tbuckley/cabot-search huggingface dataset:
Clinicopathologic features of advanced <i>RET</i> fusion-positive lung cancers and outcomes in comparison to other fusion-positive lung cancers.
Authors: Alexander E. Drilon, Matthew David Hellmann, Lu Wang, Eun Jung Cho, Marc Ladanyi, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2014)

8076 Background: Recurrent gene rearrangements are important drivers of lung cancer growth. While RET fusions are recognized as actionable targets, the clinicopathologic features of these drivers in advanced (stage IIIB/IV) disease and survival in comparison to ALK and ROS1 fusion-positive lung cancers are less well-characterized. Methods: A FISH study using dual-color break-apart probes was performed to screen for RET fusions in patients (pts) with advanced lung ADCs that tested negative for mutations in EGFR, KRAS, NRAS, BRAF, MAP2K1, ERBB2, PIK3CA, or AKT, and fusions of ALK or ROS1. In pts with sufficient tissue, fusion partners were identified (RT-PCR/next-generation sequencing). Pathologic review of available tumor specimens and assessment of radiographic response via RECIST v1.1 were conducted. Overall survival (OS) and progression-free survival (PFS) were determined using Kaplan-Meier estimates. Comparisons to control groups of ALK and ROS1 fusion-positive lung cancers were performed (Mantel-Haenszel/log rank tests). Results: 17% (n=18/104, 95%CI 9-22%) of tumors from screened pts harbored a RET fusion (56% male, median age 61). Majority of pts had no history of chest RT [89%, n=16] and were never smokers [72% (n=13) <1, 22% (n=4) 1-15, and 6% (n=1) >15 pack-years]. In 8 pts with sufficient tissue, known upstream partners were identified in 7 pts (NCOA4, TRIM33, 6 KIF5B). An upstream partner not previously described in lung cancers (CLIP1) was found. Morphology in surgical specimens (n=8) was as follows: 63% (n=5) predominantly solid, 25% (n=2) predominantly cribriform, 13% (n=1) predominantly papillary. OS of RET (n=18) vs ALK (n=45; HR 0.84, 95%CI 0.34-2.08, p=0.71) and ROS1 (n=10; HR 1.59, 95%CI 0.34-7.31, p=0.55) fusion-positive lung cancers was similar. In patients who received first-line chemotherapy, PFS of RET (n=12) vs ALK (n=22; HR 0.53, 95%CI 0.25-1.13, p=0.10) and ROS1 (n=8; HR 1.19, 95%CI 0.34-4.17, p-0.78) fusion-positive lung cancers was similar. Conclusions: Advanced RET fusion-positive lung cancers represent a distinct group of tumors with clinical outcomes comparable to ALK and ROS1 fusion-positive lung cancers.
Abstract 9821: Fetal Rhythm Phenotype Predicts LQTS Mutation: Risk Stratification of Perinatal Long QT Syndrome
Authors: Bettina F Cuneo, Jeannette Barczak, Denver Sallee, D. Woodrow Benson
Journal: Circulation (2012)

Introduction: Torsade de pointe (TdP) and/or 2° atrioventricular block (2° AVB) are signature rhythms for perinatal LQTS known for their high morbidity and mortality. We hypothesized that the clinical profile of patients with complex fetal arrhythmias might be mutation specific. Methods: Perinatal records of subjects with LQTS exhibiting complex fetal arrhythmia were reviewed. Fetal echocardiograms, neonatal ECG and genetic testing were evaluated. Results: We studied 11 LQTS subjects exhibiting complex fetal arrhythmias. Mutation in a known LQTS gene was identified in 9: SCN5A (5), KCNH2 (2) and KCNQ1 (2). Most mutations were de novo including 4 SCN5A-1623Q. TdP occurred in 8 cases (7 prenatal, mean gestational age=30.5 weeks). Most fetuses with TdP also had 2° AVB, but 3 cases had 2° AVB alone. TdP exhibited 2 patterns: fast (&gt;270 bpm) and incessant or slow (&lt;250 bpm) and intermittent. All cases with SCN5A mutation had fast-incessant TdP, while cases with KCNH2 mutations had slow-intermittent TdP. Cases with KCNQ1 mutations had 2° AVB. Fetuses with TdP were delivered earlier (33.6 weeks) than those with 2° AVB (38.5 weeks). Neonatal QTc intervals were 652 ± 42 (in utero TdP) and 507 ± 43, p=0.01 (in utero 2° AVB). Prenatal treatment was administered in 6 cases without maternal complications; 4 fetuses improved and TdP ceased in 2. Despite medical and pacemaker therapy, cardiac arrest (n=6) resulting in sudden death (n=2) were common. Conclusion: Complex rhythm phenotypes of fetal LQTS have mutation specific features that may allow risk stratification in these high risk patients.
Abstract 2752: EGFR tyrosine kinase inhibitor limits tumor relapse through enhancing anti-tumor T cell responses
Authors: Zhida Liu, Chuanhui Han, Aijun Shen, Chunbo Dong, Jian Qiao, Yang-Xin Fu
Journal: Cancer Research (2018)

Abstract EGFR tyrosine kinase inhibitors (TKIs) have been clinically considered as the first line therapy for EGFR-driven tumor patients. Although the initial outcome of patients has significantly improved, almost all patients eventually relapse. Fully understanding the mechanisms of the anti-tumor effect of EGFR TKIs will help promote the clinical development of more efficient therapeutic strategies. The traditional view of the main mechanism is that the inhibitors can directly inhibit EGFR downstream signaling pathways to induce tumor cell death. Whether and how EGFR TKIs affect the host immune system is largely unknown. In current study, we have established syngeneic murine tumor models that are sensitive to EGFR TKIs treatment. To our surprise, we revealed that EGFR TKI treatment could control tumor growth and limit tumor relapse in T cells dependent manner. Mechanistically, EGFR TKI triggers type I IFN and its stimulation gene CXCL10 production through the Myd88 signaling pathway to enhance tumor specific T cells infiltration and activation. However, EGFR TKI cannot efficiently limit tumor relapse in advanced tumor models because of PD-L1 upregulation in the tumor microenvironment after treatment. We have observed that anti-PDL1 blockade can synergize with EGFR TKI to control advanced tumors. Our study will challenge the current regimen of EGFR TKI in clinic and provide new efficient therapeutic strategies for EGFR dependent cancer patients. Citation Format: Zhida Liu, Chuanhui Han, Aijun Shen, Chunbo Dong, Jian Qiao, Yang-Xin Fu. EGFR tyrosine kinase inhibitor limits tumor relapse through enhancing anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2752.
Post docetaxel treatment for castration-resistant prostate cancer (CRPC): Does sequencing matter?
Authors: Zafar I Malik, Amir H Montazeri, Helen Wong, Chinnamani Eswarvee
Journal: Journal of Clinical Oncology (2012)

e15135 Background: Two phase 3 studies have demonstrated efficacy for cabazitaxel (CAB) and abiraterone (AB) post docetaxel (DT) for CRPC. Both studies show survival benefit in patients who have progressed during or shortly after DT. Currently there is no data to show which agent is superior. It may be possible that as these agents have different mechanisms of resistance and the benefits are additive. Currently no predicative markers are available to identify response to therapy or optimal sequencing. Both agents are available for prescription at our centre. In this study we investigated the number of patients who were able to receive both treatments sequentially and whether therapy sequencing matters. Methods: In this retrospective study, patients with CRPC treated with CAB or AB after DT between Jan2011- Jan 2012 were included. Baseline patient characteristics were recorded as well as treatments following progression. In particular patient numbers receiving both CAB &amp; AB were recorded. Statistical analysis was performed using SPSS v18. Results: 42 consecutive patients post DT included, 24 CAB and 18 AB. Median follow up was 7.9 months for CAB and 2.5 months for AB. At analysis, 18 CAB patients and 9 AB patients had progressed. Of those who progressed following CAB, 13 received AB, 1 restarted Goserelin and 4 patients received best supportive care (BSC). 9 patients progressed on AB and none were able to receive CAB, 4 received BSC, 1 was treated with stilboestrol and 4 remained on AB despite progression. Conclusions: Our series provides insight into the sequencing of these agents in the real world. As these agents have different resistant mechanisms it is possible that the benefits may be additive .Our study suggests that if patients receive CAB as the first option, they are more likely to receive AB subsequently whilst the converse does not apply. At this time the series is not mature enough to determine if differences in sequencing will impact on survival benefit, however progression free survival and overall survival will be updated for the meeting. [Table: see text]
Abstract 3358: FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST)
Authors: Leili Ran, Yuedan Chen, Wai Pung E. Wong, Dan Li, Zhen Cao, Shipra Shukla, Yuanyuan Xie, Deyou Zheng, Richard P. Koche, Cristina R. Antonescu, Yu Chen, Ping Chi
Journal: Cancer Research (2018)

Abstract The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behaviour and shapes treatment responses in distinct cancer types. Here, we uncover that in GIST, the forkhead family member, FOXF1, directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal (ICC) lineage-specification and GIST tumorigenesis. Further, FOXF1 co-localizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST-lineage specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo. The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behaviour and treatment response. Citation Format: Leili Ran, Yuedan Chen, Wai Pung E. Wong, Dan Li, Zhen Cao, Shipra Shukla, Yuanyuan Xie, Deyou Zheng, Richard P. Koche, Cristina R. Antonescu, Yu Chen, Ping Chi. FOXF1 defines the core-regulatory circuitry in gastrointestinal stromal tumor (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3358.
Abstract 1817: Establishment and characterization of non-small cell lung cancer cell line variants selected for resistance to osimertinib
Authors: Peter J. Ferguson, Mark D. Vincent, James Koropatnick
Journal: Cancer Research (2018)

Abstract Many non-small cell lung cancers (NSCLC) are oncogenically driven by mutant epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors (TKIs) are commonly used as a first-line treatment against such tumors, but NSCLC tumors often recur with a mutant EGFR (often with a T790M mutation in exon 20) that confers resistance to these drugs [Ther Adv Respir Dis 10(6): 549-565, 2016]. Third generation EGFR TKIs (e.g., osimertinib) have been designed that are highly active aganst both T790M EGFR and the original non-T790M-mutated, oncogenic EGFR. Clinical resistance to third generation TKIs has been observed, but model systems in which to study the mechanisms of resistance are few. The human NSCLC cell line H1975, derived from an EGFR-TKI-resistant tumor, contains EGFR mutations T790M and L858R (exon 21). To explore mechanisms mediating resistance to third generation TKIs, we selected variants of the H1975 cell line for resistance to osimertinib to create models in which mechanisms of resistance can be characterized and tested for potential methods to overcome that resistance. Cells were exposed continuously to a single concentration of osimertinib, in some cases with the inclusion of verapamil to avoid possible selection of multidrug resistant cells. After 4 weeks, with weekly changes of drug-medium, clonal cell lines were selected in the presence of 6 and 10 μM osimertinib (one each) or in 5 μM osimertinib plus 10 μM verapamil (3 cell lines). These clonal lines were, respectively, 90-, 95-, 38-, 227-, and 244-fold resistant to osimertinib. The RAD51 inhibitor 2-(benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline (IBR2), which enhances cytotoxicity of several EGFR inhibitors against numerous cell lines (Ferguson et al., JPET 2017, doi.org/10.1124/jpet.117.241661), decreased osimertinib-resistance by up to 80% in these cell lines. Sequence analysis indicates that cell line H1975/osi-6b retained the same EGFR sequence as that in the parent cell line. H1975/osi-5b/VPL appears to have undergone epithelial-to-mesenchymal transition. Further analyses of the resistant cell lines are being undertaken. These cell lines are a valuable resource in which to test methods to circumvent resistance to third generation EGFR TKIs. Citation Format: Peter J. Ferguson, Mark D. Vincent, James Koropatnick. Establishment and characterization of non-small cell lung cancer cell line variants selected for resistance to osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1817.
Abstract 2279: The GenePattern Notebook environment for reproducible cancer research
Authors: Michael M. Reich, Thorin T. Tabor, Ted Liefeld, Barbara Hill, Helga Thorvaldsdottir, Jill P. Mesirov
Journal: Cancer Research (2018)

Abstract As the availability of genetic and genomic data and analysis tools from large-scale cancer initiatives continues to increase, the need has become more urgent for a software environment that supports the entire “idea to dissemination” cycle of an integrative cancer genomics analysis. Such a system would need to provide access to a large number of analysis tools without the need for programming, be sufficiently flexible to accommodate the practices of non-programming biologists as well as experienced bioinformaticians, and would provide a way for researchers to encapsulate their work into a single “executable document” including not only the analytical workflow but also the associated descriptive text, graphics, and supporting research. To address these needs, we have developed GenePattern Notebook, based on the GenePattern environment for integrative genomics and the Jupyter Notebook system. GenePattern Notebook unites the phases of in silico research - experiment design, analysis, and publication - into a single interface. GenePattern Notebook presents a familiar lab notebook format that allows researchers to build a record of their work by creating “cells” containing text, graphics, and executable analyses. Researchers add, delete, and modify cells as the research evolves, supporting the initial research phases of prototyping and collaborative analysis. When an analysis is ready for publication, the same document that was used in the design and analysis phases becomes a research narrative that interleaves text, graphics, data, and executable analyses. The online notebook format allows researchers to explain the analytical and scientific considerations of each step in any level of detail, promoting reproducibility and adoption. Notebooks can also be shared between researchers for collaborative development. GenePattern Notebook features are designed to help nonprogramming users create and adapt notebooks. We have developed additional cell types allowing users to choose analyses, specify inputs, navigate results, send result files to new analyses, and create richly formatted text, all without the need for programming. A free online GenePattern Notebook workspace is available at http://www.genepattern-notebook.org, where researchers can develop, share, and publish notebook documents. We have provided a collection of template notebooks that walk users through various genomic and machine learning analyses, and are collaborating with cancer research laboratories to create integrative cancer genomics notebooks. Citation Format: Michael M. Reich, Thorin T. Tabor, Ted Liefeld, Barbara Hill, Helga Thorvaldsdottir, Jill P. Mesirov. The GenePattern Notebook environment for reproducible cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2279.
Abstract 4616: Cancer-associated MUC1 epitope-recognizing antibody as a novel immunohistochemical marker for breast carcinoma
Authors: Ai Shimizu, Kanako Hatanaka, Yutaka Hatanaka, Kentaro Naruchi, Masaharu Sato, Hiroshi Kase, Tomoko Mitsuhashi, Hiroko Yamashita, Yoshihiro Matsuno
Journal: Cancer Research (2018)

Abstract Background: MUC1 has been used in clinical practice as a serum tumor marker (CA15-3) for monitoring recurrence and response to the treatment of breast cancers. However, it is not so practical to use the conventional anti-MUC1 antibody (C-Ab) for the differential diagnoses among malignant and benign tumors, because of its limited specificity to cancer-associated sugar chain structures. Recently, a novel epitope-defined (ED) antibody, which specifically recognizes MUC1 with cancer-associated carbohydrate antigens including Tn and sialyl-T antigens, was developed by our collaborators. In the present work, we focused on this Tn antigen-recognizing ED antibody (Tn-ED Ab) for MUC1, and examined the potential utility of this novel antibody as an immunohistochemical diagnostic marker of the breast.Design: Tissue microarray (TMA) consisting of invasive lesions and their non-neoplastic counterparts were constructed from 169 lesions of 167 individuals with invasive breast carcinomas (including 2 bilateral cases) resected and diagnosed at Hokkaido University Hospital from 2000 to 2003. We compared MUC1 immunoreactivity of Tn-ED Ab (clone SN-102) to commercially available C-Ab (clone Ma552) using TMA to evaluate its diagnostic performance and to analyze the association with clinicopathologic factors. Results: In invasive cancer parts, the immunoreactive positivity of Tn-ED Ab was observed predominantly in the cytoplasm (146/169) rather than in the cell membrane (5/169). The positive reaction of C-Ab was found in the cytoplasm and the membrane as well (156/169 and 93/169). Tn-ED Ab showed a lower expression rate in non-neoplastic parts and a high specificity in invasive cancer parts. Sensitivity/specificity in invasive parts was 86%/92% for Tn-ED Ab and 92%/47% for C-Ab. Moreover, the invasive cancer group with Tn-ED-positivity was significantly correlated with their molecular subtypes, low Ki-67 indices, and high ages, compared to those with Tn-ED-negativity (p=0.008, p=0.010 and p=0.027, respectively). Conclusion: Compared to C-Ab, the newly-developed Tn-ED Ab for MUC 1 showed a higher specificity for invasive breast cancer with a low reactivity to non-neoplastic components. Future study plans are ongoing to show that this cancer-specific Tn-ED MUC1 Ab could be useful for differentiating malignant from benign intraductal breast lesions as well. Citation Format: Ai Shimizu, Kanako Hatanaka, Yutaka Hatanaka, Kentaro Naruchi, Masaharu Sato, Hiroshi Kase, Tomoko Mitsuhashi, Hiroko Yamashita, Yoshihiro Matsuno. Cancer-associated MUC1 epitope-recognizing antibody as a novel immunohistochemical marker for breast carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4616.
Clinical Profile and Influences on Outcomes in Patients Hospitalized for Acute Pericarditis
Authors: VilleKytö, JussiSipilä, PäiviRautava
Journal: Circulation (2014)

Background—The clinical profile with regard to sex and the influences on outcomes in patients who have been hospitalized for acute pericarditis is largely uncharacterized. Methods and Results—We studied all patients aged ≥16 years admitted to the hospital because of acute pericarditis (postpericardiotomy and myocardial infarction associated pericarditis were excluded). Data were collected from a Finnish national registry that included data on all cardiovascular admissions (670 409) during 9.5 years in 29 hospitals nationwide. During the study period, there were 1361 admissions for acute pericarditis. Pericarditis patients were more likely to be male (64.9% of patients) than female (35.1%), with an age-adjusted likelihood ratio of 1.85 (95% confidence interval [CI], 1.65–2.06; P<0.0001) for male sex. The standardized incidence rate of hospitalizations for acute pericarditis was 3.32 per 100 000 person-years. Men 16 to 65 years of age were at higher risk for pericarditis (relative risk, 2.02; 95% CI, 1.81–2...
Cancer in People Living With HIV, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology
Authors: Erin Reid, Gita Suneja, Richard F. Ambinder, Kevin Ard, Robert Baiocchi, Stefan K. Barta, Evie Carchman, Adam Cohen, Neel Gupta, Kimberly L. Johung, Ann Klopp, Ann S. LaCasce, Chi Lin, Oxana V. Makarova-Rusher, Amitkumar Mehta, Manoj P. Menon, David Morgan, Nitya Nathwani, Ariela Noy, Frank Palella, Lee Ratner, Stacey Rizza, Michelle A. Rudek, Jeff Taylor, Benjamin Tomlinson, Chia-Ching J. Wang, Mary A. Dwyer, Deborah A. Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2018)

People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non–small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug–drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.
Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in <i>PIK3CA</i>-Mutant Lung Squamous Cell Carcinoma
Authors: Ruoshi Shi, Ming Li, Vibha Raghavan, Shirley Tam, Michael Cabanero, Nhu-An Pham, Frances A. Shepherd, Nadeem Moghal, Ming-Sound Tsao
Journal: Clinical Cancer Research (2018)

Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer characterized by multiple genetic alterations, particularly PI3K pathway alterations which have been identified in over 50% of LUSC cases. Despite being an attractive target, single-agent PI3K inhibitors have demonstrated modest response in LUSC. Thus, novel combination therapies targeting LUSC are needed.PI3K inhibitors alone and in combination with CDK4/6 inhibitors were evaluated in previously established LUSC patient-derived xenografts (PDX) using an in vivo screening method. Screening results were validated with in vivo expansion to 5 to 8 mice per arm. Pharmacodynamics studies were performed to confirm targeted inhibition of compounds.Consistent with results from The Cancer Genome Atlas analysis of LUSC, genomic profiling of our large cohort of LUSC PDX models identified PI3K pathway alterations in over 50% of the models. In vivo screening using PI3K inhibitors in 12 of these models identified PIK3CA mutation as a predictive biomarker of response (<20% tumor growth compared with baseline/vehicle). Combined inhibition of PI3K and CDK4/6 in models with PIK3CA mutation resulted in greater antitumor effects compared with either monotherapy alone. In addition, the combination of the two drugs achieved targeted inhibition of the PI3K and cell-cycle pathways.PIK3CA mutations predict response to PI3K inhibitors in LUSC. Combined PI3K and CDK4/6 inhibition enhances response to either single agents alone. Our findings provide a rationale for clinical testing of combined PI3K and CDK4/6 inhibitors in PIK3CA-mutant LUSC.