tbuckley/cabot-search huggingface dataset:
Abstract 280: The maximum tumor length and lymph node metastasis in esophageal squamous cell carcinomas
Authors: Shuang Lv, Shuang Lv, Fu You Zhou, Hai Jun Yang, Bei Li, Li Na Liu, Yan Jie Xia, Yan Ru Qin, Rui Tai Fan, Fan Kai Xiao, Li Dong Wang
Journal: Cancer Research (2017)

Abstract The lymph node metastasis (LNM) is one of the crucial risk factors for esophageal squamous cell carcinomas (ESCC) prognosis. However, it is difficult to precisely determine the LNM status before surgery. The maximum tumor length (MTL) may reflect the ESCC growth speed and could be calculated accurately either with computed tomography or ultrasound endoscopy before esophagectomy. Therefore the present study was designed to determine if the MTL could reflect the LNM status for ESCC. A total of 22,660 ESCC patients was enrolled in this study from the ESCC database (1973-2015) in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University. Of these patients, there were 13,793 males with an mean age of 60±8, and 8,867 females with an mean age of 61±8. All the cases had been performed radical esophagectomy. The MTL and LNM records were retrieved from the medical records in hospitals. Based on the 6th version of UICC criteria, the LNM was classified as N0 and N1. The MTL was classified as 5 groups: &amp;lt;2cm, ≥2 and &amp;lt;4cm, ≥4 and &amp;lt;6cm , ≥6 and &amp;lt;8cm , ≥8cm. The SPSS21.0 software and Spearman rank correlation were used to determine the correlation of MTL and LNM. The results demonstrated that the average and median of MTL were 4.1±1.8 cm and 4.0 cm (range: 0.1-18 cm) in these ESCC patients. The positive lymph node metastasis rates in each MTL groups were 19.1%, 34.1%, 45.8%, 51.5%, and 54.1%, respectively. Spearman rank correlation analysis indicated that MTL was strongly correlated with LNM (r=0.997, P&amp;lt;0.001), suggesting that MTL could reflect the LNM status in ESCC and that MTL could be used as one of clinical staging parameters for ESCC. [Supported by Major Science and Technology Projects of Henan Province (161100311300). National Key Research and Development Program: Precision Medicine (2016).] Note: This abstract was not presented at the meeting. Citation Format: Shuang Lv, Shuang Lv, Fu You Zhou, Hai Jun Yang, Bei Li, Li Na Liu, Yan Jie Xia, Yan Ru Qin, Rui Tai Fan, Fan Kai Xiao, Li Dong Wang. The maximum tumor length and lymph node metastasis in esophageal squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 280. doi:10.1158/1538-7445.AM2017-280
Abstract 5247: δ-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice
Authors: Xu Yang, Wang Hong, Guocan Wang, Anna Liu, Maarten c. Bosland, Chung s. Yang
Journal: Cancer Research (2017)

Abstract PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, metabolism, migration, differentiation, and survival. Activation of this signal pathway is frequently found in human cancers. Data from our previous studies demonstrated that δ-tocopherol (δ-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibiting proliferation and inducing apoptosis. Herein, we investigated whether δ-T is able to inhibit the development of prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice, in which the activation of AKT resulted from loss of Pten is the driver. By feeding Ptenp-/- mice with the AIN93M or 0.2% δ-T supplemented diet starting at the age of 6 or 12 weeks, we found that, at the age of 40 weeks, δ-T treatment reduced the number of invasive prostate adenocarcinoma by 53.3% (p&amp;lt;0.005) and 42.7% (p&amp;lt;0.001), respectively. By immunohistochemical analysis, the activation of AKT via phosphorylation of AKT(T308) was found reduced in the prostate of the mice on δ-T diet. Consistently, proliferation was reduced and apoptosis was increased in prostate of the mice on δ-T diet. We also determined oxidative stress by immunohistochemical staining of 8-OH-dG and nitro-tyrosine, and found that these markers were not altered during prostate tumorigenesis, nor they were affected by δ-T. A 0.2% α-tocopherol diet was also used to feed Ptenp-/- mice, but did not inhibit the development of prostate adenocarcinoma, consistent with previous data demonstrating that α-tocopherol did not inhibit the activation of AKT. Together, these results support that δ-T is effective in supressing the development of prostate adenocarcinoma in Ptenp-/- mice through inhibition of AKT activation. Citation Format: Xu Yang, Wang Hong, Guocan Wang, Anna Liu, Maarten c. Bosland, Chung s. Yang. δ-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5247. doi:10.1158/1538-7445.AM2017-5247
Abstract 1710: Providing confidence around computational tissue analysis using heterogeneity assessments
Authors: Carsten Schnatwinkel, Daniel Rudmann, Famke Aeffner, Jasmeet Bajwa, Natalie Hutnick, Michael Sharp, Gerry Chu, JD Alvarez
Journal: Cancer Research (2017)

Abstract Background: Though the techniques to interrogate the appearance of a biomarker in tissue sections have greatly advanced, there are limitations as to how representative an analysis of a tissue section is compared to the entire diseased tissue. Depending on the heterogeneous expression level of a biomarker, tissue sampling can result in different interpretations of the biomarker’s appearance, and hence could potentially lead to a false therapeutic intervention. Hypothesis: Digital image analysis has demonstrated tremendous value in quantifying many features related to biomarker distribution and expression in biological tissues. The information can be collected for various indications and biomarkers and a phenotypic signature can be established that describes a biomarker representation across indications. Moreover, the assessment of new samples can be compared to the established phenotypic signature and a confidence score applied in support to the determined endpoint. Approach: For a proof of concept, 6 prostate cancer samples were processed and a single section was collected after every 100microns. A total of 7 sections per sample were stained for the lymphocyte marker CD3, and the number of positive target cells were determined in the tumor and tumor microenvironment using tissue Image Analysis (tIA™). To assess how indicative the evaluation of a single tissue section would be for the entire tumor, the heterogeneity level was determined on the section level as well as by random grid analysis on each individual section. Both criteria were utilized to define an indication and biomarker specific confidence interval and heterogeneity score. Conclusion: The combination of IHC and tIA is a powerful tool to convert complex data into meaningful interpretations. tIA is also a capable tool to catalogue valuable information about the biomarker’s expression pattern across different disease stages and hence could be used to evaluate how representative a single biomarker evaluation is in the grand scheme. Ultimately, we demonstrated a technique that can be applied to any biomarker and would assist in guiding therapeutic decisions. Citation Format: Carsten Schnatwinkel, Daniel Rudmann, Famke Aeffner, Jasmeet Bajwa, Natalie Hutnick, Michael Sharp, Gerry Chu, JD Alvarez. Providing confidence around computational tissue analysis using heterogeneity assessments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2017-1710
Abstract 2887: Macrophage conditioned medium promotes colon cancer stem cell phenotype via the hedgehog signaling pathway
Authors: Fan Fan, Rui Wang, Delphine R. Boulbes, Huiyuan Zhang, Stephanie S. Watowich, Rajat Bhattacharya, Ling Xia, Xiang-Cang Ye, Lee M. Ellis
Journal: Cancer Research (2017)

Abstract Background: Contradicting studies have shown that increased macrophages infiltration in colorectal cancer (CRC) could either result in anti-tumoral or in pro-tumoral effects. Because of these inconsistencies, we sought to determine the role of conditioned medium from macrophages, in particular classically activated macrophages, on the development of the CSC phenotype in CRC cells, which is believed to mediate tumor growth and chemoresistance. Methods: Murine (CT26) and human (HCP-1) CRC cell lines were treated with conditioned media (CM) from lipopolysaccharide (LPS)-activated murine macrophages. Viability studies were performed using the MTT assay, annexin V-FITC assay, and Western blot analysis. The CSC population was assessed using the sphere-forming assay and aldehyde dehydrogenase assay. Results: The results showed that 1) murine LPS-activated macrophage CM induced apoptosis in murine and human CRC cells, 2) murine and human LPS-activated macrophage CM secreted paracrine factors that promoted the CSC phenotype in murine and human CRC cells via the Sonic hedgehog (SHH)-Gli signaling pathway, which is known to drive self-renewal and 3) these effects were blocked by depletion of SHH in macrophage CM. Conclusions: Our data show that LPS-activated macrophages play an active role in promoting the CSC phenotype through activation of the SHH-Gli signaling pathway. Citation Format: Fan Fan, Rui Wang, Delphine R. Boulbes, Huiyuan Zhang, Stephanie S. Watowich, Rajat Bhattacharya, Ling Xia, Xiang-Cang Ye, Lee M. Ellis. Macrophage conditioned medium promotes colon cancer stem cell phenotype via the hedgehog signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2887. doi:10.1158/1538-7445.AM2017-2887
Abstract DDT01-01: The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma
Authors: Paul E. Hughes
Journal: Cancer Research (2017)

Abstract Mcl-1 is a prosurvival member of the Bcl-2 family of proteins, which regulate programmed cell death via protein-protein interactions between prosurvival and proapoptotic members of the family. A variety of studies have demonstrated that Mcl-1 is a key prosurvival factor for many human cancers, making it a highly desirable target for therapeutic intervention. However, targeting Mcl-1 to induce tumor cell death has been an exceptional challenge for the development of drug-like small molecule inhibitors due to the high-affinity interaction of Mcl-1 with proapoptotic binding partners and the lack of an obvious small molecule binding pocket. In this presentation we will describe the application of structural analysis and molecular modeling to the optimization of an HTS screening hit that culminated in the identification of a clinical candidate, AMG 176. In addition, we will present data demonstrating that AMG 176 is a potent, highly selective, and reversible Mcl-1 inhibitor. Mechanism-of-action studies revealed that AMG 176 induces a rapid and irreversible commitment to apoptosis in tumor cells via the disruption of protein-protein interactions with proapoptotic members of the Bcl-2 family. Furthermore, the extensive profiling of a large and diverse tumor cell line panel revealed that lines derived from hematologic malignancies, such as multiple myeloma, acute myeloid leukemia, and non-Hodgkin lymphoma, are particularly sensitive to Mcl-1 inhibition with the expression of Bcl-xL inversely correlating with response. In addition, cell line profiling data revealed an activity profile distinct from a selective Bcl-2 inhibitor, further underscoring the unique therapeutic opportunity for an Mcl-1 inhibitor. Synergistic combinations were identified with therapies selectively targeting Bcl-2, the MAPK pathway, and proteasome inhibitors. In vivo, AMG 176 demonstrated robust inhibition of tumor xenograft growth with a clear PK/PD relationship, exhibiting on-mechanism activity as measured by Bak and caspase activation on a discontinuous dosing schedule of once or twice weekly. An ongoing phase 1 clinical trial is currently evaluating AMG 176 in multiple myeloma. Citation Format: Paul E. Hughes. The discovery and preclinical characterization of AMG 176: A first-in-class Mcl-1 inhibitor in clinical development for multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-01. doi:10.1158/1538-7445.AM2017-DDT01-01
Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631
Authors: Matthew A. Kutny, Todd A. Alonzo, Robert B. Gerbing, Yi-Cheng Wang, Susana C. Raimondi, Betsy A. Hirsch, Cecilia H. Fu, Soheil Meshinchi, Alan S. Gamis, James H. Feusner, John J. Gregory
Journal: Journal of Clinical Oncology (2017)

Purpose The Children's Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine. Results One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003), and EFS was 95% versus 83% ( P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients. Conclusion ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.
Abstract 4270: Family history in first degree relatives and risk of gastric cancer in the alpha-tocopherol, beta-carotene cancer prevention study
Authors: Minkyo Song, Maria Constanza Camargo, Stephanie J. Weinstein, Demetrius Albanes, Charles S. Rabkin
Journal: Cancer Research (2017)

Abstract Background: Studies of the familial associations of gastric cancer risk have largely been limited to case-control approaches which are susceptible to recall bias and cannot distinguish temporality. Furthermore, associations with family history could be explained by shared exposure to Helicobacter pylori infection, the most important environmental risk factor for gastric cancer. Notably, the risks of early onset disease and diffuse-type tumors are thought to have a greater genetic component. We therefore examined in a prospective study the associations of gastric cancer risk with history of gastric cancer in first degree relatives, controlling for H. pylori infection. Methods: We selected 405 incident gastric cancer cases and 4,129 controls with known H. pylori serology status from the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study among male smokers aged 50-69 at baseline. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression with adjustment for H. pylori and other potential confounders. All statistical tests were two-sided. Results: Family history of gastric cancer was associated with increased risk (OR=1.84, 95% CI=1.32-2.58). The association appeared stronger with gastric cancer in siblings (OR=2.87, 95% CI=1.64-5.03) than with gastric cancer in parents (OR=1.53, 95% CI=1.05-2.24). Distinguishing cases by anatomic subsite, the family history association was significant for noncardia gastric cancer (n=305; OR=2.15, 95% CI=1.50-3.07), but not for cardia cancer (n=100; OR=1.25, 95% CI=0.63-2.49). With regard to histological subtype, family history was significantly associated with both diffuse-type (n=90; OR=2.12, 95% CI=1.10-4.12) and intestinal-type (n=153; OR=1.70, 95% CI=1.02-2.83) gastric cancer. In age-specific analyses, the association with family history was strongest in the youngest age-group at baseline 50-54 years (OR=3.42, 95% CI=1.85-6.30) and absent in the oldest age group 65-69 years (OR=0.85, 95% CI=0.28-2.58). Conclusion: The results suggest that certain subtypes of sporadic gastric cancer are strongly associated with family history of gastric cancer. These associations do not appear to be explained by the associations with H. pylori infection. Citation Format: Minkyo Song, Maria Constanza Camargo, Stephanie J. Weinstein, Demetrius Albanes, Charles S. Rabkin. Family history in first degree relatives and risk of gastric cancer in the alpha-tocopherol, beta-carotene cancer prevention study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4270. doi:10.1158/1538-7445.AM2017-4270
Abstract CT161: METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC
Authors: Minish P. Mehta, Vinai Gondi, Paul D. Brown
Journal: Cancer Research (2017)

Abstract BACKGROUND Tumor Treating Fields (TTFields) are noninvasive regional antimitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly diagnosed glioblastoma patients. TRIAL DESIGN 270 patients with 1-10 brain metastases (BM) from NSCLC will be randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2st cerebral progression. Objectives: To test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Endpoints: Time to 1st cerebral progression based on the RANO-BM Criteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT, COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Main eligibility criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, no electronic implantable devices in the brain. Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day will be applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients will receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Citation Format: Minish P. Mehta, Vinai Gondi, Paul D. Brown. METIS: A phase 3 study of radiosurgery with TTFields for 1-10 brain metastases from NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT161. doi:10.1158/1538-7445.AM2017-CT161
Abstract 4331: Novel Wnt-SCD-LRP5/6 pathway linking liver fibrosis to cancer
Authors: Keane Lai, Soo-Mi Kweon, Feng Chi, Edward Hwang, Raymond Wu, Yasuaki Kabe, Ramachandran Murali, Lopa Mishra, James Ntambi, Hidekazu Tsukamoto
Journal: Cancer Research (2017)

Abstract Activated hepatic stellate cells (HSCs) are primarily responsible for the genesis of liver fibrosis which promotes liver tumor development. Stearoyl-CoA desaturase (SCD) which synthesizes monounsaturated fatty acid (MUFA such as oleic acid or palmitoleic acid), is implicated in metabolic syndrome, tumorigenesis and stemness. Indeed, we demonstrate SCD upregulation in both HSCs and liver tumor cells in patients. Further, SCD correlates with the advancing grade of HCC and mortality in patients. However, its causality in tumorigenesis and mesenchyme-tumor crosstalk, and underlying mechanisms, are unknown. The present study aimed to determine whether and how SCD promotes and links liver fibrosis and cancer. In both HSCs and liver tumor-initiating stem cell-like cells (TIC), we reveal that the Wnt effector β-catenin is a potent co-activator for SREBP-1-dependent Scd transcription as demonstrated by promoter-reporter assay and re-ChIP analysis. We also discover β-catenin which drives SCD expression is in turn stabilized by SCD-derived MUFA. To identify molecular targets of MUFA mediating this SCD-β-catenin positive loop, we performed MUFA-nano-beads pull-down assay with TIC lysate, ESI-MS based identification of MUFA interacting proteins, computational docking analysis, co-IP and ribonucleoprotein-IP. These analyses reveal that MUFA is essential for LRP5/6 expression: MUFA interferes Transportin-1 and Ran-1 interaction, resulting in suppressed nuclear import of the mRNA binding protein HuR, HuR cytoplasmic accumulation, and increased HuR binding to and stabilization of Wnt co-receptor Lrp5/6 mRNA. As such, genetic or pharmacologic SCD inhibition reduces cytosolic HuR, LRP5/6 expression, β-catenin stabilization, HSC activation and TIC self-renewal and attenuates liver fibrosis and tumorigenesis in mice. Moreover, conditional genetic ablation of Scd2 in HSCs not only abrogates HSC-mediated promotion of TIC-derived tumorigenesis in a xenograft mouse model but also inhibits DEN-induced liver tumor development in Col1a1-Cre; Scd2flox/flox mice (tumor volume reduced to 21.5 + 7.9 vs. 360.9 + 193 mm3 in Scd2flox/flox mice; tumor multiplicity decreased to 18 + 5.4 vs. 45 + 8.4 in Scd2flox/flox mice, both p&amp;lt;0.05). Collectively, our findings support that a newly disclosed Wnt-SCD-LRP5/6 loop may serve as a novel therapeutic target for liver cancer and underlies a known crosstalk between liver mesenchyme and liver tumor development. Citation Format: Keane Lai, Soo-Mi Kweon, Feng Chi, Edward Hwang, Raymond Wu, Yasuaki Kabe, Ramachandran Murali, Lopa Mishra, James Ntambi, Hidekazu Tsukamoto. Novel Wnt-SCD-LRP5/6 pathway linking liver fibrosis to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4331. doi:10.1158/1538-7445.AM2017-4331