tbuckley/cabot-search huggingface dataset:
Patient-reported quality of life (QOL) analysis of radium-223 dichloride (Ra-223) evaluating pain relief from the phase 3 ALSYMPCA study.
Authors: Sten Nilsson, Michael Tomblyn, Paul Cislo, Jonathan Reuning-Scherer, Chris Parker
Journal: Journal of Clinical Oncology (2014)

5069 Background: Ra-223, a first-in-class α-emitter, significantly improved overall survival vs placebo (pbo) and was well tolerated (Parker. NEJM 2013; ALSYMPCA). Ra-223 had a positive impact on pain, significantly delaying time to external beam radiotherapy and reducing pain and opioid use (Nilsson. ASCO GU 2013). This post hoc analysis assessed Ra-223 treatment (tx) effects on QOL Functional Assessment of Cancer Therapy-Prostate (FACT-P) pain-related score (PRS), with subgroup assessments by prior docetaxel use (pD) and baseline number of bone mets. Methods: Pain was assessed at baseline and wk 16 and 24 with FACT-P; PRS was derived from 4 pain-related questions. In responders, baseline PRS increased 2 points (improved pain). Nonresponders had neutral response (baseline PRS change -1, 0, +1) and failure (2-point baseline PRS decrease [worse pain], including pts starting opioids during tx). Chi-square tests calculated P values of responder rates between tx groups. Logistic regression determined odds ratios (ORs) (Ra-223 vs pbo) adjusted for stratification factors (pD, baseline total ALP, concurrent bisphosphonate) and baseline PRS as covariates. Results: Of 921 pts (Ra-223, n = 614; pbo, n = 307), analysis included pts with recorded PRS at each assessment visit (wk 16; Ra-223, n = 405; pbo, n = 175, wk 24, Ra-223, n = 305; pbo, n = 118, wk 16 and 24, Ra-223, n= 283; pbo, n = 109). Significantly more Ra-223 vs pbo pts were responders; pain improved at each visit (wk 16, P = 0.028; wk 24, P = 0.007) and across visits (improved for wk 16 and 24, P = 0.013). Ra-223 tx significantly increased odds of improved pain vs pbo at wk 16 (OR, 1.70; 95% CI, 1.08-2.70; P = 0.023) and wk 24 (OR, 2.18; 95% CI, 1.17-4.06; P= 0.014); Table shows increased odds for wk 16 and 24. For all assessed subgroups and time points, a nominally higher % of Ra-223 pts had improved pain vs pbo pts. Conclusions: Ra-223 was associated with greater odds of pain relief vs pbo based on FACT-P PRS. Clinical trial information: NCT00699751. Group OR for continued pain improvement, wk 16 and 24 Ra-223 (n) Pbo (n) OR 95% CI All pts 283 109 2.58 1.18-5.62 < 6 mets 54 21 1.65 0.27-10.19 6-20 mets 123 52 2.57 0.79-8.39 > 20 mets/superscan 106 36 2.80 0.74-10.60 No pD 116 51 1.75 0.65-4.68 pD 167 61 5.20 1.17-23.09
Abstract 280: Synergisticin vitroactivity of MOR209/ES414 in combination with enzalutamide
Authors: Toddy Sewell, Michelle Blake, Jane A. Gross, Jan Endell, Johannes Weirather, John W. Blankenship
Journal: Cancer Research (2016)

Abstract Metastatic castration-resistant prostate cancer (mCRPC) presents a daunting therapeutic challenge for patients who eventually progress after androgen ablation therapy. Although newer AR antagonists show a survival benefit, these patients ultimately relapse. Thus, it is critical to identify new therapies that will work in combination with AR antagonists or in AR-antagonist resistant settings. MOR209/ES414 is a bispecific ADAPTIR™ (modular protein technology) molecule currently under investigation in a phase 1 clinical trial in mCRPC, including patients that have progressed on enzalutamide. In pre-clinical studies, MOR209/ES414 has previously been shown to redirect T cell cytotoxicity against cells expressing Prostate Specific Membrane Antigen (PSMA). Here, we aimed to determine whether enzalutamide affects PSMA expression on CRPC cells in vitro, and could alter the effectiveness of MOR209/ES414 at inducing T-cell mediated tumor cell death. To address these questions, we utilized a CRPC cell line, 22Rv1, which has low expression of PSMA and is resistant to enzalutamide. Treatment of 22Rv1 cells with 10 μM enzalutamide for 3 weeks resulted in increased PSMA cell surface expression as measured by flow cytometry. 22Rv1 cells exposed to enzalutamide were also more sensitive to MOR209/ES414-mediated T-cell lysis, with a 25% increase in cytotoxicity over a 4 hour chromium release assay compared to 22Rv1 cells that were not exposed to enzalutamide. A concomitant decrease in EC50 for MOR209/ES414-mediated lysis from 0.8 pM to 0.5 pM was also observed in 22Rv1 cells exposed to enzalutamide. MOR209/ES414 and enzalutamide were next tested in combination using a PSMA-positive, enzalutamide-sensitive cell line, LNCaP cultured with primary T cells over several days. Suboptimal doses of MOR209/ES414 and enzalutamide were added to the cultures, and surviving LnCaP cells were quantitated 4 days later. Enzalutamide did not interfere with the ability of MOR209/ES414 to target T cells to LNCaP cells, and Combination Index analysis showed the activity of MOR209/ES414 and enzalutamide to be synergistic in vitro. These studies provide a rationale for further examination of combining MOR209/ES414 with enzalutamide, even in enzalutamide-resistant settings. Citation Format: Toddy Sewell, Michelle Blake, Jane A. Gross, Jan Endell, Johannes Weirather, John W. Blankenship. Synergistic in vitro activity of MOR209/ES414 in combination with enzalutamide. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 280.
Abstract 237: Enrichment of AXL-high/ MITF-low melanoma cells in the presence of MAPK inhibitorsin vitro
Authors: Ken Dutton-Regester, Levi Garraway
Journal: Cancer Research (2016)

Abstract BRAF and MEK inhibitors have become a standard of care for patients with metastatic BRAF mutant (V600) melanoma. Despite their success, 10- 20% of patients exhibit ‘intrinsic’ resistance and fail to respond to treatment. Recently, distinct transcriptional profiles have been associated with sensitivity to these drugs with intrinsically resistant melanomas exhibiting an AXL-high/ MITF-low phenotype (1). Using melanoma cell lines from the Cancer Cell Line Encyclopedia with matched gene expression data, we confirmed that AXL-high/ MITF-low cell lines had increased resistance to both BRAF (Dabrafenib) and MEK (Trametinib) inhibitors, either singly or in combination. Using flow cytometry with an AXL antibody, we observed that AXL-high/ MITF-low resistant cell lines frequently exhibited a high percentage of AXL+ cells (≥90%) while AXL-low/ MITF-high sensitive cell lines showed the opposite (≤5%). We hypothesized that the small percentage of AXL+ cells in the sensitive cell lines may be responsible for mechanisms of adaptive or acquired resistance (a feature that is frequently observed with the use of BRAF and MEK inhibitors in vitro and in the clinic). To explore this, we cultured sensitive cell lines in vitro for 5 days in the presence of combined Dabrafenib and Trametinib (DT) and performed flow cytometry to determine if there was a change in the percentage of AXL+ cells. All sensitive cell lines exhibited an enrichment of AXL+ cells with increasing concentrations of DT (maximum increase compared to DMSO control across individual cell lines ranged from 10% to 85%). It is unknown whether this phenomenon could be explained by a clonal selection or ‘plastic’ epigenetic reprogramming process and as such, we are currently performing experiments to determine this. Looking to the future, identifying potential dependencies of AXL-low/ MITF-high melanomas will deepen our understanding of the biology supporting this resistant state and provide a platform for the design of future clinical intervention strategies in this subset of patients. 1) Konieczkowski et al. 2014. Cancer Discovery. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. 4(7):816-27. Citation Format: Ken Dutton-Regester, Levi Garraway. Enrichment of AXL-high/ MITF-low melanoma cells in the presence of MAPK inhibitors in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 237.
Abstract 1908: Lung tumorigenesis and metastasis is suppressed by the miR-200-GATA4/6-BMP4 axis
Authors: Jeong Seon Kim, Jonathan M. Kurie, Young-Ho Ahn
Journal: Cancer Research (2016)

Abstract MicroRNA-200 (miR-200) family members suppress the epithelial-mesenchymal transition of various cancer cells, including lung adenocarcinoma cells. Previously, we found that forced expression of miR-200 decreased bone morphogenetic protein 4 (BMP4). In this study, we explored the mechanism and role of BMP4 depletion by miR-200 in murine lung adenocarcinoma cells. miR-200 down-regulated BMP4 via direct targeting of the GATA4 and GATA6 transcription factors that stimulate Bmp4 transcription. Bmp4 knockdown suppressed cancer cell growth, migration, and invasion and inhibited tumorigenesis and metastasis of lung cancer cells when injected into syngeneic mice. In addition, BMP4 was required for normal sphere formation in Matrigel 3-D culture, which might be mediated by MYH10, a downstream target of BMP4. These findings suggest that BMP4 functions as a pro-tumorigenic factor in a murine lung cancer model, and its transcription is regulated by miR-200 and GATA4/6. Citation Format: Jeong Seon Kim, Jonathan M. Kurie, Young-Ho Ahn. Lung tumorigenesis and metastasis is suppressed by the miR-200-GATA4/6-BMP4 axis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1908.
Genetics and Epigenetics of the PU.1 Upstream Regulatory Element: AML1 Binding Sites Are Critical for Leuekmia Induced by the AML/ETO9a Fusion Oncogene
Authors: Pu Zhang, Gang Huang, Alex Ebralidze, Jun-Yan Zhang, Annalisa DiRuscio, Chris Hetherington, Elena Levantini, Daniel G. Tenen
Journal: Blood (2008)
SPARC and CA19–9 as biomarkers in patients with advanced pancreatic cancer treated with nab paclitaxel plus gemcitabine
Authors: L. S. Smith, R. L. Drengler, T. E. Wood, D. A. Laheru, M. Hidalgo, M. J. Borad, V. Trieu, D. Knauer, N. Desai, D. D. Von Hoff
Journal: Journal of Clinical Oncology (2008)

15592 Background: Pancreatic cancers are known to overexpress SPARC (Secreted Protein And Rich in Cysteine) (Von Hoff et al., 2006). Increased SPARC expression in tumors resulted in improved response to albumin- bound paclitaxel (nab-paclitaxel, nab-pac) due to SPARC-albumin binding (Trieu et al., SKCC, 2007). A disease specific phase I trial of nab-pac + gemcitabine (gem) in pts with advanced pancreatic cancer was initiated and pretreatment tumor biopsies tested for SPARC to investigate any correlation with response. Serum CA19–9 levels were monitored since a decrease in this biomarker was correlated with improved survival by multiple investigators (Ko et al., 2005, Maisey et al 2005). Methods: Pts with no prior chemotherapy except as a radiation sensitizer received nab-pac (100 mg/m2) + gem (1000 mg/m2) on days 1, 8, 15 every 28 days. Response (RECIST) was determined by CAT or PET scans. SPARC immunohistochemistry (IHC) in panc tumors was scored on a 0–3 scale (3=positive) at a central laboratory. CA19–9 was monitored at every cycle. Fisher's exact test was used for statistical analysis. Results: To date, 20 pts are enrolled. 16 pts were evaluable for response (9PR [5 confirmed, 4 unconfirmed], 6SD, 1PD). Clinical details are reported in another abstract. CA19–9 data were available for 15 evaluable patients. CA19–9 decrease of ≥40% from baseline was noted in 11/15 (73%) pts. CA19–9 drop of ≥40% correlated with response and occurred in all 9 responders and only in 2 of 6 non-responders (p = 0.011). SPARC IHC was available for 12 evaluable pts. SPARC positive pts (8/12) included 6PR, 2SD; while SPARC negative pts included 1PR, 2SD and 1PD. Patients with response were more likely to be SPARC positive. Conclusions: The combination of nab-paclitaxel and gemcitabine appears to be active in pancreatic cancer and warrants further study. These preliminary data suggest that SPARC positivity and decrease in CA19–9 may correlate with response and may support the hypothesis that SPARC plays an important role in the concentration of albumin bound paclitaxel in tumors. The study has been expanded to enroll additional pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis BioScience, LLC Concordia, Genentech Abraxis BioScience, LLC Abraxis BioScience, LLC, Anza, Bristol-Myers Squibb, Cell Genesys, Concordia, Genentech, Genvec
Abstract 3440: Time and regional incidence trends of human papillomavirus-associated oropharyngeal cancer in Ontario, Canada
Authors: Wei Shi, Stephen F. Hall, Katrina Rey-McIntyre, Rebecca Griffiths, Wei Xu, Jie Su, Jeff Bruce, Shaohui Huang, Brian O’Sullivan, Kenneth W Yip, Fei-Fei Liu
Journal: Cancer Research (2016)

Abstract Background: Despite the increasing incidence of human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) in the Western World, there are little data describing the change in HPV incidence within Ontario, Canada. We therefore assessed HPV-positivity in a retrospective study of 612 OPC patient samples. Methods: Diagnostic formalin-fixed and paraffin embedded OPC patient samples belonging to two cohorts were retrieved from institutions across Ontario, Canada over two time periods: 1998-1999 (n = 245) and 2003-2004 (n = 367). In all samples, HPV status was assessed initially using p16 immunohistochemistry (IHC). For p16 negative and equivocal staining samples, HPV in situ hybridization (ISH; using an HPV subtype 16/18 probe) was performed as the final indicator for HPV positivity. HPV-positivity rate was then compared over time and geographic region. Results: Overall, p16-positivity was observed in 52.3% (320 of 612) of the OPC patients. For the p16-negative (n = 246) and p16-equivocal (n = 46) samples, 25.3% (n = 74) were positive by HPV16/18 ISH. The HPV infection incidence for the 1998-1999 cohort was 54.3% (133 of 245 samples; 95% CI: 53.9(47.4-60.2)). The HPV infection incidence increased significantly in the 2003-2004 cohort to 71.1% (261 of 367 samples; 95% CI: 71.4(66.5-76.0)) (p&amp;lt;0.0001). When divided based on geographical region, HPV incidence also increased significantly over time (Northern Ontario by 49%, p = 0.04; Eastern Ontario by 23%, p = 0.009; Southern Ontario by 17%, p = 0.009; Central Ontario by 12%, p = 0.05). There were no significant differences between urban and rural areas over the two cohort periods (urban p = 0.8; rural, p = 0.6). Conclusions: HPV-associated OPC increased in incidence in Ontario, Canada, over a 6-year period from 1998 to 2004, which appeared to be applicable across the entire province, regardless of urban or rural regions. A composite HPV detection method using p16 in combination with HPV ISH identified an additional 25% of HPV-positive OPC cases. Citation Format: Wei Shi, Stephen F. Hall, Katrina Rey-McIntyre, Rebecca Griffiths, Wei Xu, Jie Su, Jeff Bruce, Shaohui Huang, Brian O’Sullivan, Kenneth W Yip, Fei-Fei Liu. Time and regional incidence trends of human papillomavirus-associated oropharyngeal cancer in Ontario, Canada. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3440.
Synergistic antiproliferative effect of recombinant interferon-gamma with recombinant interferon-alpha on chronic myelogenous leukemia hematopoietic progenitor cells (CFU-GEMM, CFU-Mk, BFU-E, and CFU-GM)
Authors: C Carlo-Stella, M Cazzola, A Ganser, G Bergamaschi, P Pedrazzoli, D Hoelzer, E Ascari
Journal: Blood (1988)
Abstract 3700: Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients
Authors: Christine G. Stoehr, Robert Stoehr, Antonia Wenners, Arndt Hartmann, Simone Bertz, Verena Spath, Bernhard Walter, Kerstin Junker, Holger Moch, Raoul Hintze, Stefan Denzinger, Elisabeth E. Bond, Gareth L. Bond, Karen Bluemke, Katrin Weigelt, Verena Lieb, Elke Nolte, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert
Journal: Cancer Research (2016)

Abstract Mdm2 (Human mouse double minute 2) is an important opponent of the tumor suppressor p53. The G/G variant of SNP309 in the MDM2 promoter can increase Mdm2 mRNA/protein expression and is associated with an increased risk and earlier onset of different cancers especially in Asian populations. But the frequency and impact of the G/G variant has not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). Next, when separating all females into two groups at their median age (68 years), 7 patients and 1 patient with the G/G variant and 9 patients and 13 patients with the T/T variant were noted in these age groups (P = 0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was analyzed, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P = 0.039 and P = 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs. 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP 309 G/G variant showed a significantly earlier tumor onset than patients with the wildtype T/T genotype. Citation Format: Christine G. Stoehr, Robert Stoehr, Antonia Wenners, Arndt Hartmann, Simone Bertz, Verena Spath, Bernhard Walter, Kerstin Junker, Holger Moch, Raoul Hintze, Stefan Denzinger, Elisabeth E. Bond, Gareth L. Bond, Karen Bluemke, Katrin Weigelt, Verena Lieb, Elke Nolte, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3700.
Mortality due to Vegetation Fire–Originated PM <sub>2.5</sub> Exposure in Europe—Assessment for the Years 2005 and 2008
Authors: Virpi Kollanus, Marje Prank, Alexandra Gens, Joana Soares, Julius Vira, Jaakko Kukkonen, Mikhail Sofiev, Raimo O. Salonen, Timo Lanki
Journal: Environmental Health Perspectives (2016)

Vegetation fires can release substantial quantities of fine particles (PM2.5), which are harmful to health. The fire smoke may be transported over long distances and can cause adverse health effects over wide areas.We aimed to assess annual mortality attributable to short-term exposures to vegetation fire-originated PM2.5 in different regions of Europe.PM2.5 emissions from vegetation fires in Europe in 2005 and 2008 were evaluated based on Moderate Resolution Imaging Spectroradiometer (MODIS) satellite data on fire radiative power. Atmospheric transport of the emissions was modeled using the System for Integrated modeLling of Atmospheric coMposition (SILAM) chemical transport model. Mortality impacts were estimated for 27 European countries based on a) modeled daily PM2.5 concentrations and b) population data, both presented in a 50 × 50 km2 spatial grid; c) an exposure-response function for short-term PM2.5 exposure and daily nonaccidental mortality; and d) country-level data for background mortality risk.In the 27 countries overall, an estimated 1,483 and 1,080 premature deaths were attributable to the vegetation fire-originated PM2.5 in 2005 and 2008, respectively. Estimated impacts were highest in southern and eastern Europe. However, all countries were affected by fire-originated PM2.5, and even the lower concentrations in western and northern Europe contributed substantially (~ 30%) to the overall estimate of attributable mortality.Our assessment suggests that air pollution caused by PM2.5 released from vegetation fires is a notable risk factor for public health in Europe. Moreover, the risk can be expected to increase in the future as climate change proceeds. This factor should be taken into consideration when evaluating the overall health and socioeconomic impacts of these fires. Citation: Kollanus V, Prank M, Gens A, Soares J, Vira J, Kukkonen J, Sofiev M, Salonen RO, Lanki T. 2017. Mortality due to vegetation fire-originated PM2.5 exposure in Europe-assessment for the years 2005 and 2008. Environ Health Perspect 125:30-37; http://dx.doi.org/10.1289/EHP194.