tbuckley/cabot-search huggingface dataset:
A randomized, double-blind, placebo-controlled multicenter phase III study comparing denosumab with placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE).
Authors: P. E. Goss, C. H. Barrios, R. Bell, D. Finkelstein, H. Iwata, M. Martin, A. H. Braun, R. D. Dansey, R. E. Coleman
Journal: Journal of Clinical Oncology (2011)

TPS152 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer. Cancer cells are thought to stimulate osteoclast-mediated bone resorption, which releases growth factors and cytokines that promote tumor growth. RANK Ligand (RANKL) is the key mediator of osteoclast-induced bone destruction. In preclinical studies, RANKL inhibition reduced the incidence of bone and lung metastases, suppressed tumor progression, and prolonged survival of tumor-bearing mice. Effects were additive with hormonal, chemotherapy, or targeted therapies. Denosumab is a fully human monoclonal antibody against RANKL, approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In patients with castrate-resistant prostate cancer, denosumab significantly improved bone metastasis-free survival (BMFS) compared to placebo. The D-CARE trial evaluates BMFS effects of denosumab in women with stage II or III breast cancer. Methods: Women with node-positive or locally advanced (T3 or T4) disease, and known hormone and HER-2 receptor status are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned with curative intent. Women with a prior history of breast cancer (other than DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year or any intravenous BP use are excluded. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 mos, then every 3 mos, for 5 yrs. Supplemental vitamin D and calcium are required at standard doses. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include disease-free (DFS) and overall survival. The study is powered for both BMFS and DFS. Safety, quality of life assessments, and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010. PG and DF are supported in part by the Avon Foundation, NY.
PTH-057 Northern Nutrition Network regional PEG audit: third cycle: Abstract PTH-057
Authors: S White, A Torrance, K Matthewson
Journal: Gut (2010)

<h3>Introduction</h3> The Northern Nutrition Network (NNN) is a multidisciplinary group of individuals with an interest in nutrition representing 17 hospitals in the Northern Region. It meets on a regular basis to promote standards of nutrition. We have previously reported to the Society the results of a 3-month audit by members of the NNN of all PEG insertons in the 17 participating hospitals which was repeated after a 2-year interval.1 The results appeared to show a decline in the rate of PEG insertions and a decline in the 28-day mortality rate following PEG insertion. We performed a further cycle of the audit to see whether the changes had been maintained. <h3>Methods</h3> The initial audits were performed from Dec 03 to Feb 04 and Dec 05 to Feb 06. A third cycle was performed from Dec 07 to Feb 08. In order to maintain consistency for each audit the data were recorded using an identical proforma. One individual from each participating unit was responsible for ensuring that data for each PEG insertion was recorded and the Newcastle PEG team collated the data. <h3>Results</h3> See Abstract 057. <h3>Conclusion</h3> The decrease in the PEG insertion rate seen between the first and second audit and the decrease in the 28-day mortality rate were only partially maintained. The trend towards less PEG insertion in stroke patients is sustained. There is a trend towards increasing PEG insertion in patients with learning disabilities. PEG insertion rate in demented patients remains low. These prospective audits provide a useful snapshot of PEG insertion practice and trends in 17 different hospitals in the Northern Region.
Abstract 213: Evaluating high risk BI-RADS 4 mammographic lesions: a pilot trial of textural analysis (TA) as a supplement to digital mammography (DM)
Authors: Melissa R. Gordon, Erkut Borazanci, Daniel D. Maki, Ron L. Korn
Journal: Cancer Research (2015)

Abstract Background: Although mammographic lesions classified as BI-RADS 4 are considered suspicious for carcinoma - by definition - and biopsy (bx) is therefore always recommended, only 20-30% of such lesions ultimately yield malignancy at biopsy. TA is an ancillary non-subjective quantitative analysis platform that can be performed as an add-on to routine mammographic analysis. The ability of TA to characterize lesions with high rates of heterogeneity led us to hypothesize that TA, as a supplement to routine DM analysis, might aid in selecting patients (pts) for bx vs. serial observation. Methods: A retrospective analysis was performed on 40 screening pts with no history of cancer, with newly identified mammographic densities characterized as BI-RADS 4. Lesions measured 1-3 cm size and had no associated microcalcifications. Twenty pts had confirmed malignant biopsy while the other 20 pts served as age matched controls with similar lesion characteristics but ultimate benign biopsy result. For each lesion, TA was performed on a 1×1cm region of interest (ROI), along with a secondary control ROI of normal breast tissue. Results: Pts with malignant and benign bx had a median age of 53 years (range 28-83) vs. 52 years (range 32-75) (p = NS) and median nodule size 1.5 cm (range 1.0-2.9 cm) vs. 1.3 cm (range 1.0-2.5 cm) (p = NS), respectively. No differences between the groups were seen in menopausal status nor parenchymal density. The mean positive pixel (MPP) value was most predictive of malignancies at a Spatial Scale Frequency (SSF) filter level of 0.8. The median MPP for malignant lesions was 577 vs 730 for benign lesions (p = 0.033). There was no difference between MPP or other TA parameters in normal tissue of either group. Conclusion: TA, as a supplement to DM, may help stratify which women with high-risk BI-RADS 4 densities that better benefit from biopsy vs. those that might be safely followed with serial surveillance. Larger scale studies will be needed to validate these findings and are currently ongoing. Citation Format: Melissa R. Gordon, Erkut Borazanci, Daniel D. Maki, Ron L. Korn. Evaluating high risk BI-RADS 4 mammographic lesions: a pilot trial of textural analysis (TA) as a supplement to digital mammography (DM). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 213. doi:10.1158/1538-7445.AM2015-213
Abstract 3873: Improving the effectiveness of chemotherapy by combining compounds that suppress drug-induced microsatellite instability
Authors: Christina L. Chang, Li-Yan Huang, Chang-Lin Wu, Jhih-Ying Chi
Journal: Cancer Research (2015)

Abstract Many chemotherapeutic agents damage DNA and induce DNA damage response (DDR) signaling, resulting in growth arrest or apoptosis. DNA mismatch repair (MMR) system not only maintains genomic stability but also participates in DDR signaling. MMR deficiency leads to genetic hypermutability, manifested as microsatellite instability (MSI), and contributes to cancer pathogenesis and drug resistance. MSI has been linked to chemotherapy and therapy-related secondary cancer. Therefore, it is important to prevent drug-induced MSI to increase the effectiveness of chemotherapy while reducing cancer mortality. The purpose of this study is to characterize the MSI-inducing ability of individual chemotherapeutic agents and identify small compounds that suppress drug-induced MSI. In a human colorectal cancer cell model, all tested drugs individually induced the instability of reporter and endogenous microsatellites while reducing steady-state levels of certain MMR proteins. Relatively, oxaliplatin induced a higher MSI frequency than many tested drugs such as 5-FU. It is known that MMR-deficient tumors are resistant to 5-FU and not oxaliplatin. We then screened a commercially available library for small compounds that suppress oxaliplatin-induced MSI using a dual-fluorescent MSI reporter. We found that the majority of compounds were capable of reducing oxaliplatin-induced MSI. However, they also undesirably decreased the cytotoxicity of oxaliplatin. On the other hand, a small number of compounds such as I-6 and II-13 suppressed oxaliplatin-induced MSI with or without an improvement of drug cytotoxicity. Relative to oxaliplatin alone, co-treatment of 1 μM oxaliplatin with 6-10 μM compound II-13 decreased drug-induced MSI frequency by 45-70% without significantly affecting the cytotoxicity of oxaliplatin. Co-treatment of oxaliplatin with 4-10 μM compound I-6, however, decreased both drug-induced MSI and cell numbers by 50-78% in a dose-dependent manner. To our surprise, compounds such as II-13 suppressed MSI induced by oxaliplatin but not by 5-FU. In conclusion, individual drugs displayed different MSI-inducing abilities whereas MSI-suppressing compounds appear to be drug-specific. Further identification and validation of MSI-suppressing compounds specific for 5-FU or leucovorin, for example, would improve the effectiveness of combination chemotherapy such as FOLFOX. Citation Format: Christina L. Chang, Li-Yan Huang, Chang-Lin Wu, Jhih-Ying Chi. Improving the effectiveness of chemotherapy by combining compounds that suppress drug-induced microsatellite instability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2015-3873
Novel factor to improve prediction of sentinel node positivity in patients with clinical T1/T2 breast cancer.
Authors: Miraj G. Shah-Khan, Tiffany Torstensen, Tanya L. Hoskin, Marilyn Morton, Darcy Adamczyk, Katie N. Jones, Stephane Chartier, Judy Caroline Boughey
Journal: Journal of Clinical Oncology (2013)

49 Background: Predicting nodal positivity can guide surgical planning in breast cancer. Memorial Sloan-Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) have established nomograms to predict sentinel node positivity. We propose that addition of distance of tumor from the nipple (DFN) can improve their performance. Methods: With IRB approval clinical T1/T2 tumors with pre-biopsy ultrasound were reviewed. MSKCC and MDACC nomogram predictions and the AUC-ROC were calculated. The addition of DFN was examined using multiple logistic regression and comparison of AUC-ROC values. Results: 401 breast cancers with clinical T1 (85%) or T2 (15%) tumors in 395 patients were included; of which 79/401 (19.7%) were node positive. Tumors were significantly closer to the nipple in those with positive nodes. 17/33 (51.5%) tumors within 2 cm of the nipple were node-positive versus 62/368 (16.8%) tumors &gt; 2 cm from the nipple (p&lt;0.0001). The MSKCC and MDACC nomograms each demonstrated good discrimination between node positive and negative patients with AUC-ROC values of 0.71 (95% CI: 0.64-0.77) and 0.74 (95% CI: 0.68-0.81), respectively. When added to the MSKCC nomogram, DFN ≤2 cm contributed significantly (OR 4.78, p=0.0001) to prediction of node positivity and improved the AUC-ROC to 0.73 (95% CI: 0.67-0.80). Similarly, DFN ≤2 cm was significant (OR 4.73, p=0.0002) when added to the MDACC nomogram and improved the AUC to 0.76 (95% CI: 0.70-0.82). Within nomogram probability categories, the proportion with positive nodes was consistently higher with DFN ≤2 cm. Conclusions: Tumor distance from nipple is associated with nodal positivity. When added to nomograms it improves prediction of node positivity. DFN should be considered when considering likelihood of nodal positivity for treatment planning. [Table: see text]
Abstract 3945: PTEN loss is associated with aggressive behavior and poor prognosis in Middle Eastern Triple Negative Breast Cancer
Authors: Abdul K. Siraj, Shaham Beg, Sarita Prabhakaran, Zeenath Jehan, Dahish Ajarim, Fouad Al-Dayel, Asma Tulbah, Khawla Al-Kuraya
Journal: Cancer Research (2015)

Abstract PTEN is a tumor suppressor that negatively regulates the PI3K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In order to learn more on the prevalence and clinical significance of PTEN protein expression and PTEN gene deletions, a tissue microarray containing more than 1000 primary breast cancers with clinical follow up data was used. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Loss of PTEN immunostaining was observed in 77% of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333) and Triple negative breast cancers (p = 0.0086). PTEN loss in Triple negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4%) of cases. It was concluded that loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore PTEN signaling pathway might be used as potential therapeutic target in Triple negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer. Citation Format: Abdul K. Siraj, Shaham Beg, Sarita Prabhakaran, Zeenath Jehan, Dahish Ajarim, Fouad Al-Dayel, Asma Tulbah, Khawla Al-Kuraya. PTEN loss is associated with aggressive behavior and poor prognosis in Middle Eastern Triple Negative Breast Cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3945. doi:10.1158/1538-7445.AM2015-3945
Aldehyde dehydrogenase‐2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP‐activated protein kinase signaling in mice
Authors: Guojun Hou, Lei Chen, Gang Liu, Liang Li, Yuan Yang, He‐Xin Yan, Hui‐Lu Zhang, Jing Tang, Ying Cheng Yang, Ximeng Lin, Xin Chen, Gui juan Luo, Yanjing Zhu, Shanhua Tang, Jin Zhang, Hui Liu, Qingyang Gu, Ling‐Hao Zhao, Yixue Li, Lei Liu, Weiping Zhou, Hongyang Wang
Journal: Hepatology (2016)

Potential biomarkers that can be used to determine prognosis and perform targeted therapies are urgently needed to treat patients with hepatocellular carcinoma (HCC). To meet this need, we performed a screen to identify functional genes associated with hepatocellular carcinogenesis and its progression at the transcriptome and proteome levels. We identified aldehyde dedydrogenase‐2 (ALDH2) as a gene of interest for further study. ALDH2 levels were significantly lower at the mRNA and protein level in tumor tissues than in normal tissues, and they were even lower in tissues that exhibited increased migratory capacity. A study of clinical associations showed that ALDH2 is correlated with survival and multiple migration‐associated clinicopathological traits, including the presence of metastasis and portal vein tumor thrombus. The result of overexpressing or knocking down ALDH2 showed that this gene inhibited migration and invasion both in vivo and in vitro . We also found that ALDH2 altered the redox status of cells by regulating acetaldehyde levels and that it further activated the AMP‐activated protein kinase (AMPK) signaling pathway. Conclusion: Decreased levels of ALDH2 may indicate a poor prognosis in HCC patients, while forcing the expression of ALDH2 in HCC cells inhibited their aggressive behavior in vitro and in mice largely by modulating the activity of the ALDH2‐acetaldehyde‐redox‐AMPK axis. Therefore, identifying ALDH2 expression levels in HCC might be a useful strategy for classifying HCC patients and for developing potential therapeutic strategies that specifically target metastatic HCC. (H epatology 2017;65:1628‐1644).
Geographic difference in safety and efficacy of systemic chemotherapy for advanced gastric or gastroesophageal carcinoma: A meta-regression approach.
Authors: C. Hsu, Y. Shen, C. Cheng, A. Cheng, F. Hu, K. Yeh
Journal: Journal of Clinical Oncology (2011)

109 Background: The standard of chemotherapy regimens for patients with advanced or metastatic gastric cancer vary and the clinical outcome were heterogeneous in Asian vs. non-Asian countries. Methods: Treatment group-based meta-analysis and meta-regression were performed to analyze results of randomized trials published since 2005 for advanced or metastatic gastric cancer patients who received systemic chemotherapy as first-line treatment. Data were extracted and synthesized according to the Cochrane guidelines. Results: Among the 24 trials (totally 6,502 patients) eligible for meta-analysis, Asian trials reported lower percentage of gastroesophageal junctional carcinoma, higher percentage of diffuse-type histology, and more frequent use of second-line chemotherapy. Meta- regression analyses indicate that, after controlling other patient or treatment factors, Asian trials are associated with 22.7% (95% CI: 19.5-26.0%, p&lt;0.0001) lower incidence of grade 3-4 neutropenia and 3.5% (95% CI: 2.1-4.9%, p&lt;0.0001) lower incidence of grade 3-4 diarrhea, which were the most commonly reported toxicity. The use of high-dose infusional 5-fluorouracil, compared with other fuoropyrimidine regimens, reported 16.6% lower incidence of neutropenia (95% CI: 13.3-19.9%, p&lt;0.0001). Higher percentage of patients with gastroesophageal junction carcinoma and patients with 2 or more organs involved predicted poor progression-free survival. The use of second-line chemotherapy predicts better 1-year overall survival, which will increase by 9% (95% CI: 8-10%) for every 10 percent increase in patients who received second-line chemotherapy. Conclusions: Geographic region (Asian vs. non-Asian) plays an important role in the heterogeneity of gastric cancer clinical trials and is an independent predictor of safety in systemic therapy for gastric cancer. No significant financial relationships to disclose.
Abstract 2162: Loss of ATF3 promotes akt activation and prostate cancer development in a pten knockout mouse model
Authors: Ziyan Wang, Dong Xu, Chunhong Yan
Journal: Cancer Research (2015)

Abstract Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (e.g., proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression was often found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas oncogenic stress caused by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation but inhibited apoptosis, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, loss of ATF3 appeared to promote activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by sgRNA-mediated targeting activated AKT, elevated NF-KB nuclear translocation and increased expression of a broad of matrix metalloproteinase such as MMP-9, MMP-10. By zymography and q-PCR assays, we found that MMP-9 expression increased in ATF3-knockdown DU145 and PC3 cells. Also from luciferase reporter result, we further confirmed that loss of ATF3 could elevate MMP-9 expression via activating NF-KB. And in vivo immunochemistry results also show increased MMP9 expression and discontinuous a-SMA staining along prostate glands. These results were well anticipated that ATF3 deficiency leads to activated AKT signaling, which further activates IKK-A to increase nuclear translocation of NF-KB, which in turn binds to the MMP-9 promoter and induces MMP-9 expression in ATF3-downregulated prostate cancer cells, then promotes invasion in Pten-lost mouse prostates. Our results thus link ATF3 to the AKT signaling, and provide the first genetic evidence supporting that ATF3 is a tumor suppressor for a subset of prostate cancers harboring dysfunctional Pten. Citation Format: Ziyan Wang, Dong Xu, Chunhong Yan. Loss of ATF3 promotes akt activation and prostate cancer development in a pten knockout mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2162. doi:10.1158/1538-7445.AM2015-2162
Abstract 236: Autocrine regulation of stress-induced cytotoxic Alu RNA expression in TNBC cells
Authors: Ashutosh Singhal, Smita Mishra, Gautum Chaudhuri
Journal: Cancer Research (2015)

Abstract Breast tumor cells are often subject to various forms of proteotoxic stress in their microenvironment mainly presented by the stromal cells. We found that the highly aggressive breast cancer cells of the triple negative subtype (TNBC) are significantly more tolerant to environmental stress than the non-aggressive breast cancer cells. Major objective of the research presented here is to understand the mechanism of induction of cytotoxic Alu RNA in the stressed breast cancer cells and how the TNBC cells pacify this non-coding RNA-mediated cytotoxicity. We present evidence that stress-induced activation of HSF1 in the breast cancer cells stimulate the RNA polymerase III-mediated transcription of Alu RNA genes in these cells resulting in induction of severe cytotoxicity and apoptosis of these cells. Highly aggressive stress-tolerant TNBC cells secrete the matrix metalloprotease MMP1 which activates the G-protein coupled receptor PAR1 on their cell surface. Activation of PAR1 through the Galpha-q/PIPLC/PIP3 pathway raises the cytosolic concentration of Ca2+ thereby activating the Ca2+-dependent protease mu-calpain. Mu-calpain then proteolytically degrades the RNA polymerase III transcription factor TFIIIC110 at the PES sequence. As TFIIIC110 is required for the transcription of Alu RNA genes, its degradation ameliorates stress-induced elevation of Alu RNA and thus its cytotoxicity. We propose that inhibition of MMP1, PAR1 or mu-calpain in the TNBC cells will prevent this pacification mechanism promoting stress-induced demise of these cells. This research is supported in part by NIH/NCI grant 1R21CA181920-01 to GC. Citation Format: Ashutosh Singhal, Smita Mishra, Gautum Chaudhuri. Autocrine regulation of stress-induced cytotoxic Alu RNA expression in TNBC cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 236. doi:10.1158/1538-7445.AM2015-236
Acute Myeloid Leukemia Cells Are Resistant to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) by a Mechanism Independent of Multidrug Resistance.
Authors: Stacy M. Fricke, Hans Minderman, Kieran L. O’Loughlin, Jinrong Cheng, Elizabeth A. Repasky, Maria R. Baer
Journal: Blood (2004)