tbuckley/cabot-search huggingface dataset:
Role of TP53 mutations in predicting response to TKI treatment in EGFR-mutated NSCLC patients.
Authors: Paola Ulivi, Matteo Canale, Elisabetta Petracci, Elisa Chiadini, Claudio Dazzi, Laura Capelli, Alessandro Gamboni, Claudia Casanova, Maximilian Papi, Marita Mariotti, Nicoletta De Luigi, Marco Angelo Burgio, Vienna Ludovini, Chiara Bennati, Rita Chiari, Daniele Calistri, Lucio Crino, Dino Amadori, Angelo Delmonte
Journal: Journal of Clinical Oncology (2016)

9052 Background: Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations are usually responsive to tyrosine kinase inhibitors (TKIs). However, about 20% of EGFR-mutated patients are resistant to TKIs. We analyzed the impact of TP53 mutations on response to first-line TKI treatment in EGFR-mutated NSCLC patients. Methods: 123 EGFR-mutated NSCLC patients receiving first-line treatment with a TKI were analyzed. The different TP53 mutations were evaluated in relation to disease control rate (DCR: complete response [CR] + partial response [PR] + stable disease [SD]), progression-free survival (PFS) and overall survival (OS). Results: TP53 mutations were observed in 37 (30%) patients, of which 10 (27%), 6 (16%), 9 (24%) and 12 (32%) in exon 5, 6, 7 and 8, respectively. Moreover, 24 were disruptive and 13 nondisruptive mutations. DCR was 70% in TP53-mutated patients with respect to 88% in TP53 wild type (wt) patients, (RR: 3.17 [95% CI 1.21-8.48], p = 0.019). In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation compared to 87% in TP53 exon 8 wt patients (RR 9.6 [2.71-36.63], p < 0.001). In patients with nondisruptive TP53 mutation, DCR was 67% with respect to 87% in patients with TP53 wt/disruptive mutations (RR 3.27 [1.14-9.12], p = 0.024). Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared to the other patients (4.2 vs 12.5 [p = 0.058] and 16.2 vs 32.3 [p = 0.114], respectively), and these differences became significant considering the subgroup of patients with EGFR exon 19 deletion (4.2 vs 16.8 [p < 0.001] and 7.6 vs not reached [p = 0.006], respectively). COX regression analyses showed that in this subgroup of patients, exon 8 TP53mutation was associated with a higher risk of recurrence (HR 6.99 [95% CI 2.34-20.87], p < 0.001) or death (HR 4.75 [95% CI 1.38-16.29], p = 0.013) than the wild type group. Conclusions: TP53 mutations, in particular exon 8 mutations and those defined as nondisruptive, reduce responsiveness to TKI treatment and induce a worse prognosis in EGFR-mutated NSCLC patients, especially in those carrying exon 19 deletions. These results highlight the importance of tumor-suppressor genes in determining response to TKIs.
Randomization—There Is No Substitute
Authors: Gregg C. Fonarow
Journal: JAMA Cardiology (2016)

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Metastatic pattern of invasive lobular carcinoma.
Authors: Padma Sheila Rajagopal, Mini Jacob, Vipin Das Villgran, Margaret Quinn Rosenzweig, Rachel Catherine Jankowitz, Steffi Oesterreich, Adam Brufsky, Aju Mathew
Journal: Journal of Clinical Oncology (2015)

e11561 Background: Invasive lobular carcinoma (ILC) histology comprises around 10 percent of invasive breast cancers. To our knowledge, patterns of metastases over the entire disease course of ILC have been poorly described. Methods: Using a prospective registry in a single-institution academic oncology practice, we identified metastatic sites among women diagnosed with metastatic ILC or IDC between 1998 and 2012. Results: Among 694 patients, 615 (88.6%) had IDC and 79 (11.4%) had ILC histology. Pts with ILC had a higher median age at diagnosis of primary cancer and metastatic disease (p<0.01), a greater stage (III and IV) at the time of first cancer diagnosis (p=0.003), more hormone receptor-positive disease, fewer HER2-positive and triple negative tumors (p=0.003) compared with IDC. Median number of metastatic organ involvement was similar between IDC and ILC. Over the course of metastatic disease, more pts with IDC had visceral disease, lung, liver and ovarian metastases, but there was no difference between IDC and ILC in frequency of bone, lymph node or CNS metastases. Pts with ILC had a longer recurrence-free survival (time from primary diagnosis to onset of metastatic disease) compared with IDC, but survival after metastatic diagnosis was similar. Conclusions: Metastatic pattern of ILC differs from IDC. Patterns of metastases. As first site of distant recurrence Site IDC ILC Total P value N % N % N % Visceral 270 43.9 24 30.4 294 42.3 0.022 Bone 229 37.2 42 53.2 271 39.0 0.006 CNS 38 6.2 2 2.5 40 5.7 0.190 Lung and pleura 150 24.4 5 6.3 155 22.3 0.001 Liver 73 11.9 4 5.1 77 11.1 0.070 Skin 16 2.6 1 1.2 17 2.4 0.470 Soft tissue 6 1 2 2.5 8 1.2 0.223 Distant lymph nodes 55 8.9 5 6.3 60 8.6 0.436 Ovary 4 0.6 2 2.5 6 0.9 0.08 During the course of metastatic disease Visceral 500 81 51 64.5 551 79.4 0.001 Bone 403 65.5 59 74.7 462 66.5 0.104 CNS 191 31.1 19 24 210 30.3 0.196 Lung and pleura 318 51.7 17 21.5 335 48.2 0.001 Liver 298 48.4 13 16.4 311 44.8 0.001 Skin 40 6.5 5 6.3 45 6.5 0.953 Soft tissue 25 4.1 5 6.3 30 4.3 0.352 Distant lymph nodes 171 27.8 17 21.5 188 27.1 0.237 Ovary 14 2.3 6 7.6 20 2.9 0.008
Abstract 934: Tributyltin-induced dysregulation of inflammatory cytokine levels in human and mouse immune cells
Authors: Shanieek Lawrence, Samuel T. Pellom, Anil Shanker, Margaret Whalen
Journal: Cancer Research (2016)

Abstract The effects of Tributyltin (TBT), a widespread environmental contaminant, on the induction of in vivo and ex vivo cytokine production and secretion were investigated. Human monocyte-depleted peripheral blood mononuclear cells and different groups of Balb/C mice were stimulated with desired concentrations of TBT (200-2.5 nM for human studies and 200-25 nM for mouse studies). The quantitative determination of IFNγ, TNFα and IL-1β was performed in mouse sera by MagPix analysis and western blot. The levels of these cytokines were measured at different time points: 6, 12, 24 and 48 h after injection. Analysis of IFNγ and TNFα in human cells were conducted by ELISA and western blot. MAPK and NF-κB pathways were inhibited to determine TBT-induced dysregulation of IFNγ and TNFα. Inhibition of the p38 and p44/42 pathways blocked the TBT-induced elevation of IFNγ, while the inhibition of the p38 pathway blocked the TBT-induced elevation of TNFα. Results showed that TBT increased the levels of IFNγ, TNFα and IL-1β in the sera of mice. IFNγ and TNFα secretion from human monocyte-depleted peripheral blood mononuclear cells also increased, showing striking agreement in the response to TBT between the mouse and human systems. These data suggest that TBT exposure can result in an inflammatory environment, which could predispose the host to various immunopathologies. Grant U54CA163066 from the National Institute of Health Citation Format: Shanieek Lawrence, Samuel T. Pellom, Anil Shanker, Margaret Whalen. Tributyltin-induced dysregulation of inflammatory cytokine levels in human and mouse immune 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 934.
Role of 18f-FDG PET/CT in the Management of Multiple Myeloma.
Authors: Elena Zamagni, Cristina Nanni, Patrizia Tosi, Stefano Fanti, Delia Cangini, Paolo Castellucci, Paola Tacchetti, Giulia Perrone, Michela Ceccolini, Mohsen Farsad, Michele Baccarani, Michele Cavo
Journal: Blood (2005)
Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between β-Amyloid and Tauopathy
Authors: Liang Wang, Tammie L. Benzinger, Yi Su, Jon Christensen, Karl Friedrichsen, Patricia Aldea, Jonathan McConathy, Nigel J. Cairns, Anne M. Fagan, John C. Morris, Beau M. Ances
Journal: JAMA Neurology (2016)

<h3>Importance</h3> In vivo tau imaging may become a diagnostic marker for Alzheimer disease (AD) and provides insights into the pathophysiology of AD. <h3>Objective</h3> To evaluate the usefulness of [<sup>18</sup>F]-AV-1451 positron emission tomography (PET) imaging to stage AD and assess the associations among β-amyloid (Aβ), tau, and volume loss. <h3>Design, Setting, and Participants</h3> An imaging study conducted at Knight Alzheimer Disease Research Center at Washington University in St Louis, Missouri. A total of 59 participants who were cognitively normal (CN) (Clinical Dementia Rating [CDR] score, 0) or had AD dementia (CDR score, &gt;0) were included. <h3>Main Outcomes and Measures</h3> Standardized uptake value ratio (SUVR) of [<sup>18</sup>F]-AV-1451 in the hippocampus and a priori–defined AD cortical signature regions, cerebrospinal fluid Aβ42, hippocampal volume, and AD signature cortical thickness. <h3>Results</h3> Of the 59 participants, 38 (64%) were male; mean (SD) age was 74 (6) years. The [<sup>18</sup>F]-AV-1451 SUVR in the hippocampus and AD cortical signature regions distinguished AD from CN participants (area under the receiver operating characteristic curve range [95% CI], 0.89 [0.73-1.00] to 0.98 [0.92-1.00]). An [<sup>18</sup>F]-AV-1451 SUVR cutoff value of 1.19 (sensitivity, 100%; specificity, 86%) from AD cortical signature regions best separated cerebrospinal fluid Aβ42-positive (Aβ+) AD from cerebrospinal fluid Aβ42-negative (Aβ−) CN participants. This same cutoff also divided Aβ+ CN participants into low vs high tau groups. Moreover, the presence of Aβ+ was associated with an elevated [<sup>18</sup>F]-AV-1451 SUVR in AD cortical signature regions (Aβ+ participants: mean [SD], 1.3 [0.3]; Aβ− participants: 1.1 [0.1];<i>F</i> = 4.3,<i>P</i> = .04) but not in the hippocampus. The presence of Aβ+ alone was not related to hippocampal volume or AD signature cortical thickness. An elevated [<sup>18</sup>F]-AV-1451 SUVR was associated with volumetric loss in both the hippocampus and AD cortical signature regions. The observed [<sup>18</sup>F]-AV-1451 SUVR volumetric association was modified by Aβ status in the hippocampus but not in AD cortical signature regions. An inverse association between hippocampal [<sup>18</sup>F]-AV-1451 SUVR and volume was seen in Aβ+ participants (<i>R</i><sup>2</sup> = 0.55;<i>P</i> &lt; .001) but not Aβ− (<i>R</i><sup>2</sup> = 0;<i>P</i> = .97) participants. <h3>Conclusions and Relevance</h3> Use of [<sup>18</sup>F]-AV-1451 has a potential for staging of the preclinical and clinical phases of AD. β-Amyloid interacts with hippocampal and cortical tauopathy to affect neurodegeneration. In the absence of Aβ, hippocampal tau deposition may be insufficient for the neurodegenerative process that leads to AD.
THE ADDITION OF CETUXIMAB TO OXALIPLATIN-FLUOROPYRIMIDINE CHEMOTHERAPY IN FIRST-LINE ADVANCED COLORECTAL CANCER IN THE MRC COIN TRIAL: IDENTIFICATION OF POTENTIALLY RESPONSIVE SUBSETS OF PATIENTS
Authors: T Maughan, R Adams, C Smith, M Seymour, R Wilson, A Meade, D Fisher, A Madi, J Cheadle, R Kaplan
Journal: Annals of Oncology (2010)
Abstract 3902: Novel selective estrogen receptor downregulators developed using endocrine-independent breast cancer cell lines
Authors: Rui Xiong, Jiong Zhao, Lauren Gutgesell, Debra Tonetti, Gregory Thatcher
Journal: Cancer Research (2016)

Abstract Approximately 70% of breast cancer patients are estrogen receptor positive (ER+). Aromatase inhibitors and the selective estrogen receptor modulator (SERM), tamoxifen, are the first line treatments for these patients; however, almost 50% of patients either do not respond or acquire resistance. Multiple mechanisms, including mutations of the ESR1 gene, contribute to resistance via ligand-independent constitutive activation of ER. Selective estrogen down-regulators (SERDs) that block ligand-dependent and independent ER signaling by ablation of ER, offer a therapeutic approach to treatment-resistant, advanced stage and early stage ER+ breast cancer. Therapeutic use of the first generation SERD, fulvestrant (Faslodex), has largely remained 2nd and 3rd line, because of poor physiochemical/pharmacokinetic properties. Novel benzothiophene based SERDs were designed, synthesized, and optimized and assayed in three tamoxifen-resistant (TR), endocrine-independent ER+ MCF-7 and T-47D cell lines. Cell viability, ERE-luciferase response, and ER degradation was measured and compared to parent endocrine-dependent MCF-7 and T-47D cell lines in 2D and/or 3D spheroid cell cultures and compared to SERDs, fulvestrant and GDC-0810. Pharmacokinetic analysis was used to select novel SERDs for xenograft studies. Citation Format: Rui Xiong, Jiong Zhao, Lauren Gutgesell, Debra Tonetti, Gregory Thatcher. Novel selective estrogen receptor downregulators developed using endocrine-independent breast cancer 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 3902.
Abstract 3761: The MDM2 inhibitor AMG 232 causes tumor regression and potentiates the anti-tumor activity of MEK inhibition and DNA-damaging cytotoxic agents in preclinical models of acute myeloid leukemia
Authors: Jude R. Canon, Tao Osgood, Anne Y. Saiki, Jonathan D. Oliner
Journal: Cancer Research (2016)

Abstract AMG 232 is a potent inhibitor of the MDM2-p53 interaction and is a promising clinical candidate for treating tumors, in particular those harboring wild-type p53. AML represents a compelling indication for AMG 232 given the low rate of p53 mutation, frequent MDM2 overexpression, and unmet medical need. We evaluated the effect of AMG 232 treatment on AML tumors in vitro and in vivo, elucidated the mechanism of anti-tumor efficacy, and tested the effect of combining AMG 232 with targeted agents and chemotherapeutics. Combinations were identified based on evidence of in vitro synergy from cell based screens, or based on biological rationale and clinical opportunity with standard of care agents. Combinations evaluated included MEK inhibitors, and p53-inducing, DNA-damaging cytotoxics cytarabine, doxorubicin, and decitabine. In vitro assays demonstrated that AMG 232 as a single agent was effective at inducing cell death across a panel of p53 wild-type AML cell lines. The anti-tumor efficacy involved activation of the p53 pathway, robust inhibition of the cell cycle and induction of apoptosis. AMG 232 treatment caused AML tumor regression in vivo which was related to dose- and time-dependent induction of the p53 targets p21 and PUMA. The combination of AMG 232 and MEK inhibition resulted in synergistic tumor cell killing in vitro, and enhanced in vivo anti-tumor activity which was significantly better than either single agent. Combinations of AMG 232 with chemotherapies which induce DNA damage resulted in synergistic in vitro cell killing, and superior anti-tumor efficacy in vivo with increased induction of p53 signaling in tumors. These data support a clinical strategy for evaluating AMG 232 as a monotherapy and in combination with targeted and cytotoxic agents to treat AML patients. Citation Format: Jude R. Canon, Tao Osgood, Anne Y. Saiki, Jonathan D. Oliner. The MDM2 inhibitor AMG 232 causes tumor regression and potentiates the anti-tumor activity of MEK inhibition and DNA-damaging cytotoxic agents in preclinical models of acute myeloid leukemia. [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 3761.
Abstract 1106: Mir-223-5p works as an oncomir in vulvar carcinoma by TP63 regulation
Authors: Rafael Rocha, Beatriz De Melo Maia, Iara S. Rodrigues, Nayra S. Amaral, Hui Ling, George A. Calin, Fernando A. Soares
Journal: Cancer Research (2016)

Abstract Recently, miR-223-5p was associated with metastasis in HPV negative vulvar samples and in several other tumor types. In the present study, we hypothesized that this microRNA would have a potential impact on in vitro vulvar cancer behavior. We artificially mimicked microRNA expression in vulvar cancer cell line, SW962, derived from lymph node metastasis of vulvar carcinoma, and performed in vitro assays as follows in the result section. Impaired cell proliferation (p&amp;lt;0.01) and migration (p&amp;lt;0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of the cells was observed (p&amp;lt;0.004). By Luciferase assay we provide evidence that miR-223-5p targets TP63 through its 3’UTR direct ligation (p&amp;lt;0.05). We also demonstrate that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p&amp;lt;0.001, and p&amp;lt;0.0001; respectively). We further demonstrated that low p63 protein expression in samples from patients was correlated with deeper tumor (p&amp;lt;0.0345) invasion and lower overall survival (p&amp;lt;0.0494). Our study highlights the complexity surrounding p63 biological mechanisms and the importance of this protein as a prognostic factor in vulvar cancer. We also point out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients. Citation Format: Rafael Rocha, Beatriz De Melo Maia, Iara S. Rodrigues, Nayra S. Amaral, Hui Ling, George A. Calin, Fernando A. Soares. Mir-223-5p works as an oncomir in vulvar carcinoma by TP63 regulation. [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 1106.
Abstract 2517: Ewing sarcoma associated long non-coding RNA determines neural cell fate of the tumors
Authors: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, Timothy J. Triche
Journal: Cancer Research (2016)

Abstract BACKGROUND: Ewing sarcoma is a highly invasive pediatric bone and soft tissue malignancy with a 20% 5-year survival rate for patients with metastatic disease. 85% of Ewing sarcomas express a chimeric oncogene, mainly EWS-FLI1, which drives the gene expression signature in these tumors. The exact cell of origin for these primitive small round cell tumors is unknown. These undifferentiated tumors express some neuroectodermal, mesenchymal, and epithelial markers. Recently published work suggests that these tumors may have risen either from neural crest or mesenchymal stem cells. These genomic and phenotypic features may be responsible for the aggressive nature of this disease and understanding the tumor biology may help better treatment options for this metastatic cancer. RESULTS: Our study on expression analysis of primary Ewing tumors using Affymetrix's Human Exon arrays identified a highly expressed novel long intergenic non-coding RNA (lincRNA), FEZF1-AS1 in these tumors. Its DNA sequence has no homology in most vertebrates. RNA-mediated knockdown of the lincRNA in Ewing cell lines decreased expression of some of the neural lineage genes as well as genes associated with cell adhesion and migration. In vitro matrigel assays detected a decrease in cell invasion capability of the lincRNA-knockdown cells. In the in vivo studies, the lincRNA-overexpressed cells had better engraftment and tumor growth in the liver than the normal controls. On attempt to differentiate the lincRNA-knockdown Ewing cell lines, we noted that a decrease in the lincRNA expression led to a decrease in the expression of neuroectodermal markers after a week of differentiation when compared to the control cells. We further detected temporal expression of this lincRNA during neuronal differentiation from embryonic stem cells. CONCLUSIONS: Our study identified a unique lincRNA in Ewing sarcoma that may be partly responsible for inducing expression of the neural lineage genes in these tumors as its reduced expression impaired differentiation in the Ewing cell lines. Its prometastatic behavior helps the aggressive nature of these tumors. Its expression during neural differentiation along with its involvement in cell migration suggests that FEZF1-AS1 may be responsible for imparting neural stem cell like-characteristics to Ewing sarcoma. Citation Format: Sheetal A. Mitra, Anirban P. Mitra, Jonathan D. Buckley, Timothy J. Triche. Ewing sarcoma associated long non-coding RNA determines neural cell fate of the 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 2517.