions: HER2-positive (IHC or FISH) MBC patients treated with CT+H, even in the absence of OCR, may achieve significantly longer TTP than patients not receiving H. These data demonstrate clinical benefit from H even among patients who do not achieve an OCR in their metastatic lesions. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech Genentech; Roche Genentech; Roche
Ultra-Low-Dose Buprenorphine for Mental Pain: Response to Ruan et al.
Authors: Yoram Yovell, Gali Bar
Journal: American Journal of Psychiatry (2016)

THE EDITOR: The article by Yovell and colleagues (1) is both interesting and informative.The authors reason that suicidality is linked to mental pain, which is modulated through endogenous opioids.In a randomized controlled trial, the authors tested the efficacy and safety of very low dosages of sublingual buprenorphine.They found patients receiving buprenorphine had a greater reduction in Beck Suicide Ideation Scale scores than patients who received placebo.They conclude that the use of sublingual buprenorphine at very low dosages was associated with decreased suicidal ideation (1).We wonder if the observed efficacy of low-dosage buprenorphine for reducing suicide ideation could actually result from its analgesic effect for relieving physical pain.A number of studies suggest that the buprenorphine dosage needed for treatment of pain is much lower compared with dosages for treatment of opioid addiction.The typical analgesic dosage of buprenorphine is 0.3-0.6 mg i.m. or i.v., and its analgesic effects last approximately 6 hours (2).In this regard, transdermal patches that provide buprenorphine at lower dosages (5, 10, and 20 mg/hour) are approved for the management of moderate chronic nonmalignant pain (3).The dosage range of the buprenorphine formation noted above is 120-480 mg/day or 0.12-0.48mg/day, comparable to sublingual buprenorphine lozenges, with an initial dosage of 0.1 or 0.2 mg/day, with increases of 0.1-0.2mg increments weekly, to a maximum daily dosage of 0.8 mg in the investigation by Yovell et al.Calati et al. ( 4) recently performed a meta-analysis comparing rates of suicidal thoughts and behaviors in individuals with and without physical pain.They found that individuals with physical pain are more likely to report lifetime death wish, current and lifetime suicidal ideation, suicide plan, and suicide attempt.Moreover, these individuals were also more likely to die by suicide.Suicide rates in the United States have risen sharply for both men and women in all age groups younger than age 75, according to a report from the U.S. National Center for Health Statistics (5).Szymanski and colleagues ( 6) recently conducted a study to assess drug type and current risk factors in suicide deaths.They found that of 342 suicide overdose cases, psychiatric illness was present in 72% of cases, while chronic pain was seen in 27.2% of cases.Therefore, without controlling for physical pain, the findings of Yovell et al. could be considered confounded.
Hypoxia-Inducible Factor (HIF)-1a Is A Therapeutic Target in Myeloma-Induced Angiogenesis and Bone Destruction in Vivo.
Authors: Marina Bolzoni, Paola Storti, Gaetano Donofrio, Irma Airoldi, Daniela Guasco, Denise Toscani, Marco Peronaci, Eugenia Martella, Mirca Lazzaretti, Luca Agnelli, Ken Patrene, Cristina Mancini, Martine Amiot, Antonino Neri, Simona Colla, Judith Anderson, Franco Aversa, G. David Roodman, Nicola Giuliani
Journal: Blood (2012)
Prognostic Significance of EVI1 Defects in MDS/AML with 3q21q26 Abnormalities.
Authors: Paolo Bernasconi, Irene Dambruoso, Marina Boni, Paola Maria Cavigliano, Silvia Calatroni, Ilaria Giardini, Barbara Rocca, Rita Zappatore, Marilena Caresana, Cesare Astori, Carlo Castagnola, Emilio Paolo Alessandrino, Mario Lazzarino
Journal: Blood (2007)
Risk and mortality associated with febrile neutropenia in lung cancer patients
Authors: D. B. Daniel, J. Crawford, N. M. Kuderer, D. C. Dale, G. H. Lyman
Journal: Journal of Clinical Oncology (2004)

7223 Background: Myelosuppression and its complications represent the major dose limiting toxicities of lung cancer chemotherapy. Methods: Length of stay, mortality and cost associated with febrile neutropenia (FN) were studied in 3,340 lung cancer patients experiencing 3,846 admissions to 115 academic institutions reporting to the University HealthSystem Consortium between 1995–2000. Those factors found to be significantly associated with complicated hospitalizations (length of stay (LOS) >8 days) or inpatient mortality were evaluated in logistic regression models. Estimates of relative risk associated with each risk factor were based on the adjusted odds ratios (OR +/- 95%CIs) for mortality and LOS greater than 8 days. Results: Overall inpatient mortality was 12.1%. Factors significantly associated with increases in the risk of inpatient mortality included metastases (OR 2.28 [1.81, 2.88]), hypotension (OR 3.79 [2.55, 5.62]), pneumonia (OR 2.39 [1.90, 3.01]) and gram-negative bacteremia (OR age ≥ 65: 8.13; OR age <65: 3.75). The mean and median LOS were 8.1 and 5 days respectively. The mean LOS was 8.1 days, median 5 days. Hospital LOS was ≥ 8 days in 32.4% patients. Factors significantly associated with longer LOS included congestive heart failure (OR 2.18 [1.61, 2.94]), functional impairment (OR 1.98 [1.35, 2.90]), pneumonia (OR 1.94 [1.63, 2.31]), and gram-positive bacteremia (OR 3.42 [2.30, 5.11]). Patients whose primary reason for admission was other than FN had higher risk of mortality (OR 3.40 [2.49, 4.64]) and LOS ≥ 8 days (OR 3.18 [2.68, 3.77]). Model R2 for the mortality and LOS models were .126 and .123 respectively while the c-statistics (ROC AUC) were .790 and .718. Conclusions: Mortality in lung cancer patients hospitalized for FN is greater than for other solid tumors. Increasing age, advanced disease, nutritional and functional impairments, and comorbidities along with infectious complications lead to prolonged hospitalization and increased risk of mortality. Prospective studies are warranted to further define risk factors and evaluate possible interventions. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen, Inc.
P3-220: Pulmonary function tests as a predictor of quantitative and qualitative outcomes after thoracic surgery for lung cancer
Authors: Laurent Greillier, Pascal A. Thomas, Anderson Loundou, Christophe Doddoli, Karine Barrau, Monique Badier, Pascal Auquier, Fabrice Barlesi
Journal: Journal of Thoracic Oncology (2007)
Heroes of peer review: Hyongbum (Henry) Kim
Authors: Hyongbum Kim
Journal: Genome biology (2016)

Peer reviewers are the unsung heroes of science. We celebrate reviewers through a series of interviews with people who have made particularly strong recent contributions to Genome Biology as reviewers. The first interview is with Hyongbum (Henry) Kim, an Associate Professor at Yonsei University College of Medicine in South Korea.
Students face deep conflict in reporting harassment
Authors: Jane H Williams, Christopher Mayes, Wendy Lipworth
Journal: BMJ (2016)

Coopes describes steps to change the culture of bullying and harassment in Australia’s medical profession.1 We applaud the Royal Australasian College of Surgeons for its action plan to tackle such harassment,2 but the problem goes much deeper than surgeons behaving badly.

In 2015 we conducted a study in New South Wales about conflicts of interest in medicine. Participants were …
Peripheral blood eosinophil counts and risk of colorectal cancer mortality in a large general population-based cohort study.
Authors: N. Taghizadeh, J. M. Vonk, H. M. Boezen
Journal: Journal of Clinical Oncology (2011)

1583 Background: Few epidemiological studies have investigated the association between blood eosinophil counts and colorectal cancer incidence. The current prospective cohort study aims to investigate the association between peripheral blood eosinophils and colorectal cancer mortality risk. Methods: Vital status at December 31st, 2008 of 8465 participants of the Vlagtwedde/Vlaardingen (a rural respectively industrial area in The Netherlands) cohort study was determined. This study started in 1965 and participants had medical examinations every 3 years until the last survey in 1989/1990. Blood eosinophil counts at the first survey were logtransformed to obtain a normal distribution. Multivariate Cox regression analyses on colorectal cancer mortality in the total population with adjustment for age, FEV1 % predicted, BMI, smoking habit, gender and place of residence, were performed. Furthermore, stratified analyses by smoking habits (never versus ever) and by gender were performed. Finally, interactions between eosinophil counts and smoking habits, respectively gender were investigated. Results: In total, 3838 subjects had died; 134 died due to colorectal cancer. There was no association between eosinophil counts and colorectal cancer mortality risk in the total population (Hazard Ratio (95% CI) == 0.84 (0.65-1.09)). The stratified analyses showed significant associations between number of eosinophils and colorectal cancer mortality in males (HR== 0.64 (95% CI 0.45-0.89)) and in ever smokers (HR== 0.63 (95% CI 0.46-0.86)). Additionally, we observed a significant interaction between male gender and eosinophil counts (HR== 0.48 (95% CI 0.28-0.80)) and between smoking and eosinophil counts on colorectal cancer mortality (HR== 0.40 (95% CI 0.23-0.70)). Conclusions: A higher number of peripheral blood eosinophils is associated with a reduced risk to die of colorectal cancer, especially in ever smokers and in males. Although the underlying mechanism explaining this observation is not clear, it suggests that a more active immune system reduces the risk to develop colorectal cancer.
Phase I dose-escalation study of ON 01910.Na in combination with oxaliplatin in patients with advanced solid tumors.
Authors: I. Chaudhary, L. Rajdev, U. Swami, F. Wilhelm, B. Cohen, M. Haigentz, A. Kaubisch, S. Goel, S. Mani, M. H. Ghalib
Journal: Journal of Clinical Oncology (2010)

e13133 Background: ON 01910.Na is a new multikinase inhibitor, which induces mitotic catastrophe and apoptosis in cancer but not in normal cells. Multiple pathways are involved including polo-like kinase. Cell killing effects are exposure time-dependent in vitro. In addition, a combination of ON 01910.Na with oxaliplatin produced significant synergy in effect, prompting phase I evaluation in humans. Methods: Patients with advanced cancer received a starting dose of ON 01910.Na 250mg/m2 as a 24hr continuous infusion (CI) repeated weekly. Oxaliplatin was administered biweekly as 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Pharmacokinetic (PK) sampling is to be performed at the maximum tolerated dose (MTD) level. Results: 13 patients (pts) (all females; ages: 38-71 yrs) have received combination therapy. At the highest dose (1350 mg/m2), 2 pts have received 6 weeks of continuous therapy. The overall mean (range) number of weeks of continuous therapy delivered was 11.1 (3-42). Grade 2 toxicities (2-grade increase in toxicity) include anorexia (1 pt), nausea (2 pt), fatigue (1 pt), peripheral sensory neuropathy (1 pt), abdominal cramps (1 pt), neutropenia (1 pt) and vomiting (2 pt). Partial response was observed in 1 pt with chemotherapy- refractory ovarian cancer (26 wk, prior progressions on paclitaxel+carboplatin [carbo], topotecan+docetaxel, carbo+gemcitabine, doxorubicin hydrochloride liposome, paclitaxel+bevacizumab, and etoposide). Stable disease was observed in a pt with colon cancer (42 wk, prior progressions on FOLFOX-4 and FOLFIRI+bevacizumab), and in a pt with ovarian cancer (19 wk, prior progressions on carbo+paclitaxel, doxorubicin hydrochloride liposome, gemcitabine+carbo, topotecan, vinorelbine, and bevacizumab+paclitaxel). Conclusions: It is feasible to administer ON 01910.Na as a 24hr infusion in combination with oxaliplatin. Tumor response was seen in chemotherapy-refractory ovarian cancer. The toxicities are tolerable and dose escalation continues. Further analysis of response and toxicity as well as PK at the MTD dose level is planned as this study continues to enroll patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onconova Therapeutics, Inc. Onconova Therapeutics, Inc. Onconova Therapeutics, Inc.
Health care utilization by cancer patients with bone metastases in the last weeks of life in the Netherlands
Authors: A. K. Reyners, J. J. Meeuse, Y. M. van der Linden
Journal: Journal of Clinical Oncology (2008)

17517 Background: In the Netherlands, cancer patients preferably stay at home in the terminal phase of life and visit the hospital only for urgent medical situations. Health care is structured to meet these preferences. However, patterns of actual use of medical care in the terminal phase have hardly been studied. Here, the health care utilization in the last six weeks of life by patients included in the Dutch Bone Metastases study is presented. In that study, single and multiple fraction radiotherapy were found to be equally effective in pain control. Methods: Between March 1996 and September 1998, 1157 patients with painful bone metastases from various solid tumors were randomized into the study. Patients filled out 13 weekly and thereafter monthly questionnaires for two years or until death. Questions on health care utilization covered General Practitioner (GP) contact (Have you visited your GP this week?) and hospital based health care (Have you visited your treating physician in the hospital this week? Have you been admitted to the hospital this week?). Patients who returned questionnaires in the last six weeks of life were included. Pooled analysis and analysis per week before death was performed. Results: Of the 851 patients who died during the study, 512 (60%) returned at least one questionnaire during the last six weeks of their life. In pooled analysis, 73% of the respondents used hospital based health care; 65% reported a contact with their GP. Hospital admissions were reported by 182 patients (36%). 10% reported no health care utilization. Analysis per week before death revealed increasing GP contact in the weeks closer to death. Hospital based care utilization remained constant. Conclusion: Although care in the terminal phase of life is structured to be primarily provided by GPs in the Netherlands, hospital based health care utilization was substantial in the last six weeks of life in this study population. No significant financial relationships to disclose.
Zoonotic tuberculosis in human beings caused by Mycobacterium bovis —a call for action
Authors: Francisco Olea-Popelka, Adrian Muwonge, Alejandro Perera, Anna S Dean, Elizabeth Mumford, Elisabeth Erlacher-Vindel, Simona Forcella, Benjamin J Silk, Lucica Ditiu, Ahmed El Idrissi, Mario Raviglione, Ottorino Cosivi, Philip LoBue, Paula I Fujiwara
Journal: The Lancet Infectious Diseases (2016)
P1-280: Survey on health system aspects concerning malignant diseases (lung cancer) in limited health resources country
Authors: Dragana Jovanovic, Nada Vasic, Ruza Stevic, Spasoje Popevic, Marta Velinovic, Natalija Samardzic, Sanja Dimic, Dragana Maric
Journal: Journal of Thoracic Oncology (2007)