tbuckley/cabot-search huggingface dataset:
Retrospective single center review of toxicity and efficacy of a modified FOLFIRINOX regimen in patients with locally advanced and metastatic pancreatic cancer.
Authors: Bhargavi Pulluri, Joan Skelly, Maura Meredith Barry
Journal: Journal of Clinical Oncology (2018)

490 Background: Conroy et al. (N Engl J Med 364:1817–1825, 2011) have shown significantly better overall survival with FOLFIRINOX compared to gemcitabine in metastatic pancreatic cancer patients (MPC). However, given the toxicity associated with FOLFIRINOX treatment, different institutions have adapted varying modifications to the original regimen. Methods: We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in patients with unresectable locally advanced pancreatic cancer (LAPC) and MPC treated between Jan 2011 and Dec 2015 at University of Vermont Medical Center. Results: 43 patients were treated, of which 33 did not receive any prior treatment (6 LAPC, 27 MPC). 41 patients received dose attenuation with 1 st cycle. Median relative dose of irinotecan, oxaliplatin and 5-FU were less than reported by Conroy (69 vs. 81%, 70 vs. 78% and 71 vs. 82%). Median number of treatment cycles 7.8 (range 1 to 41). Median progression free survival in our MPC cases compared to Conroy’s data was 5.7 vs. 6.4 months; overall survival at 6 and 12 months were 78 vs. 75.9% and 41 vs. 48.4% respectively. Grade ¾ toxicities were less, including neutropenia (p&lt;0.001), fatigue (p =0.01) and neuropathy (p=0.04). One patient had grade 3 pneumonitis related to oxaliplatin. Conclusions: Our findings suggest that dose attenuation of 5-FU, irinotecan and oxaliplatin improve tolerability with fairly similar outcome as reported by Conroy et al. [Table: see text]
Changes in Electronic Cigarette Use Among Adults in the United States, 2014-2016
Authors: Wei Bao, Guifeng Xu, Jiachun Lu, Linda G. Snetselaar, Robert B. Wallace
Journal: JAMA (2018)

Electronic cigarettes (e-cigarettes) are widely marketed as a tool for smoking cessation and a safer alternative to conventional cigarettes.However, the efficacy of e-cigarettes for successful smoking cessation is inconclusive. 1,2Previous studies have reported a rapid increase in the prevalence of e-cigarette use among US adults since 2010. [3]4][5] We analyzed new national survey data to estimate the changes in e-cigarette use among US adults in 2014-2016.
Local level of CD 44+ cells in colon cancer.
Authors: Elena Alekseevna Nikipelova, Oleg Ivanovich Kit, Elena Yurievna Zlatnik, Inna Arnoldovna Novikova, Alexander Vasilievich Shaposhnikov, Roman Evgenievich Tolmakh
Journal: Journal of Clinical Oncology (2015)

e22095 Background: The purpose of the study was to analyze levels of non-hematopoietic (CD45-CD34-) and mesenchymal (CD45-CD34-CD44+) cells in tumor and tissues in patients with colon cancer. Methods: Subpopulations of CD45-CD34- and CD45-CD34-CD44+ cells were determined in tissues of tumor, peritumoral zone (1-3 cm from tumor) and along the resection line (7-10 cm from tumor) obtained during surgery from 50 patients with stage III-IV colon cancer (T3-4N1-2M1). Immunophenotyping of cells of colon tissue samples was performed by flow cytometry. Results: The study of content of CD45-CD34- and CD45-CD34-CD44+ cells in the samples showed that levels of CD45-CD34- cells were similar in tumor and in non-malignant colon tissues (in tumor – 99.04±0.29%, in peritumoral zone – 99.5±0.29%, in the resection line – 98.8±0.4%), and level of their mesenchymal CD45-CD34-CD44+ cells in tumor tissue (0.36±0.13%) was 3 times higher than in the resection line (0.109±0.02%) and 4.5 times higher than in peritumoral zone (0.08±0.01%) (p < 0.05). Conclusions: In stage III-IV colon cancer, tumor is infiltrated with non-hematopoietic cells, in particular mesenchymal cells (CD45-CD34-CD44+), that are known to be cancer stem cells; they may play an important role in tumor progression.
Patient Age and the Seasonal Pattern of Onset of Kawasaki’s Disease
Authors: Naomi Kitano, Hiroyuki Suzuki, Takashi Takeuchi
Journal: New England Journal of Medicine (2018)

Age and Seasonal Variation in Kawasaki’s Disease In Wakayama Prefecture, Japan, children older than 7 years of age in whom Kawasaki’s disease developed were more likely to be female, have disease o...
Advancing evidence-based decisions in the management of pancreatic cancer.
Authors: Tara Herrmann, Gwen Littman, Leah Piatt
Journal: Journal of Clinical Oncology (2018)

506 Background: As a result of updates to pancreatic cancer treatment guidelines, oncologists face a host of escalating treatment challenges that may hinder their abilities to select the most appropriate regimen for patients. A study was conducted to determine if simulation-based educational interventions could improve decisions of oncologists in the management of pancreatic cancer. Methods: A cohort of US-practicing oncologists who participated in a virtual patient simulation (VPS)-based education initiative was evaluated. The VPS consisted of 2 cases presented on a platform that allowed oncologists to assess each patient and make decisions limited only by an extensive database of treatment possibilities matching the scope and depth of actual practice. Clinical decisions made by participants were analyzed using a decision engine, and instantaneous clinical guidance (CG) employing current evidence-based and expert faculty recommendations was provided immediately after each decision. Oncologists were allowed a second chance at each decision point; decisions before and after CG were compared using a 2-tailed paired T-test. P values are shown as a measure of significance; P values &lt; .05 are statistically significant. Results: 410 oncologists made clinical decisions within the VPS. Significant improvements were observed in: Selecting the most appropriate first-line regimen in a patient with a PS of 2 (29%, P&lt; 0.001); Ordering an anti-emetic in patients who are receiving chemotherapy (24% , P&lt; 0.001); Evidence-based treatment selection for individuals whose disease progressed on therapy (17%, P= .003); and Ordering adverse event education and counseling (11% and 16%, P= .001). In addition, this study revealed that up to 55% of oncologists would test patients for BRCA mutations while 52% would consider enrolling a patient in a clinical trial if they have progressed on therapy. Conclusions: This study showed improvements in evidence-based practices of oncologists in the management of advanced pancreatic cancer across the continuum of care, thus demonstrating that VPS-based instruction can result in an increase in evidence-based clinical decisions. Therefore, VPS may have a role in improving the quality of care and patient outcomes.
Optimising experimental research in respiratory diseases: an ERS statement
Authors: Philippe Bonniaud, Aurélie Fabre, Nelly Frossard, Christophe Guignabert, Mark Inman, Wolfgang M. Kuebler, Tania Maes, Wei Shi, Martin Stampfli, Stefan Uhlig, Eric White, Martin Witzenrath, Pierre-Simon Bellaye, Bruno Crestani, Oliver Eickelberg, Heinz Fehrenbach, Andreas Guenther, Gisli Jenkins, Guy Joos, Antoine Magnan, Bernard Maitre, Ulrich A. Maus, Petra Reinhold, Juanita H.J. Vernooy, Luca Richeldi, Martin Kolb
Journal: European Respiratory Journal (2018)

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective. The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models. Focus was put on their specific benefits and limitations. This will result in more efficient use of resources and greater reduction in the numbers of animals employed, thereby enhancing the ethical standards and translational capacity of experimental research. The task force statement addresses general issues of experimental research (ethics, species, sex, age, ex vivo and in vitro models, gene editing). The statement also includes research recommendations on modelling asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung infections, acute lung injury and pulmonary hypertension. The task force stressed the importance of using multiple models to strengthen validity of results, the need to increase the availability of human tissues and the importance of standard operating procedures and data quality.
Impact of maternal death from female cancers on child mortality.
Authors: Raymond Mailhot Vega, Onyinye Balogun, Silvia Formenti
Journal: Journal of Clinical Oncology (2015)

6591 Background: Cervical and breast cancers are the most common causes of cancer mortality in women of childbearing age. The impact of maternal mortality on child mortality remains an under-investigated area. Elevated mortality rates in offspring are significantly associated with maternal death in both Bangladeshi and Scandinavian cohorts (Ronsmans 2010, Li 2014). This effect is contextual: when a mother dies, a child in Bangladesh is 10 times more likely to die before 10, versus 1.5 times more for a Scandinavian child. By ignoring this impact disease mortality rates underrepresent life lost, and this underestimation affects appropriate resource allocation. We propose a country-specific model to allow for estimates of offspring death rates attributable to breast and cervical cancers in women of childbearing age. Methods: A Monte Carlo simulation model (TreeAge) analyzed a sample population of 1 million 15yo fertile girls of a specific nationality and at risk of dying from cervical and breast cancer. Information was obtained from Globocan and UN World Population Prospects. Criteria included: 1) country-specific life tables for baseline child mortality 2) child risk of dying due to maternal loss until 10 years of age; and 3) definition of a coefficient “Q” = the multiplicative contextual increase in all cause mortality. Bangladesh and Denmark served as two benchmark populations, and coefficient Q was varied. Sensitivity analyses were performed in five nations with the highest breast or cervical mortality. The outcome measurement is relative mortality increase (RMI), such that a value of 2% denotes for every 100 women succumbing to disease, 2 children die in association. Results: Benchmark cases illustrate RMIs of 0.83% in Bangladesh and 0.01% and in Denmark. For 19,012 estimated maternal deaths, Bangladeshi absolute mortality increase equals 154 child deaths. Sensitivity analyses in nations with high burden of disease illustrate RMIs as high as 7.2% in Nigeria and 5.6% in Malawi. Conclusions: Current cause-specific mortality rates ignore child deaths in association with maternal deaths and under-allocate resources due to underestimation of effect. This model serves as a means to accurately reflect disease burden and as a guide for policymakers.
Aberrant Expansion and Function of Follicular Helper T Cell Subsets in IgG4‐Related Disease
Authors: Yu Chen, Wei Lin, Hongxian Yang, Mu Wang, Panpan Zhang, Ruie Feng, Hua Chen, Linyi Peng, Xuan Zhang, Yan Zhao, Xiaofeng Zeng, Fengchun Zhang, Wen Zhang, Peter E. Lipsky
Journal: Arthritis & Rheumatology (2018)

Objective To determine the number and function of follicular helper T (Tfh) cell subsets in IgG4‐related disease (IgG4‐ RD ). Methods Mononuclear cells from the peripheral blood and involved tissue of patients with IgG4‐ RD were assessed for Tfh cells and their subsets, and levels of B cell lymphoma 6 (Bcl‐6), B lymphocyte–induced maturation protein 1 ( BLIMP ‐1), and interleukin‐21 ( IL ‐21) messenger RNA ( mRNA ). Immunohistochemical and immunofluorescence techniques were used to assess the involved tissue of patients to determine the location of IL ‐21, Bcl‐6, and CD 4+ CXCR 5+ Tfh cells. Furthermore, the ability of circulating Tfh ( cT fh) cell subsets to induce B cell proliferation, apoptosis, and differentiation and to produce IgG4 was explored in cell cocultures in vitro. Results Frequencies of cT fh cells were significantly increased in the peripheral blood of patients with IgG4‐ RD , and even higher frequencies were observed in the involved tissue. Percentages of programmed cell death protein 1 in CD 4+ CXCR 5+ ICOS + cT fh cells were positively correlated with the serum levels of IgG and IgG4, IgG4:IgG ratio, number of involved organs, and frequency of CD 19+ CD 24− CD 38 high plasmablasts/plasma cells. Levels of BLIMP ‐1 and IL ‐21 mRNA in peripheral CD 4+ T cells were increased in patients with IgG4‐ RD compared to healthy controls, and this was correlated with the levels of serum IgG4. Moreover, in the involved tissue, Bcl‐6, IL ‐21, and Tfh cells were highly expressed. Compared to cT fh cells from healthy controls, cT fh cells from patients with IgG4‐ RD could facilitate B cell proliferation and inhibit B cell apoptosis more efficiently, and enhanced the differentiation of naive B cells into switched memory B cells and plasmablasts/plasma cells, with a resultant increase in the secretion of IgG4. Notably, the cTfh1 and cTfh2 cell subsets were the most effective at providing B cell help. Conclusion Tfh cell subsets are expanded in IgG4‐ RD and may play pivotal roles in the pathogenesis of the disease.
Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).
Authors: Erkut Hasan Borazanci, Carol Guarnieri, Susan Haag, Ronald Lee Korn, Courtney Edwards Snyder, Kristin Hendrickson, Lana Caldwell, Daniel D. Von Hoff
Journal: Journal of Clinical Oncology (2018)

389 Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.
Mitigating SOX2-potentiated Immune Escape of Head and Neck Squamous Cell Carcinoma with a STING-inducing Nanosatellite Vaccine
Authors: Yee Sun Tan, Kanokwan Sansanaphongpricha, Yuying Xie, Christopher R. Donnelly, Xiaobo Luo, Blake R. Heath, Xinyi Zhao, Emily Bellile, Hongxiang Hu, Hongwei Chen, Peter J. Polverini, Qianming Chen, Simon Young, Thomas E. Carey, Jacques E. Nör, Robert L. Ferris, Gregory T. Wolf, Duxin Sun, Yu L. Lei
Journal: Clinical Cancer Research (2018)

Purpose: The response rates of Head and Neck Squamous Cell Carcinoma (HNSCC) to checkpoint blockade are below 20%. We aim to develop a mechanism-based vaccine to prevent HNSCC immune escape.Experimental Design: We performed RNA-Seq of sensitive and resistant HNSCC cells to discover central pathways promoting resistance to immune killing. Using biochemistry, animal models, HNSCC microarray, and immune cell deconvolution, we assessed the role of SOX2 in inhibiting STING-type I interferon (IFN-I) signaling-mediated antitumor immunity. To bypass SOX2-potentiated STING suppression, we engineered a novel tumor antigen-targeted nanosatellite vehicle to enhance the efficacy of STING agonist and sensitize SOX2-expressing HNSCC to checkpoint blockade.Results: The DNA-sensing defense response is the most suppressed pathway in immune-resistant HNSCC cells. We identified SOX2 as a novel inhibitor of STING. SOX2 facilitates autophagy-dependent degradation of STING and inhibits IFN-I signaling. SOX2 potentiates an immunosuppressive microenvironment and promotes HNSCC growth in vivo in an IFN-I-dependent fashion. Our unique nanosatellite vehicle significantly enhances the efficacy of STING agonist. We show that the E6/E7-targeted nanosatellite vaccine expands the tumor-specific CD8+ T cells by over 12-fold in the tumor microenvironment and reduces tumor burden. A combination of nanosatellite vaccine with anti-PD-L1 significantly expands tumor-specific CTLs and limits the populations expressing markers for exhaustion, resulting in more effective tumor control and improved survival.Conclusions: SOX2 dampens the immunogenicity of HNSCC by targeting the STING pathway for degradation. The nanosatellite vaccine offers a novel and effective approach to enhance the adjuvant potential of STING agonist and break cancer tolerance to immunotherapy. Clin Cancer Res; 24(17); 4242-55. ©2018 AACR.
High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling
Authors: Takuji Hayashi, Kazutoshi Fujita, Satoshi Nojima, Yujiro Hayashi, Kosuke Nakano, Yu Ishizuya, Cong Wang, Yoshiyuki Yamamoto, Toshiro Kinouchi, Kyosuke Matsuzaki, Kentaro Jingushi, Taigo Kato, Atsunari Kawashima, Akira Nagahara, Takeshi Ujike, Motohide Uemura, Maria Del Carmen Rodriguez Pena, Jennifer B. Gordetsky, Eiichi Morii, Kazutake Tsujikawa, George J. Netto, Norio Nonomura
Journal: Clinical Cancer Research (2018)

Purpose: High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation.Experimental Design: We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre+;Pten(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. IHC analyses using prostatectomy specimens of obese patients were performed.Results: HFD accelerated tumor growth and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib-suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated STAT3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of nonobese patients with prostate cancer.Conclusions: HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese patients with prostate cancer. IL6-mediated inflammation could be a therapeutic target for prostate cancer. Clin Cancer Res; 24(17); 4309-18. ©2018 AACR.
Abstract A31: Biallelic Dicer1 loss in endothelial cells drives angiosarcoma development
Authors: Jason A. Hanna, Catherine J. Drummond, Matthew R. Garcia, Jonathan C. Go, David Finkelstein, Jerold E. Rehg, Mark E. Hatley
Journal: Cancer Research (2018)

Abstract Angiosarcoma is an aggressive and highly metastatic vascular sarcoma with an extremely poor prognosis. Because of the rarity of the disease, the molecular drivers and optimal treatment strategies for patients remain unclear, highlighting the need for novel genetic and in vivo animal models. MicroRNAs are small RNAs that regulate gene expression and DICER1 is the RNase III endoribonuclease that processes pre-microRNAs into mature microRNAs. DICER1 and microRNAs are central to numerous cellular processes and are often dysregulated in many cancers, including sarcomas. Here we show that biallelic Dicer1 deletion with endothelial expression of aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/- mice histologically and genetically resemble human angiosarcoma, and we found microRNA-23 target genes enriched in mouse and human angiosarcoma. Because Ras mutations and Cdkn2a loss are common in angiosarcoma, we interrogated them as angiosarcoma modifiers. Interestingly, we found that both oncogenic LSL-KrasG12D and loss of conditional Cdkn2aFlox decreased tumor latency. In addition, aP2-Cre;LSL-KrasG12D;Cdkn2aFlox/Flox mice developed angiosarcomas, providing a model with Dicer1 expression intact to further study the function of microRNAs in angiosarcoma. Thus, these findings illustrate that Dicer1 can function as a traditional loss-of-function tumor-suppressor gene and provide simple and fully penetrant animal models for the study of angiosarcoma development and metastasis. Citation Format: Jason A. Hanna, Catherine J. Drummond, Matthew R. Garcia, Jonathan C. Go, David Finkelstein, Jerold E. Rehg, Mark E. Hatley. Biallelic Dicer1 loss in endothelial cells drives angiosarcoma development [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A31.