tbuckley/cabot-search huggingface dataset:
Abstract 1122: FGFR1 can act as an oncogene or a tumor suppressor depending on the molecular context
Authors: Álvaro Quintanal-Villalonga, Laura Ojeda-Márquez, Ángela Marrugal, Rocío Suárez, Irene Ferrer, Amancio Carnero, Sonia Molina-Pinelo, Luis Paz-Ares
Journal: Cancer Research (2016)

Abstract FGFR family of proteins has been extensively related to oncogenic properties in several types of tumors, including lung cancer. Among its members, FGFR1 has been related to squamous cell lung carcinoma, where FGFR1 amplification is present in 20% of patients. However, its role in lung cancer has not yet been thoroughly described. Several lung cancer cell lines with different genetic backgrounds were transfected with plasmids to either overexpress or silence FGFR1. Then several tumorigenic abilities were tested in vitro and in vivo. mRNA from Paraffin-embedded tissue of a cohort of lung cancer patients was extracted and FGFR1 expression levels were measured and related to clinical characteristics. FGFR1 increases oncogenic properties in SCC cell lines, but exerts anti-oncogenic effects in several lung ADC cell lines, suggesting a tumor suppressor role under certain circumstances. This is a consequence of differentially expressed genes among these two histologies. According to this, analysis of FGFR1 mRNA expression of a cohort of lung cancer patients revealed that high FGFR1 mRNA expression was associated to a shorter overall survival (OS) and progression free survival (PFS) in lung SCC patients. However, a trend for longer OS was observed for the ADC patients with higher FGFR1 mRNA expression. FGFR1 has the potential to be either a tumor suppressor or an oncogene and the molecular context is a determining factor to define its final role in tumorigenesis. Citation Format: Álvaro Quintanal-Villalonga, Laura Ojeda-Márquez, Ángela Marrugal, Rocío Suárez, Irene Ferrer, Amancio Carnero, Sonia Molina-Pinelo, Luis Paz-Ares. FGFR1 can act as an oncogene or a tumor suppressor depending on the molecular context. [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 1122.
Renal cell carcinoma: The effect of targeted therapies on clear cell and non-clear cell histologies.
Authors: Joseph A Marascio, Bryan M Rabatic, David Zaenger, Nicholas A Madden, Edward M Marchan, David McDermott, Anne Kathryn Misiura, Sherif Shaaban, Byron G Dasher, Ke Huang, Mahboubeh Pishgou, William D Martin, Maryam Aletan, Jed W Howington, Ahmad M Albasheer, Ahmad Amoush, John G Stewart, Feng-Ming (Spring) Kong, Catherine L Ferguson, Waleed F Mourad
Journal: Journal of Clinical Oncology (2016)

e16077 Background: Beginning in 2005 treatment of advanced renal cell carcinoma (RCC) saw a shift from cytokine to targeted therapies. Medication classes introduced in this period included Tyrosine kinase inhibitors, VEGF inhibitors, and mTOR inhibitors. Clinical trials leading to the approval of these medications often excluded non-clear cell histologies. However, retrospective and prospective data have shown there may be a benefit in non-clear cell histology. The aim of this review was to evaluate the impact of targeted therapies on survival with respect to the histologic subtypes. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients with RCC diagnosed in 2000-2004 and 2007-2011. Only patients with distant disease at presentation were included. 12 month cause specific survival (CSS) was then calculated for histologic subtypes within the respective timeframes. Results: 12,239 patients met the above criteria. 5,776 patients were diagnosed from 2000-2004. The median age at diagnosis was 64. 65% were male. Histologic classification, (% of overall cases), and [12 month CSS] are as follows: Renal cell (64.3%) [28.3%], clear cell (27.1%) [52.5%], sarcomatoid (5.1%) [20.5%], papillary (2.1%) [50.3%], chromophobe (0.7%) [58.1%], collecting duct (0.5%) [21.9%], medullary (0.1%) [12.5%]. From 2007-2011 6,463 patients were diagnosed. The median age was 65. 67% were male. Histologic classification, (% of overall cases), and [12 month CSS] are as follows: Renal cell (47.8%) [28.6%], clear cell (41.1%) [57.7%], sarcomatoid (5.8%) [22.2%], papillary (3.5%) [44.7%], chromophobe (0.7%) [58.3%], collecting duct (0.6%) [20.0%], medullary (0.4%) [15.4%]. The only significant effect on 12 month CSS was for clear cell type: 52.5% (95% CI 49.9 – 54.9%) to 57.7% (95% CI 55.8-59.6%). Conclusions: While studies have shown activity of targeted therapies in non-clear cell histologies, only clear cell histology has seen a statistically significant improvement in CSS in this review. Notably, prognosis with regard to histologic subtype varied greatly and this is likely a reflection of a heterogeneous family of tumors which will require a more individualized approach in the future.
FIESTA: A phase Ib and pharmacokinetic trial of AZD4547 in combination with gemcitabine and cisplatin.
Authors: Robert Hugh Jones, David Alan Anthoney, Robert J. Jones, Simon J. Crabb, Syed A. Hussain, Alison J. Birtle, Pavlina Spiliopoulou, Timothy Robinson, Margaret Knowles, Lyndall McLellan, Hazel Jones, Zoe Boylan, Donal Landers, Kwame Atuah, Debbie Sherratt, Sarah R Brown, Louise Flanagan, Paul Loadman, Chris Twelves, John David Chester
Journal: Journal of Clinical Oncology (2016)

4521 Background: gemcitabine (G) plus cisplatin (C) is a standard-of-care, combination chemotherapy regimen for patients (pts) with bladder cancer (BC), in both neoadjuvant and palliative settings. AZD4547 is a selective fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor with potential to improve outcomes for tumors with FGFR mutation and/or over-expression, as commonly seen in BC. We have conducted a phase Ib dose escalation trial, combining GC with AZD4547. Methods: eligible pts were treated with escalating doses of oral AZD4547 (40mg, 80mg,100mg BD, 2 weeks on/1 week off) and GC (G 1000mg/m2 IV, days 1&8; C 70mg/m2 IV, day 1), every 21 days. Pts were prospectively screened, then monitored, for retinal pigmented epithelial detachment (RPED). Results: 19 pts were recruited to 3 dose levels at 3 UK centers. There were no treatment-related deaths or serious treatment-emergent adverse events. One dose-limiting toxicity was seen at 80mg BD of AZD4547 (G4 thrombocytopenia) and 2 at 100mg BD (G4 thrombocytopenia; G3 hyponatremia). The maximum tolerated dose was therefore defined as 80mg BD. 3 pts completed 3 or more cycles, without significant toxicity, at this dose level. The recommended dose for subsequent studies is therefore 80mg BD. RPED was seen in 4 of 6 pts at 80mg BD and 4 of 9 pts at 100mg BD. Only one reported symptoms prior to RPED screening. In all cases, RPED resolved spontaneously, on withdrawal of AZD4547. A protocol amendment permitted re-starting of AZD4547 in 2 pts, after resolution of RPED. In both cases, RPED recurred. Tmax pharmacokinetic data for the 3-drug combination were in line with those previously reported for AZD4547 alone; Cmax values, in the presence vs absence of GC, gave an 8-day accumulation factor of approximately 2. Conclusions: a recommended dose of 80mg BD, 2 weeks on/1 week off, has been determined for AZD4547 in combination with GC, with manageable toxicity. A comparison of toxicities of GC with and without AZD4547 is under way in a randomised expansion cohort of advanced bladder cancer patients. FIESTA was developed by the UK NCRI Bladder Cancer Clinical Studies Group, sponsored by the University of Leeds, funded by the Cancer Research UK/Astra Zeneca Combinations Alliance. Clinical trial information: 44149443.
Abstract 3433: Association between serum concentrations of polychlorinated biphenyls (PCBs) and increased risk of breast cancer among US women
Authors: Marisa Morgan, Alok Deoraj, Deodutta Roy
Journal: Cancer Research (2016)

Abstract The main objective of this study was to examine the cross-sectional relationship between exposure to PCBs or their congeners and breast cancer among US women. There is limited information on the association of specific PCB congener or their combination levels in blood serum with increased breast cancer risk. PCBs are weak estrogens which has been shown to act as endocrine disrupters by increasing or blocking estrogen like activities in animals and humans. We analyzed National Health and Nutrition Examination Survey (NHANES) data from 1999-2004 in the lipid adjusted blood samples of female participants (&amp;gt;20 years of age). Exposure assessment was based on lipid adjusted serum levels of 6 individual PCB congeners (PCB 074, 099, 118, 138, 153, and 180), the sum of dioxin-like PCBs (074 and 118), and the sum of non-dioxin-like PCBs (099 + 138 + 153+187) in conjunction with data obtained from the medical and reproductive health questionnaires. We calculated geometric means to compare PCB concentrations in women's blood samples who also self-reported a breast cancer diagnosis and women who were never diagnosed with cancer. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between PCB, their congener or their combinations and breast cancer. We evaluated age, race/ethnicity, age at menarche, body mass index (BMI; kg/m2), and lactation as potential confounders. Our results show a weighted geometric mean levels of 6 PCB congeners to be significantly higher in blood serum among women with breast cancer when compared to the rest of the study population. After adjusting for age, race, BMI, lactation, and age at menarche we found significant association of PCB 138 with breast cancer [odds ratios of 2.88; 95% confidence interval (CI): 1.14-7.30; 2.93, 95% CI: 1.04-8.26; and 3.43, 95% CI: 1.12-10.4] in women with higher body burdens of individual PCB congeners (&amp;gt; 50th percentile, 50th-75th percentile, and ≥75th percentile), respectively. After adjusting for age and race, it was also found that the sum of non-dioxin-like PCBs (074 and 118) in blood serum is significantly associated with breast cancer [OR of 1.14; 95% CI: 1.00-1.29]. In summary, our results suggest a possible link between environmental exposures to PCBs and increased risk of breast cancer among U.S. women. Citation Format: Marisa Morgan, Alok Deoraj, Deodutta Roy. Association between serum concentrations of polychlorinated biphenyls (PCBs) and increased risk of breast cancer among US women. [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 3433.
DPP4 (CD26) Truncation Of GM-CSF and IL-3 Alters Their Signaling and Functional Activity In Normal and Leukemic Hematopoietic Stem and Progenitor Cells
Authors: Heather A. O'Leary, Charlie Mantel, Xianyin Lai, Scott Cooper, Giao Hangoc, H. Scott Boswell, Frank Witzmann, Hal E. Broxmeyer
Journal: Blood (2013)
Lymphangiography for refractory postoperative chylothorax
Authors: Yozo Sato, Hidekazu Yamaura, Mina Kato, Hiroshi Kawada, Shinichi Murata, Takaaki Hasegawa, Tetsuya Abe, Norihisa Uemura, Yoshitaka Inaba
Journal: Annals of Oncology (2015)

Purpose: The purpose of this study was to assess the effectiveness of lymphangiography as a treatment for postoperative lymphatic leakage.Materials and methods: Lymphangiography was performed in 9 patients (7 male and 2 female; mean age, 65 years; range, 54–74 years) presenting with chylothorax following esophagectomy (n = 8) and pulmonary lobectomy (n = 1) from March 2005 to June 2013. All patients were unresponsive to conservative treatment including total parenteral nutrition, octreotide acetate, and chest drainage tube insertion. Pedal lymphangiography was performed in 8 patients and intranodal lymphangiography was performed in one patient. The median period between operation and lymphangiography was 19 days (range, 10–99 days). CT scan was examined on the same day after procedure. The technical success and clinical outcomes were evaluated retrospectively.Results: Lymphangiography was performed successfully in all patients. The chyle leakage site was detectable by CT in 8 patients (89%). Lymphatic leakage was decreased after procedure in all patients. Healing was achieved in 4 patients (44%) including 1 patient without detection of leakage. In remaining 5 patients, subsequent pleurodesis (n = 4) and surgical ligation of the thoracic duct (n = 1) were performed. Finally, the resolution of chylothorax was achieved in all patients.Conclusion: Lymphangiography can be useful for the treatment of refractory postoperative chylothorax. Purpose: The purpose of this study was to assess the effectiveness of lymphangiography as a treatment for postoperative lymphatic leakage. Materials and methods: Lymphangiography was performed in 9 patients (7 male and 2 female; mean age, 65 years; range, 54–74 years) presenting with chylothorax following esophagectomy (n = 8) and pulmonary lobectomy (n = 1) from March 2005 to June 2013. All patients were unresponsive to conservative treatment including total parenteral nutrition, octreotide acetate, and chest drainage tube insertion. Pedal lymphangiography was performed in 8 patients and intranodal lymphangiography was performed in one patient. The median period between operation and lymphangiography was 19 days (range, 10–99 days). CT scan was examined on the same day after procedure. The technical success and clinical outcomes were evaluated retrospectively. Results: Lymphangiography was performed successfully in all patients. The chyle leakage site was detectable by CT in 8 patients (89%). Lymphatic leakage was decreased after procedure in all patients. Healing was achieved in 4 patients (44%) including 1 patient without detection of leakage. In remaining 5 patients, subsequent pleurodesis (n = 4) and surgical ligation of the thoracic duct (n = 1) were performed. Finally, the resolution of chylothorax was achieved in all patients. Conclusion: Lymphangiography can be useful for the treatment of refractory postoperative chylothorax.
Prognostic factors for overall survival and distant metastasis free survival in cervical cancer patients with locally advanced disease and the role of consolidation chemotherapy.
Authors: Ana Carolina Matos Queiroz, Solange Moraes Sanches, Andrea Paiva Guimaraes, Adriana Regina G. Ribeiro, Glauco Baiocchi, Alexandre Andre Balieiro Anastacio da Costa
Journal: Journal of Clinical Oncology (2016)

e17004 Background: Chemotherapy (CT) concomitantly to external radiotherapy (RT) is the santard treatment for locally advanced cervical cancer (LACC). A few studies suggest a benefit for consolidation CT, but its use is still debated. Our goal was evaluate prognostic factors for overall survival (OS) in LACC patients treated with RT and their association to locoregional recurrence or distant metastasis. Methods: A restrospective review of data from LACC patients treated with RT from Jan/2005 to May/2014 at AC Camargo Cancer Center in Brazil. Primary endpoint was OS, secondary endpoints were distant metastasis free survival (DMFS) and locorregional recurrence free survival (LRFS). All survival intervals were calculated from the beginning of RT. Kaplan-Meier curves were used to calculate survivals, log-rank test to compare survival curves, Cox regression to multivariable analysis. Results: Among 124 patients, median age was 51.4 years, squamous cell carcinoma (SCC) was present in 79,8% of patients, 46.8% had FIGO stage IIB, 38.7% stage III, 11.3% IVA and 3.2% IVB with positive para-aortic lymphnodes. Positive lymphnodes were present in 53.2% of patients and ECOG was 0 in 66.9% and 1 in 25.0% of patients. Eight six percent were treated with concomitant CT and 86.3% recieved brachiterapy (BQT) after RT. Consolidation CT was done in 16.1% of patients. For a median follow-up time of 43.7 months, median OS was 80.8 months and OS rate at 4 years was 62.8%. Factors related to a longer OS in univariate analysis were SCC histology (p = 0.008), stage IIB (p = 0.024), ECOG 0 (p = 0.005), use of consolidation CT (p = 0.048) and BQT (p < 0.001). In multivariate analysis SCC (HR 0.35; p = 0.007), stage ≥ IIIA (HR 2.36; p = 0.031) and use of consolidation CT (HR 0.20; p = 0.026) remained significantly related to OS. Factors related to a longer DMFS were SCC histology (HR 0,42; p = 0,010) and use of consolidation CT (HR 0.34; p = 0.037). Factors related to a longer LRFS were use of concomitant CT (HR 0.20; p = 0.001) and BQT (HR 0.24; p = 0.010). Conclusions: Our study supports the role of consolidation CT in the treatment of LACC with a benefit mostly due to a higher distant metastasis control.
Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering
Authors: Giuseppe Danilo Norata, Hagai Tavori, Angela Pirillo, Sergio Fazio, Alberico L. Catapano
Journal: Cardiovascular Research (2016)

Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.
Abstract 4128: Anti-angiogenic and anti-metastatic activities of juglone in pancreatic cancer cells
Authors: Namrata Karki, Frank Greenway, William Hansel, Sita Aggarwal, Jack N. Losso
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is the fourth leading cause of cancer related deaths in the US. The late diagnosis, early metastasis and poor survival rate make this disease lethal. This current study was designed to examine the effect of juglone, 5 hydroxy-1, 4-naphthoquinone in modulating the angiogenic and metastatic potential of pancreatic cancer cells in vitro, using the MIA Paca-2 human pancreatic cancer cell line. Juglone is a natural quinoid abundantly found abundantly in plants of Juglandacea family. To understand the anti-angiogenic and anti-metastatic properties of juglone, expression of markers related to angiogenesis were measured by Western blot or ELISA and the effect on ability of cancer cells to migrate and invade after treatment was analyzed by transwell invasion and migration assay, wound healing assay, and in vitro tube formation assay in human umbilical vein endothelial cells. The Akt pathway is highly upregulated and is responsible for the regulation of various biological processes in pancreatic cancer cells including proliferation, growth, survival and angiogenesis. Akt activation is also associated with regulation of key angiogenic markers such as, VEGF (Vascular Endothelial Growth Factor) and HIF-1 (Hypoxia Inducible Factor). Upon treatment of pancreatic cancer cells with juglone, reduced expression of serine-phosphorylated Akt expression was observed. Juglone inhibited metastasis of pancreatic cancer cells as indicated by the results of cell migration, invasion and wound healing assay. Juglone treatment also downregulated the levels of VEGF and HIF-1α. Significantly, it was found that juglone inhibited pancreatic cancer cell motility, migratory and invading capabilities. These findings suggest that Akt inhibitors such as juglone possess ability to attenuate the aggressiveness of pancreatic cancer cells and can be used as a novel anti-cancer agent to prevent metastasis of highly invasive pancreatic adenocarcinomas. Citation Format: Namrata Karki, Frank Greenway, William Hansel, Sita Aggarwal, Jack N. Losso. Anti-angiogenic and anti-metastatic activities of juglone in pancreatic cancer cells. [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 4128.
Abstract 4037: Enhancement of efferocytosis by rhoA kinase inhibitor following doxorubicin treatment synergistically reduces tumor growth
Authors: Gihoon Nam, In-San Kim
Journal: Cancer Research (2016)

Abstract Massive dying of tumor cells after chemotherapy may promote chronic inflammation which favors tumor growth by uncleared secondary necrotic cells. Given that defects in apoptotic cell clearance have been linked with various inflammatory diseases and autoimmunity, the prompt removal of apoptotic cells by phagocytes is important for anti-tumor immunity. To improve the anti-tumor effect of doxorubicin, we investigated the role of RhoA-kinase (ROCK) inhibitors on efferocytosis by macrophages, which is important for anti-tumor immunity and tissue regeneration. Treatment of bone marrow-derived macrophages (BMDMs) with ROCK inhibitor increased efferocytosis of dying tumor cells by doxorubicin in vitro. ROCK-blockade after doxorubicin treatment group showed effective inhibition of tumor growth and also T cell-mediated elimination of immunogenic tumors more than the doxorubicin monotherapy group in established tumor models. Furthermore, we also confirmed that macrophage depletion abrogated the therapeutic effect of ROCK inhibitor after doxorubicin treatment on tumor growth. Taken together, our findings indicate that ROCK inhibitor following doxorubicin treatment reduced tumor growth via efferocytosis enhancement. Citation Format: Gihoon Nam, In-San Kim. Enhancement of efferocytosis by rhoA kinase inhibitor following doxorubicin treatment synergistically reduces tumor growth. [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 4037.