tbuckley/cabot-search huggingface dataset:
FOLFOX6 as first-line treatment in metastatic gastric cancer: Preliminary results of a phase II trial.
Authors: A. Fontana, L. Losi, F. Bertolini, S. Zironi, R. Depenni, N. Malavasi, L. Scarabelli, G. Luppi, P. F. Conte
Journal: Journal of Clinical Oncology (2010)

4091 Background: In metastatic gastric cancer, the superiority of a 3-drug regimen compared with a two drug regimen in terms of response rates (RR) and survival has not been definitely demonstrated; on the contrary, the doublet seems to be better tolerated. Tumor biomolecular characteristics might be helpful to select the more appropriate treatment for the individual patient. Aims of this study were: response rate and identification of biomolecular parameters potentially predictive of response to treatment. Methods: Between May 2005 and February 2009, 54 pts were enrolled and treated with FOLFOX6 until progression, unacceptable toxicity or refusal. Tumor evaluation by RECIST criteria was scheduled every 8 weeks. Biomarkers evaluation, as excision repair cross-complementing (ERCC1) and thymidylate synthase (TS), was performed on diagnostic biopsy with immunohistochemical analysis and correlated with RR, disease control, time to progression (TTP) and overall survival (OS). Results: Of 54 pts enrolled (M/F 40/14, median age at diagnosis 66 years: range, 22-83), 53 underwent at least one cycle of chemotherapy and were evaluable for toxicity and response. ERCC1 and TS was performed on 44 pts. RR was as follows: 2 complete response (CR), 13 partial response (PR) (CR+PR 27.8 %); stable disease (SD) in 21 pts (38.8%) and progression disease (PD) in 15 pts (27.8%). Disease control (CR+PR+SD) was reached in 36 pts (66%). TTP of the entire study group was 6.4 months (range: 0.3-27.3); OS was 10.5 months (range: 0.7-28.1). ERCC1 was positive in 32 pts (72.7%), negative in 12 (27.3%), TS positive in 38 pts (86.4%), negative in 6 (13.6%). We did not found any statistically significant correlation of ERCC1 and TS with RR, disease control, TTP and OS. The treatment was well tolerated (G3 33.3%, G4 6.7%). The main G3-G4 toxicities recorded were: 17.8% haematological (only one febrile neutropenia, 2.2%), 11.1% peripheral neuropathy, 8.9% gastrointestinal, 6.7% astenia, 2.2% thromboembolism. Conclusions: FOLFOX6 in first line treatment of metastatic gastric cancer is a feasible and effective. No correlation with biological parameters expression was found, but evaluation of the TS and ERCC1 mRNA expression analysis is ongoing by RT-PCR. No significant financial relationships to disclose.
Abstract 4103: Cancer cell-stromal cell crosstalk drives fibroblast senescence and tumor progression in large cell carcinoma of the lung in culture and in vivo
Authors: Roberto Lugo, Marta Gabasa, Francesca Andriani, Marta Puig, Federica Facchinetti, Josep Ramírez, Abel Gómez-Caro, Ugo Pastorino, Pere Gascón, Albert Davalos, Noemí Reguart, Luca Roz, Jordi Alcaraz
Journal: Cancer Research (2016)

Abstract Permanent cell cycle arrest through senescence has been previously regarded as a protective mechanism against tumor progression. In contrast, there is evidence that senescence in tumor-associated fibroblasts (TAFs) enhances tumor growth. Senescence has been reported in tumor associated fibroblasts (TAFs) from a growing list of selected cancer types. However, the presence of senescent TAFs in lung cancer remains undefined. To address this gap of knowledge, we examined common markers of senescence in primary TAFs from the 3 major non-small cell lung cancer (NSCLC) subtypes: adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Given the difficulties in gathering LCC-TAFs owing to the lower prevalence of LCC compared to the other subtypes, primary fibroblasts from 2 independent cell collections were used. We found an enrichment of the myofibroblast-like phenotype in TAFs regardless their histologic subtype, yet senescence was observed in LCC-TAFs only. Likewise, co-culturing normal lung fibroblasts with LCC (but not ADC or SCC) cancer cells was sufficient to induce senescence, and this induction was prevented in the presence of an antioxidant, indicating that it is mediated through oxidative stress. Of note, senescent fibroblasts provided growth and invasive advantages to LCC cells in culture and in vivo beyond those provided by control (non-senescent) fibroblasts. These results expand recent evidence that challenges the common assumption that lung TAFs are a heterogeneous myofibroblast-like cell population regardless their histologic subtype. Of note, because LCC often distinguishes itself in the clinic by its aggressive nature, our findings support that senescent or senescent-like TAFs may contribute to the selective aggressive behavior of LCC tumors. Citation Format: Roberto Lugo, Marta Gabasa, Francesca Andriani, Marta Puig, Federica Facchinetti, Josep Ramírez, Abel Gómez-Caro, Ugo Pastorino, Pere Gascón, Albert Davalos, Noemí Reguart, Luca Roz, Jordi Alcaraz. Cancer cell-stromal cell crosstalk drives fibroblast senescence and tumor progression in large cell carcinoma of the lung in culture and in vivo. [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 4103.
Abstract 719: ICAM3 and CCL16, inflammation genes screened by high-throughput siRNA library, govern cancer stemness in malignant tumors
Authors: Wenzhi Shen, Junling Xie, Renle Du, Shan Jiang, Xiaohe Luo, Huiwen He, Rong Xiang, Yunping Luo
Journal: Cancer Research (2016)

Abstract Cancer stem cells (CSCs) have the ability of both self-renewal and differentiation, were thought to be the main root of tumorigenesis, metastasis, recurrence and drug resistance. Current studies have focused on the maintenance of cancer stem cell abilities. Moreover, existing studies have shown that tumor associated inflammation microenvironment (TIM) play a pivotal role in different stages of tumor development. The linkage between inflammation and tumor stemness has been established. However, the evidence of TIM function on maintaining and nourishing CSCs properties remains insufficient. Here, we performed a high throughput siRNA interference platform to systemically screen out the inflammatory genes that regulate tumor stemness via OCT4 promoter linked reporter system in HMLE-Snail cells. 10 candidates were screened out which knockdown could both down-regulate OCT4 expression and decrease ALDH+ subpopulation. Furthermore, we validated the function of genes ICAM3 and CCL16 and found that knockdown ICAM3 or CCL16 inhibit cell migration, sphere formation in 231, A549 and HepG2 cell lines. We also found ICAM3 or CCL16 deficiency decrease side population and reduce chemo-resistance. In addition, mice bearing ICAM3 or CCL16 knockdown breast cancer cells develop smaller tumors and less lung metastases verse controls. Taken together, our study demonstrated that the inflammation related genes ICAM3 and CCL16 govern cancer cell migration and stemness in malignant tumors in vitro and in vivo, and that will provide new possible targets to CSCs for cancer therapy. Citation Format: Wenzhi Shen, Junling Xie, Renle Du, Shan Jiang, Xiaohe Luo, Huiwen He, Rong Xiang, Yunping Luo. ICAM3 and CCL16, inflammation genes screened by high-throughput siRNA library, govern cancer stemness in malignant tumors. [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 719.
Multivariate analysis of potential risk factors for lymph node metastasis in patients with cutaneous squamous cell carcinoma of the head and neck
Authors: Marjolijn S. Haisma, Boudewijn E.C. Plaat, Hendrik P. Bijl, Jan L.N. Roodenburg, Gilles F.H. Diercks, Tonnis R. Romeijn, Jorrit B. Terra
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 3933: CETSA as a diagnostic tool to guide personalized breast cancer therapy
Authors: Anette Öberg, Henriette Laursen, Sylvia Packham, Daniel Martinez Molina, Takahiro Seki, Yihai Cao, Johan Hartman, Jonas Bergh, Pär Nordlund, Sara Lööf.
Journal: Cancer Research (2016)

Abstract The increased knowledge of fundamental cancer biology has translated into the development of a large number of targeted drugs. However, the potential for breakthroughs in cancer therapy is hampered by the lack of knowledge regarding which patients would benefit from a specific drug. Therefore, there is a need of diagnostic tools that can predict if the individual patient will respond or develop resistance to a specific treatment plan. In the present project we aim to meet this challenge by developing stringent clinical diagnostic assays for assessing target engagement (TE; i.e. drug binding to its target protein in situ) of current and emerging drugs in breast cancer treatment. The key to develop these clinical TE assays is our novel technology Cellular Thermal Shift Assay (CETSA). This method allow for the first time direct monitoring of biophysical drug TE in cells, animals and patient samples. The main aim of the project is to correlate the results obtained by CETSA on breast cancer biopsies to the treatment outcome for the biopsied patient, with the goal of creating a diagnostic tool for guiding personalized breast cancer treatment. We also aim to identify new biomarkers of efficacy and resistance for specific drugs, by implementing proteome wide CETSA based on a quantitative mass spectrometry read out. Our recent data demonstrates that CETSA can assess TE in intact cells of drugs commonly used in breast cancer treatment, such as microtubule inhibitors, anthracyclins and CDK4/6 inhibitors. Further we show that CETSA can be applied in vivo on human breast cancer Xenografts and breast cancer patient samples. These data further strengthens the potential of CETSA to become a valuable clinical tool and complement other diagnostic methods to improve efficacy and minimize adverse effects of cancer drugs. Citation Format: Anette Öberg, Henriette Laursen, Sylvia Packham, Daniel Martinez Molina, Takahiro Seki, Yihai Cao, Johan Hartman, Jonas Bergh, Pär Nordlund, Sara Lööf. CETSA as a diagnostic tool to guide personalized breast cancer therapy. [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 3933.
Should We Offer Medication to Reduce Breast Cancer Risk?
Authors: Risa B. Burns, Mara A. Schonberg, Nadine M. Tung, Howard Libman
Journal: Annals of Internal Medicine (2016)

In November 2013, the U.S. Preventive Services Task Force issued a guideline on medications for risk reduction of primary breast cancer in women. Although mammography can detect early cases, it cannot prevent development of breast cancer. Tamoxifen and raloxifene are selective estrogen receptor modulators that have been shown to reduce the risk for estrogen receptor–positive breast cancer and are approved by the U.S. Food and Drug Administration (FDA) for this indication. However, neither medication reduces the risk for estrogen receptor–negative breast cancer or all-cause mortality. The Task Force concluded that postmenopausal women with an estimated 5-year risk for breast cancer of 3% or greater will probably have more net benefit than harm and recommends that clinicians engage in shared, informed decision making about these medications. The American Society of Clinical Oncology issued a practice guideline on use of pharmacologic interventions for breast cancer in 2013. It recommends that women aged 35 years or older at increased risk, defined as a 5-year absolute risk for breast cancer of 1.66% or greater, discuss breast cancer prevention medications with their primary care practitioner. The Society includes the aromatase inhibitor exemestane in addition to tamoxifen and raloxifene as a breast cancer prevention medication, although exemestane is not FDA approved for this indication. Here, an oncologist and an internist discuss how they would balance these recommendations and what they would suggest for an individual patient.
P0912 : Early-phase HCV kinetics and role of pre-existing resistance in cirrhotic or interferon-insensitive patients on daclatasvir plus asunaprevir
Authors: V. Cento, V. Calvaruso, S. Marenco, R. Alfieri, M. Aragri, F.P. Antonucci, V.C. Di Maio, S. Petta, A. Mazzola, L. Milanesi, A. Picciotto, F. Ceccherini-Silberstein, A. Craxì, C.F. Perno
Journal: Journal of Hepatology (2015)
The PROMIS study: A paired-cohort, blinded confirmatory study evaluating the accuracy of multi-parametric MRI and TRUS biopsy in men with an elevated PSA.
Authors: Hashim Uddin Ahmed, Ahmed El-Shater Bosaily, Louise C Brown, Richard S. Kaplan, Yolanda Colaco-Moraes, Katie Ward, Richard G Hindley, Alex Freeman, Alex K Kirkham, Robert Oldroyd, Rhian Gabe, Chris C. Parker, Mark Emberton
Journal: Journal of Clinical Oncology (2016)

5000 Background: Multi-parametric magnetic resonance imaging (MP-MRI) as a triage test might allow men to avoid unnecessary transrectal ultrasound-guided (TRUS) prostate biopsy since many men with an elevated PSA do not have clinically significant prostate cancer. Methods: PROMIS (ClinicalTrials.gov/NCT01292291) is a prospective, paired-cohort confirmatory study representing level Ib evidence. PROMIS tested MP-MRI and TRUS-biopsy with respect to an accurate reference test, 5mm sampling of the prostate with template prostate mapping biopsy (TPM-biopsy). In 11 UK centres, men with an elevated PSA up to 15ng/ml with no prior biopsy underwent MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was performed blind to the other test results. Clinically significant cancer was defined as Gleason ≥4+3 and/or maximum cancer core length ≥6mm. Results: Between May 2012 and December 2015, 576 men underwent all 3 tests. The reference TPM-biopsy detected clinically significant cancer in 230 (40%). For MP-MRI, sensitivity was 93% [95%CI 88-96], specificity 41% [36-46], positive predictive value 51% [46-56] and negative predictive value 89% [83-94]. TRUS-biopsy was significantly less sensitive than MP-MRI; 48% [95%CI 42-55] (p=<0.0001). TRUS-biopsy also had significant worse negative predictive value than MP-MRI: 74% [69-78] vs. 89% [83-94] (p<0.0001). We considered two scenarios compared to the current standard of TRUS-biopsy for all. First, using MP-MRI as a triage test would, at a minimum, avoid a primary biopsy in 158 (27%) men with 14 (2%) fewer cases of clinically significant cancer detected. Second, if biopsy targeted to MP-MRI findings achieves the sensitivity of TPM-biopsy, triage with MP-MRI would again avoid primary biopsy in 158 (27%) but detect 17 (3%) more cases of clinically significant cancer than the standard TRUS-biopsy for all pathway. Conclusions: TRUS-biopsy performs poorly both in detecting and ruling-out clinically significant prostate cancer. MP-MRI as a triage test can identify one quarter of men who might safely avoid unnecessary biopsy, without impairing the detection of clinically significant cancer. Clinical trial information: NCT01292291.
Abstract 1757: Male pattern baldness and risk of incident skin cancer in a cohort of men
Authors: Wen-Qing Li, Eunyoung Cho, Jiali Han, Martin Weinstock, Abrar Qureshi
Journal: Cancer Research (2016)

Abstract Background: Male pattern baldness (androgenic alopecia) has been associated with scalp skin cancer in case-control studies. A potential androgen basis of melanoma has been hypothesized and baldness has been associated with higher levels of androgens. We examined the association between male pattern baldness and risk of skin cancer, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) in a prospective cohort study. Methods: We included 36,032 participants from the Health Professionals’ Follow-up Study. In 1992, participants reported their status of male-pattern baldness at age 45 years by choosing from five crown-view pictograms based on Norwood's classification. Diagnosis of skin cancers was reported in the self-reported questionnaires biennially and report on melanoma and SCC was pathologically confirmed. Cox proportional hazard models were used to compute the hazard ratios (HR) and 95% confidence intervals (CI). Results: We identified 327 cases of melanoma, 1324 cases of SCC, and 8438 cases of BCC during the follow-up. Male-pattern baldness at age 45 was not associated with risk of incident melanoma, but was significantly associated with increased risk of both SCC and BCC. The multivariate-adjusted HR (95% CI) for the highest category of baldness (frontal plus severe vertex baldness) was 1.33 (1.06-1.68) for SCC (Ptrend = 0.001) and 1.23 (1.12-1.35) for BCC (Ptrend&amp;lt;0.0001), compared with no baldness. Analyses by body sites of tumors found significant associations between frontal plus moderate to severe vertex baldness and risk of melanoma (HR = 1.83, 95% CI: 1.01-3.34) and SCC (HR = 1.30, 95% CI: 1.02-1.66) at head and neck. The associations were particularly stronger for scalp melanoma (HR = 7.15, 95% CI: 1.29-39.42) and scalp SCC (HR = 7.09, 95% CI: 3.84-13.08), but not for non-scalp head and neck sites. Conclusion: Male pattern baldness was positively associated with increased risk of skin cancer. The associations may only exist for skin cancer at head and neck, particularly those occurring at scalp. Citation Format: Wen-Qing Li, Eunyoung Cho, Jiali Han, Martin Weinstock, Abrar Qureshi. Male pattern baldness and risk of incident skin cancer in a cohort of men. [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 1757.
Abstract 1145: Zhx2 promotes survival of B-cell acute lymphoblastic leukemia cell lines
Authors: Namit Sharma, Huayun Hou, Michael D. Wilson, Catherine Jane McGlade.
Journal: Cancer Research (2016)

Abstract Zhx2, a zinc finger containing transcription factor is frequently overexpressed in B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL), however its role in development of B cell malignancies remains unknown. Previously, dysregulated activity of transcription factors due to mutation e.g. Myc or overexpression e.g. Sox11 has been shown to perturb B cell differentiation leading to malignant phenotypes, resistance to chemotherapeutics and genetic heterogeneity. Zhx2 is required for normal neuronal and erythropoietic differentiation and has been identified as a tumor suppressor in hepatocellular carcinoma. Furthermore, analysis of public databases shows that Zhx2 is highly overexpressed in several cell lines representing B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL) and B cell lymphoma. Consistently, Zhx2 is also overexpressed in patient samples derived from different subtypes of B cell malignancies. Quantification of Zhx2 mRNA expression obtained from human donors showed a marked upregulation during transition from common lymphoid progenitor to Pro B-cell stage suggesting potential role in B cell differentiation. Here we report that Zhx2 is overexpressed in Philadelphia chromosome positive (Ph+) B-ALL and T-ALL cell lines as well as Ph- B-ALL cell line. Zhx2 silencing in BV-173 (Ph+ B-ALL) and CMLT1 (Ph+ T-ALL) showed enhanced apoptosis with low doses of Dasatinib, a dual Src/Abl kinase inhibitor. Furthermore, global gene promoter and gene expression analysis on Zhx2 silenced cells identified putative Zhx2 regulated genes including CREB and YY1. Both of these transcription factors have roles in B cell differentiation, survival, proliferation and are commonly deregulated in B cell malignancies. We propose that Zhx2 regulates a B cell differentiation program and that overexpression of Zhx2 could lead to blocked differentiation of B cell progenitors promoting the malignant phenotype. Therefore, Zhx2 could be exploited as a chemo-therapeutic target in B cell malignancies. Citation Format: Namit Sharma, Huayun Hou, Michael D. Wilson, Catherine Jane McGlade. Zhx2 promotes survival of B-cell acute lymphoblastic leukemia cell lines. [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 1145.
Abstract 5075: Hedgehog Pathway Transcription Factor Gli1 Promotes Glioma Invasiveness through Up-regulating Aquaporin 1
Authors: Zhenzhen Yao, Chaoxu Yang, Lie Ma, Yexiong Tan
Journal: Cancer Research (2016)

Abstract Gliomas, especially Glioblastoma multiformes (GBMs) express increased aquaporin1(AQP1) compared to normal brain. AQPs may contribute to brain edema, cell motility, and tumor angiogenesis. Although the physiology of AQP1 has been the subject of several publications, much less is known about the trans-acting factors involved in the control of AQP1 gene expression and the relationship between the regulation of the AQP1 expression and the major intracellular signaling pathways is also poorly concerned. Hedgehog signaling pathway activation is required for sustained glioma growth and survival. playing an important role in the genesis of glioma and In the present study, we report that Gli1, the transcriptional activator of the Hedgehog pathway, is co-expressed with AQP1 in human glioma tissues and can enhance AQP1 gene transcription by binding to conserved core Gli-binding site in the 5’-flanking promoter region of the AQP1. Transfection of 293T and U251 (human glioblastoma cell line) with Gli1 can markedly increase the AQP1 promoter reporter activity and the AQP1 expression level. Moreover, suppressing the Gli1 expression with the specific RNAi can abort this effect. The ChIP and reporter mutation analysis showed that the -406∼-398 region of the AQP1 promoter is essential for regulation activity of Gli1. To elucidate the possible pathophysiological importance of this molecular interaction, we investigated the migration and invasion ability of cell lines expressing different levels of Gli1 and AQP1. The results demonstrated that restoring the AQP1 expression in the Gli1-knockdown cell line can abort the decrease in the migration ability, which suggested that Gli1 may contribute to the invasion ability of glioma cells through AQP1. The up-regulation of Gli1 and its consequences of increased AQP1 in gliomas may provide a new therapeutic target, either as a cell surface marker or as a functional intervention. Citation Format: Zhenzhen Yao, Chaoxu Yang, Lie Ma, Yexiong Tan. Hedgehog Pathway Transcription Factor Gli1 Promotes Glioma Invasiveness through Up-regulating Aquaporin 1. [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 5075.