tbuckley/cabot-search huggingface dataset:
Abstract 5205: Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan
Authors: Hiroko Nakagawa, Hidemi Ito, Satoyo Hosono, Isao Oze, Haruo Mikami, Masakazu Hattori, Yoshikazu Nishino, Hiromi Sugiyama, Kayo Nakata, Hideo Tanaka
Journal: Cancer Research (2016)

Abstract Although colorectal cancer (CRC), a major cancer worldwide, has shown a proximal or right-sided shift in subsite distribution in western countries, trends in subsite incidence in Asian countries remain unclear. Here, we evaluated subsite-specific trends in CRC incidence rate between 1978 and 2004 in Japan using large data from 10 population-based cancer registries. The colorectal sites (C18-20) were categorized into three groups, proximal colon (C18.0-18.5), distal colon (C18.6-C18.7) and rectum (C19.9 and C20.9). Trends in age-standardized incidence rates (ASRs) were characterized by Joinpoint regression analysis. A total of 474,651 colorectal cancer cases were analyzed. Overall, ASRs increased remarkably until 1993, with an annual percent change (APC) of 4.9%, and then stabilized thereafter. By subsite, however, ASRs of proximal colon significantly increased, with APCs of 7.1% (1978∼1991), 3.8% (1991∼96) and 0.9% (1996∼2004); distal colon showed an initial significant increase, with an APC of 7.6%, but stabilized from 1991 until the end of observation; and rectal cancer showed an initial significant increase, with APCs of 1.9% (1978∼88) and 5.6% (1988∼92), but then decreased abruptly in 1992, the year colorectal cancer screening was introduced nationwide, with an APC of -1.0%. Thus, we revealed that changes in incidence trends for the three anatomic sites apparently began to differ in the 1990s, and this is a first report to our knowledge. We also discuss factors that could explain these changes in Japanese. Careful monitoring is necessary to confirm whether these trends are changing in the Japanese population. Citation Format: Hiroko Nakagawa, Hidemi Ito, Satoyo Hosono, Isao Oze, Haruo Mikami, Masakazu Hattori, Yoshikazu Nishino, Hiromi Sugiyama, Kayo Nakata, Hideo Tanaka. Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan. [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 5205.
Abstract LB-284: Multiscale systems pharmacology model for time sequence combination chemotherapy in breast cancer
Authors: Sihem Ait-Oudhia
Journal: Cancer Research (2016)

Abstract Background: HER2-positive (HER2+) breast cancer (BC) is more quickly-growing and aggressive than other types of BC. Trastuzumab (TZM) is a humanized monoclonal antibody directed against HER2 receptor. It is clinically used for BC in combination with paclitaxel (PAC) in a 24 h sequence treatment during the first week of therapy followed by a simultaneous administration during the subsequent weeks. To our knowledge there is no scientific rationale for such therapeutic regimes. We propose to develop and optimize a sequential combination of PAC+TZM to optimize their anti-tumoral activity, and hence, HER2+ BC patients’ outcome. Method: Six therapeutic regimens were investigated in vivo on Balbc nude mice xenografted with BT474 cells, a human breast cancer cell line that overexpresses HER2 receptor, including 1) a tumor priming regimen (TPR) with PAC administered 24 h prior to TZM, 2) reverse-TPR with TZM administration first then PAC 24 h later, 3) simultaneous administration of both drugs, 4) PAC alone, 5) TZM alone, 6) vehicle as a control. The doses were 10 and 3 mg/kg for PAC and TZM. The anti-tumoral response in all treatment arms was monitored over time through the measurement of the reduction in tumor volumes as well as animals survival. Results: In vivo studies showed a greater tumor volume shrinkage response in the animals from the TPR treatment arm compared to the other therapeutic schemes with: 1) an enhanced in vivo antitumor response, and 2) a longer animal survival. These results support our in vitro findings of drug synergy and apoptosis. Conclusion: TPR anti-tumor results are promising. The proposed research will develop and employ a systems pharmacology model based on our results to hypothesize optimal regimens for the association (PAC+TZM) breast cancer killing, which will be tested in vivo. Citation Format: Sihem Ait-Oudhia. Multiscale systems pharmacology model for time sequence combination chemotherapy in breast cancer. [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 LB-284.
Abstract SY15-03: Drugging “undruggable” transcription factor drivers in cancer
Authors: John Bushweller
Journal: Cancer Research (2016)

Abstract Dysregulation of gene expression is a hallmark of all cancers. It is critical for conferring stem cell like properties, such as self-renewal and chemo-resistance, on these cancer cells. Such properties contribute to the inability to completely eradicate cancer cells, thereby leading to relapse. The specific gene expression program that confers these properties derives from aberrant activity of specific transcription factors which are drivers of disease. There are numerous examples of such transcription factor drivers in cancer (ERG in prostate cancer, ETV1 in prostate cancer and GIST, RUNX1-ETO and CBFβ-SMMHC in acute myeloid leukemia, etc.). Clearly, the most direct and effective approach to alter this gene expression program is to target the activity of these transcription factors which are drivers of disease. While the paradigm is shifting significantly, transcription factors have traditionally been viewed as “undruggable”. This results from the challenges associated with targeting either the protein-DNA or protein-protein interactions that typically mediate their function. Recent successes in this area are clearly breaking down this paradigm. Targeting of transcription factors is a very different approach to current approaches to targeted therapy which have heavily focused on kinase inhibitors. Targeting transcription factor drivers will likely alter the stem cell like properties of the cancer cell such as self-renewal, the DNA repair alterations which lead to enhanced rates of mutagenesis, and the chemo-resistance which limits effectiveness of chemotherapy drugs. It is also likely that agents targeting transcription factors will show synergy with appropriately targeted kinase inhibitors. We have developed a specific, potent, and effective protein-protein interaction inhibitor for the CBFβ-SMMHC fusion protein which is a driver in inv(16) acute myeloid leukemia (Illendula et al. Science 347: 779-784 (2015)). The efficacy of this inhibitor of a critical protein-protein interaction of the CBFβ-SMMHC transcription factor fusion protein clearly demonstrates the utility of directly targeting transcription factor drivers in cancer. Based on this success, we are targeting other transcription factor drivers in leukemia as well as in other cancers. Two examples of our efforts in this area will be presented. Citation Format: John Bushweller. Drugging “undruggable” transcription factor drivers in cancer. [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 SY15-03.
Abstract 3420: Clinical prognostic factors in adult with astrocytoma: Historic cohort
Authors: Talia Wegman-Ostrosky, Nancy Reynoso Noverón, Sonia Iliana Mejía-Pérez, Thalía Estefania Sánchez-Correa MD, Rosa María Álvarez, Bernardo Cacho, Luis A. Montalvo, Teresita Corona
Journal: Cancer Research (2016)

Abstract Introduction: Malignant tumors of the central nervous system contribute extremely to cancer mortality especially in the high risk age groups. In USA are the second and the fifth leading cause of cancer mortality in men and women aged 20 to 39 years respectively. Astrocytomas are the most common and lethal tumors of the CNS, being the most common grade IV (glioblastoma) (4.37 per 100,000 population). The prognosis of astrocytomas can be predicted by specific clinical factors allowing neurosurgeons and neuro-oncologists to define the best treatment for each patient. Some patients’ features like age, gender, performance status and tumor localization have been studied as potential prognostic factors. In Mexico there are few reports on demographic, clinical characteristics and prognostic factors in adults. Objective: To explore the clinical prognostic factors for adults affected with astrocytoma Methods: Using a historic cohort, we selected by simple randomization, 155 clinical files from patients with astrocytoma. The main outcome variable was overall survival time (OS). To identify clinical prognosis factors we used: bivariate analysis, Cox regression models, log rank test and Kaplan-Meier survival function. Results: The mean age at diagnosis was 45.7 years. Compared with other studies, our population was 15 years younger when diagnosed. Analysis by stage in grade II, III and IV also showed a younger age of presentation. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. Kaplan-Meier survival estimate showed that the variables grade, Karnofsky Performance Status (KPS)&amp;gt;70, the type of resection, chemotherapy, radiotherapy, alcohol consumption, familiar history of cancer and clinical presentation were significantly associated to survival time. Using proportional Hazard Model the variables: age, grade IV, resection, chemotherapy + radiotherapy and KPS where prognosis factors. Conclusion: Astrocytoma in our study was present in young adults. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. The variables alcoholism, family history of cancer and clinical presentation influenced significantly survival time, and showed a tendency in the mortality analyses. Citation Format: Talia Wegman-Ostrosky, Nancy Reynoso Noverón, Sonia Iliana Mejía-Pérez, Thalía Estefania Sánchez-Correa MD, Rosa María Álvarez, Bernardo Cacho, Luis A. Montalvo, Teresita Corona. Clinical prognostic factors in adult with astrocytoma: Historic cohort. [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 3420.
Visual Inspection and the US Preventive Services Task Force Recommendation on Skin Cancer Screening
Authors: Hensin Tsao, Martin A. Weinstock
Journal: JAMA (2016)

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Improved Metastasis-Free and Survival Outcomes With Early Salvage Radiotherapy in Men With Detectable Prostate-Specific Antigen After Prostatectomy for Prostate Cancer
Authors: Bradley J. Stish, Thomas M. Pisansky, William S. Harmsen, Brian J. Davis, Katherine S. Tzou, Richard Choo, Steven J. Buskirk
Journal: Journal of Clinical Oncology (2016)

Purpose To describe outcomes of salvage radiotherapy (SRT) for men with detectable prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer and identify associations with outcomes. Patients and Methods A total of 1,106 patients received SRT between January 1987 and July 2013, with median follow-up 8.9 years. Outcomes were estimated using Kaplan-Meier for overall survival (OS) and cumulative incidence for biochemical recurrence (BcR), distant metastases (DM), and cause-specific mortality (CSM). Variable associations with outcomes used Cox or Fine-Gray methods, as appropriate. Multiple variable analyses used backward selection with P < .05 for retention. Results In multiple variable analyses, pathologic tumor stage, Gleason score, and pre-SRT PSA were associated with BcR, DM, CSM, and OS; androgen suppression and SRT doses > 68 Gy were associated with BcR; and age was associated with OS. Each pre-SRT PSA doubling increased significantly the relative risk of BcR (hazard ratio [HR], 1.30; P < .001), DM (HR, 1.32; P < .001), CSM (HR, 1.40; P < .001), and all-cause mortality (HR, 1.12; P = .02). Using a pre-SRT PSA cutoff ≤ 0.5 versus > 0.5 ng/mL, 5-year and 10-year cumulative incidences for BcR were 42% versus 56% and 60% versus 68% ( P < .001), DM 7% versus 14% and 13% versus 25% ( P < .001), CSM 1% versus 4% and 6% versus 13% ( P < .001), and OS of 94% versus 92% and 83% versus 73% ( P > .05). Conclusion SRT outcomes are in part affected by factors associated with prostatectomy findings but may be positively affected by using SRT at lower PSA levels, including reductions in BcR, DM, CSM, and all-cause mortality. These findings argue against prolonged monitoring of detectable postprostatectomy PSA levels that delay initiation of SRT.
Inhibition Of The Immunoproteasome Subunit LMP7 Decreases Alloresponses In Both MHC-Mismatched and miHA-Disparate Murine Models Of Graft Versus Host Disease
Authors: Jennifer Matos, Zheng Yang, Eugenia Dziopa, Leah Dziopa, Christopher J. Kirk, Robert Korngold, Jenny Zilberberg
Journal: Blood (2013)
299P The role of haematopoietic stem cell transplantation (HSCT) for peripheral T-cell lymphoma (PTCL) in CR1/PR1; Single-institute analysis in Japan
Authors: Y. Kamiyama, S. Yano, T. Saito, K. Sugiyama, T. Shimada, Y. Yahagi, Y. Ogasawara, S. Takahara, J. Minami, H. Yokoyama, A. Katsube, K. Suzuki, H. Uryu, N. Usui, K. Aiba
Journal: Annals of Oncology (2015)
Effect of coadministration of propranolol and etodolac (VT-122) plus sorafenib for patients with advanced hepatocellular carcinoma (HCC).
Authors: Andrew N de la Torre, Ismael Castaneda, Aram F. Hezel, Newell F. Bascomb, Gouri Shankar Bhattacharyya, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2015)

390 Background: Propranolol and etodolac (designated VT-122) target the adrenergic and prostaglandin stress systems activated in HCC. These stress-induced systems are proposed to induce changes in the tumor microenvironment and immune system leading to tumor promotion and immune tolerance. In a separate study, administration of VT-122 prior to sorafenib showed an increase in median overall survival (OS) of 21 months when VT-122 is administered before sorafenib compared to 10 months OS for sorafenib alone. The aim of the current study was to evaluate the effect of administering VT-122 at least 30 days after starting sorafenib. Methods: Patients with HCC receiving sorafenib for at least 30 days were eligible for this double-blind, placebo-controlled study. Patients were randomized to receive sorafenib with either VT-122 or placebo. Patients received therapy for up to 12 months or until treatment failure. VT-122 was administered twice daily. The primary endpoint was duration of therapy (DoT) and the secondary endpoint was OS. Results: Twenty patients were randomized, 11 and 9 patients to the VT122 and placebo arm, respectively. Each arm was balanced with regards to age (mean of 60.4 years), Child Pugh status (9 Child Pugh A, 11 Child Pugh B7), hepatitis virus status (6 HBV and 1 HCV positive) and C-reactive protein (CRP) (20.4 mg/L). VT122 with sorafenib was well tolerated with no unexpected serious adverse events reported. Mean OS was 13.9 months and 9.6 months in the VT-122 and placebo arms, respectively. Mean DoT (unvalidated) was 10.1 months and 7.5 months in the VT-122 and placebo arms, respectively. Conclusions: Co-administration of VT-122 with sorafenib was well tolerated and showed an increase in duration of therapy and OS versus sorafenib alone. The small sample size and number of events precludes the ability to make any significant efficacy conclusions. The increase in survival was not as great as that seen in a separate study in which VT122 was started prior to sorafenib. A further Phase 3 study of VT122 administered prior to sorafenib in patients with HCC is warranted. Clinical trial information: NCT01265576.
ELYPSE-7: A randomized, placebo-controlled, phase 2a study evaluating the impact of IL-7 on CD4 count, hematological toxicity, and tumor progressionin metastatic breast cancer (MBC) patients (pts).
Authors: Jean-Yves Blay, Olivier Tredan, Christine Menetrier-Caux, Claire Cropet, Thomas Denis Bachelot, Pierre Heudel, Paul E. Rebattu, Gwenaelle Garin, Sylvie Chabaud, Estelle Verronese, Anne Claire Cadore, Valerie Fouillat, Therese Croughs, Michel Morre, Gilles Clapisson, Christophe Caux, David Pérol, Isabelle Laure Ray-Coquard
Journal: Journal of Clinical Oncology (2014)

3033 Background: Lymphopenia is an independent predictive and prognostic factor for chemotherapy (CT)-induced death, febrile neutropenia, overall survival and progression in several cancers, including breast carcinoma. CYT107 is a glycosylated recombinant human IL-7 (CYTHERIS) able to increase lymphocyte pool in man. Whether IL-7 can correct lymphopenia in cancer pts receiving CT and improve patient outcome is not known. Methods: Using a 2x2 factorial design, 20 lymphopenic (<1000/µL) MBC pts, treated with capecitabine (2.5g/m2/d1-14, d1=21), were randomly allocated to 4 arms to receive 1) before the 1st cycle of CT : IL-7 (CYT107:10µg/kg, SC, weekly) or placebo (pbo), then 2) during the 3rdcycle of CT: IL-7 weekly or pbo. The primary endpoint was CD4 count changes before (D0 to D21) and during CT (D57 to D78). Secondary endpoints were toxicity, safety and PFS. Quantitative and functional changes in immune cells were also analyzed. Results: From Nov. 2011 to Jun. 2013, 20 pts (median CD4 count D0 : 242 /µL) were enrolled. Before CT (n=20), IL-7 induced a significant increase of CD4 count (median relative change : +148.1% in IL-7 groups vs +9.9% in placebo [Wilcoxon, p=0.002]), CD8 as well as naïve and memory T cell subsets. During CT (n=11), IL-7 increased CD4 count (+58.6% in IL-7 group vs -2.4% in pbo group [p=0.121]), as well as CD8CD45RO memory cells. CYT107 was well tolerated with injection site reactions as the main AE, no anti-IL-7 antibodies, and no IL-7-related ≥ Grade 3 AE. Interestingly, IL-7 during CT reduced the incidence of Grade 3 haemotological AE compared to placebo (0 vs 5 events, respectively). With a median follow-up of 14 [7-15] months, 6/10 and 2/10 deaths were observed in the groups having received pbo or IL-7 before CT, respectively. 3 objective responses (OR) were observed in pts receiving IL-7 (before and/or during CT) vs 1 OR in pts receiving only pbo. Survival data will be presented at the meeting. Conclusions: IL-7 treatment was safe, restored CD4 and T cell subsets in lymphopenic pts with severe haematological toxicity. Further investigations of IL-7 in oncology are warranted. Clinical trial information: NCT01368107.
Abstract 4406: Inducible knockdown of insulin receptor substrate I desensitizes ER alpha response to both agonist (estradiol) and antagonist (fulvestrant) in MCF-7L breast cancer cells
Authors: Xihong Zhang, Sidhant Varma, Douglas Yee
Journal: Cancer Research (2016)

Abstract Insulin receptor substrate (IRS) proteins are adaptor proteins phosphorylated by insulin and insulin-like growth factor (IGF) receptors. In addition to their roles in regulating IGF and insulin responses, IRS proteins function in other pathways in normal and malignant physiology. Our data suggested that IRS1 enhanced IGF/insulin stimulated proliferation while IRS-2 was important in regulating motility. Therefore IRS proteins could be potential therapeutic target for cancer therapy. We have previously shown that reduced IRS1 can hinder cancer cell growth and tumorigenicity stimulated by IGF-I, IGF-II and insulin. In this study, we evaluated whether inducible IRS1 suppression affected estrogen receptor-alpha (ER) responsiveness to ER agonist estradiol and antagonist fulvestrant. We evaluated several doxycycline inducible shRNA IRS1 constructs (Thermo Scientific pTRIPZ inducible Lentiviral IRS1 shRNA) expressed in the ER+ MCF-7L cell line. Doxcycline treatment reduced IRS1 mRNA and protein levels confirmed by qRT-PCR and immunoblot in several independently selected clones. We used a representative clone (3G5) to evaluate effects on ER function. After IRS1 inducible knockdown, estradiol (E2) stimulated growth was suppressed. To investigate if reduced IRS1 regulated E2 stimulated binding of ER to the pS2 estrogen response element (ERE), chromatin immunoprecipitation (ChIP) assays were performed. Compared to non-induced MCF-7L cells, inducible IRS1 suppression demonstrated significantly reduced binding of ER to this promoter. The pharmacologic antagonist of IRS proteins, NT157, also resulted in diminished ER binding to pS2 promoter. mRNA of several ER regulated genes, such as PGR, TFF1, etc, showed downregulation in response to E2 when IRS-1 was suppressed. We have shown that the pure steroidal ER antagonist fulvestrant activates EGFR signaling in an ER dependent manner through upregulation of EGFR ligands. However, inducible IRS1 suppression blocked this ER-dependent activation of EGFR phosphorylation by fulvestrant yet EGFR phosphorylation remained intact when stimulated by addition of EGF. These data suggest that regulation of EGFR ligands by fulvestrant also requires IRS-1 expression. We conclude that ER function is affected by IRS-1 expression. Thus, IRS-1 may also be a target in endocrine responsive and resistant breast cancers. Citation Format: Xihong Zhang, Sidhant Varma, Douglas Yee. Inducible knockdown of insulin receptor substrate I desensitizes ER alpha response to both agonist (estradiol) and antagonist (fulvestrant) in MCF-7L breast 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 4406.