tbuckley/cabot-search huggingface dataset:
Abstract 5200: Preclinical model of patient-derived tumor xenograft in humanized mice
Authors: Annika Wulf-Goldenberg, Maria Stecklum, Iduna Fichtner, Jens Hoffmann
Journal: Cancer Research (2016)

Abstract Human patient-derived xenografts (PDX) from different tumor indications transplanted on immunodeficient mice have demonstrated strong predictive power for many drug development programs in cancer research. However, one caveat of PDX models is that they lack a functional immune system, which allows tumor engraftment in the xenogenic host mice. Immunotherapy has emerged as one of the most promising avenues for cancer therapy. For translating immunotherapies into the clinics preclinical animal models are needed which harbor human immune cell repertoire for rising an immune response. To overcome these constraints our aim is the development of PDX models on mice with a functional human immune system to improve predictability of drug efficacy and safety. We reconstituted a human immune system in mice by engrafting human hematopoietic stem cells in immunodeficient mice. We were able to demonstrate that in the mice a full set of human immune cells, including T cells, B cells, NK cells, monocytes and dendritic cells can be analyzed by flow cytometry. At the time when the human immune system was developed, established patient-derived tumors were transplanted on these reconstituted humanized mice. PDX from different tumor entities were transplanted. The tumors are growing on these humanized mice either similar to non humanized mice or slightly slower. During the observation period no rejections by the human immune cells were evident, although tumor growth was accompanied by an increase of human T cells in the peripheral blood. Ex vivo analysis will be performed demonstrating the cytotoxicity of these T cells and the functionality of the human immune cells. Humanized mice bearing various PDX tumors were treated with therapeutic checkpoint inhibitors. Ipilimumab that target the CTLA-4 receptor lead to a slight tumor growth delay and an increased percentage of T cells in the blood and in the tumor. Nivolumab that targets the PD-1 receptor showed similar results. The combination of both inhibitors showed a synergistic effect which lead to a greater tumor growth inhibition. Our humanized mouse models enable appropriate preclinical assessment of immune-based therapeutic anti-tumor strategies especially when combing the humanized mouse with patient-derived tumor xenografts. Citation Format: Annika Wulf-Goldenberg, Maria Stecklum, Iduna Fichtner, Jens Hoffmann. Preclinical model of patient-derived tumor xenograft in humanized mice. [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 5200.
Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer (mCRC): AIO KRK-0104 trial.
Authors: V. Heinemann, L. Fischer von Weikersthal, U. Vehling-Kaiser, M. Stauch, H. Hass, H. F. Dietzfelbinger, D. V. Oruzio, S. Klein, K. Zellmann, T. Decker, M. Schulze, W. Abenhardt, G. Puchtler, H. W. Kappauf, J. Mittermueller, C. Haberl, C. A. Giessen, N. Moosmann, S. Stintzing
Journal: Journal of Clinical Oncology (2011)

3589 Background: The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of two capecitabine-based regimens: CAPIRI plus cetuximab (CAPIRI-C) and CAPOX plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment related skin toxicity was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed skin toxicity (Cape-ST) and parameters of treatment efficacy. Methods: mCRC patients were randomized to cetuximab (400mg/m2 day 1, followed by 250mg/m2 weekly) plus CAPIRI (irinotecan 200mg/m2, day 1; capecitabine 800mg/m2 twice daily, days 1-14, every 3 weeks) or cetuximab plus CAPOX (oxaliplatin 130mg/m2 day 1; capecitabine 1000mg/m2 twice daily, days 1-14, every 3 weeks). Results: Of 185 recruited patients, 149 patients (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumor assessment and were evaluable for efficacy. While cetuximab-specific skin toxicity such as acneiform rash, dry skin and others occurred in >90% of patients, Cape-ST, predominantly hand-foot syndrome, was observed in only 33.2% of patients. No Cape-ST grade 4 was documented. Cape-ST grade 1-3 was associated with a significantly higher CR rate (13.9% vs 2.1%, p=0.038) and disease control rate (DCR) (97.9% vs 86.1%, p=0.038) compared to grade 0 toxicity. Moreover, Cape-ST grade 1-3 related to a markedly longer PFS (9.9 vs 5.6 months, p<0.001) and OS (32.8 vs 22.4 months, p=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for the CAPIRI-C arm (8.5 vs 5.2 months, p=0.011) and the CAPOX-C arm (9.9 vs 6.5 months, p=0.004), while the effect on OS remained apparent as a strong trend for the CAPIRI-C arm (32.0 vs 19.7 months, p=0.125) and the CAPOX-C arm (37.5 vs 24.0 months, p=0.056). Conclusions: This analysis supports the hypothesis that for the evaluated regimens a correlation exists between capecitabine-specific skin toxicity and treatment efficacy regarding DCR, PFS and OS.
Estimated Costs of Sporadic Gastrointestinal Illness Associated with Surface Water Recreation: A Combined Analysis of Data from NEEAR and CHEERS Studies
Authors: Stephanie DeFlorio-Barker, Timothy J. Wade, Rachael M. Jones, Lee S. Friedman, Coady Wing, Samuel Dorevitch
Journal: Environmental Health Perspectives (2016)

The burden of illness can be described by addressing both incidence and illness severity attributable to water recreation. Monetized as cost, attributable disease burden estimates can be useful for environmental management decisions.We characterize the disease burden attributable to water recreation using data from two cohort studies using a cost of illness (COI) approach and estimate the largest drivers of the disease burden of water recreation.Data from the NEEAR study, which evaluated swimming and wading in marine and freshwater beaches in six U.S. states, and CHEERS, which evaluated illness after incidental-contact recreation (boating, canoeing, fishing, kayaking, and rowing) on waterways in the Chicago area, were used to estimate the cost per case of gastrointestinal illness and costs attributable to water recreation. Data on health care and medication utilization and missed days of work or leisure were collected and combined with cost data to construct measures of COI.Depending on different assumptions, the cost of gastrointestinal symptoms attributable to water recreation are estimated to be $1,220 for incidental-contact recreation (range $338-$1,681) and $1,676 for swimming/wading (range $425-2,743) per 1,000 recreators. Lost productivity is a major driver of the estimated COI, accounting for up to 90% of total costs.Our estimates suggest gastrointestinal illness attributed to surface water recreation at urban waterways, lakes, and coastal marine beaches is responsible for costs that should be accounted for when considering the monetary impact of efforts to improve water quality. The COI provides more information than the frequency of illness, as it takes into account disease incidence, health care utilization, and lost productivity. Use of monetized disease severity information should be included in future studies of water quality and health. Citation: DeFlorio-Barker S, Wade TJ, Jones RM, Friedman LS, Wing C, Dorevitch S. 2017. Estimated costs of sporadic gastrointestinal illness associated with surface water recreation: a combined analysis of data from NEEAR and CHEERS Studies. Environ Health Perspect 125:215-222; http://dx.doi.org/10.1289/EHP130.
Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)
Authors: Donna Niedzwiecki, Wendy L. Frankel, Alan P. Venook, Xing Ye, Paula N. Friedman, Richard M. Goldberg, Robert J. Mayer, Thomas Anthony Colacchio, Jude Marie Mulligan, Timothy S. Davison, Eamonn O’Brien, Peter Kerr, Patrick G. Johnston, Richard D. Kennedy, D. Paul Harkin, Richard L. Schilsky, Monica M. Bertagnolli, Robert S. Warren, Federico Innocenti
Journal: Journal of Clinical Oncology (2016)

Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.
Outcome of Patients with Myelodysplastic Syndrome (MDS) with Bone Marrow (BM) Blasts Between 10 to 30% Treated with Hypomethylating Agents Versus Intensive Chemotherapy
Authors: Aziz Nazha, Hagop M. Kantarjian, Jorge E. Cortes, Stefan Faderl, Sherry A. Pierce, Naval G. Daver, Naveen Pemmaraju, Farhad Ravandi, Gautam Borthakur, Tapan M. Kadia, Alfonso Quintas-Cardama, Guillermo Garcia-Manero
Journal: Blood (2012)
Abstract 5173: Role of Gli2 in mediating the progression of prostate cancer to CRPC
Authors: Lu Xia, Tai Qin, Luzhe Sun
Journal: Cancer Research (2016)

Abstract Background: Prostate cancer is a leading cause of cancer-related death in the US men, largely due to the development of castration resistant prostate cancer (CRPC) in the patients treated with androgen deprivation therapy. There is increasing evidence indicating that Hedgehog pathway is involved in the malignancy of prostate cancer, which includes the finding of two prostate tumors with loss-of-function mutations in the SuFu gene, correlation of tumor grade with high expression of Sonic hedgehog, Gli2 and/or hedgehog target genes including Ptch1 and HIP, and increased Gli2 expression in therapy-resistant tumor cells from patients. In addition, treatment of mice with hedgehog inhibitors significantly attenuated the growth of prostate tumor xenografts. Some recent studies also implicated a crosstalk between Hedgehog/Gli signaling and androgen signaling pathways in prostate cancer. However, the role of Gli2 in CRPC progression has not been investigated. Methods: A human Gli2 specific small hairpin RNA (shRNA) expression vector was constructed using Tet-PLKO-puro lentivector, which was delivered into the androgen-dependent human prostate cancer LNCaP cells. RT-PCR, Western Blot and Luciferase Reporter Assay were performed to confirm doxycycline-inducible Gli2 knockdown. The effect of Gli2 knockdown on anchorage-dependent or -independent growth was assessed with MTT and Soft Agar Assays respectively. Cells were cultured in androgen depleted medium or treated with the anti-androgen, Casodex, to mimic androgen deprivation condition. Mouse xenograft models were used to assess the role of Gli2 in the development of CRPC in vivo. Results: Androgen deprivation promoted the expression of Hedgehog signaling components including Gli2 in the LNCaP cells. Gli2 knockdown inhibited anchorage-dependent and -independent growth of LNCaP cells. Casodex complemented the inhibition of Gli2 knockdown on the growth of LNCaP cells. Gli2 knockdown prevented the outgrowth of androgen-independent cells from LNCaP cells cultured in androgen depleted medium. Induced-knockdown of Gli2 by doxycycline inhibited the growth of castration-resistant tumors in vivo in mice. Conclusions: Our study demonstrated the important role of Gli2 in the development of CRPC. Therefore, it may have the potential to serve as a novel therapeutic target for the prevention of CRPC. Citation Format: Lu Xia, Tai Qin, Luzhe Sun. Role of Gli2 in mediating the progression of prostate cancer to CRPC. [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 5173.
Global Disparities of Hypertension Prevalence and Control
Authors: Katherine T. Mills, Joshua D. Bundy, Tanika N. Kelly, Jennifer E. Reed, Patricia M. Kearney, Kristi Reynolds, Jing Chen, Jiang He
Journal: Circulation (2016)

Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010.We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates.In 2010, 31.1% (95% confidence interval, 30.0%-32.2%) of the world's adults had hypertension; 28.5% (27.3%-29.7%) in high-income countries and 31.5% (30.2%-32.9%) in low- and middle-income countries. An estimated 1.39 (1.34-1.44) billion people had hypertension in 2010: 349 (337-361) million in high-income countries and 1.04 (0.99-1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries.Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries.
Caregiver Perspectives on End-of-Life Experiences of Patients With Left Ventricular Assist Devices—Reply
Authors: Colleen K. McIlvennan, Larry A. Allen, Daniel D. Matlock
Journal: JAMA Internal Medicine (2016)

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Overall survival (OS) of advanced colorectal cancer (aCRC) patients (pts) treated with the multipeptide vaccine IMA910: Results of a matched-pair analysis with arm C pts from COIN.
Authors: Tim Maughan, Richard A. Adams, Andrea Mayer-Mokler, Elzbieta Nowara, Laszlo Torday, Jozsef Cseh, Thomas Hoehler, Erika Hitre, Gunnar Folprecht, David Fisher, Joerg Ludwig, Bernhard Roessler, Sabrina Kuttruff, Steffen Walter, Norbert Hilf, Oliver Schoor, Toni Weinschenk, Harpreet Singh, Carsten Reinhardt, Frank Mayer
Journal: Journal of Clinical Oncology (2012)

3530 Background: IMA910 is a novel cancer vaccine consisting of 10 class I and 3 class II tumor-associated peptides (TUMAPs), naturally presented on HLA molecules of CRC. Vaccine-induced immune responses are associated with prolonged OS of renal cell carcinoma pts treated with IMA901, a multi-peptide vaccine identified by the same antigen discovery platform. Methods: 92 HLA-A*02+ aCRC pts with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After immunomodulation with cyclophosphamide (300 mg/m 2 ) to reduce regulatory T cells, pts were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod. Safety and PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of IMA910 pts was compared to matched pts from arm C (intermittent chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011]. Matching was performed in a prospectively defined, fully blinded fashion based on a propensity score involving all available prognostic factors. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs, OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1 matched HLA-A*02+ COIN pts (HR 0.675, 95% CI 0.458-0.995, p=0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP responders (≥2 CD8+ and ≥2 CD4+ vaccine-induced T cells) had a significantly longer OS (HR 0.45, p=0.04) compared to matched COIN pts while non-multi-TUMAP responders showed similar OS compared to matched COIN pts (HR 0.76, p=0.22). Conclusions: OS of IMA910 pts was significantly longer in comparison to matched COIN pts with separation of survival curves at ~9 months and increasing OS difference over time. Multi-TUMAP immune responders had a significantly longer OS compared to non-multi-TUMAP responders and compared to matched COIN pts. These clinical and immune response data strongly suggest clinical activity of IMA910 in 1st line CRC pts and warrant further development.
Abstract 4495: Development and clinical application of an integrative genomic approach to personalized cancer therapy
Authors: Rong Chen
Journal: Cancer Research (2016)

Abstract We implemented a personalized cancer therapy (PCT) program in a clinical setting, applying an integrative genomics approach to maximally elucidate the complexity of each tumor. For patients in the study, we performed whole exome sequencing and SNP microarrays on tumor and patient-matched normal samples, as well as RNA sequencing on available frozen samples, to identify somatic mutations, copy number alterations, gene fusions, and gene expression alterations in the tumor. Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was used to ensure high sensitivity in cancer mutation hotspots. Genomics results were integrated with cancer knowledge databases and for each cancer type a specific workflow was developed to optimize data interpretation. We returned genomics findings to 46 patients and their physicians, characterizing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-, 6.9-, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91% of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in 4 cases. These results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics-based personalized cancer therapy strategies. Citation Format: Rong Chen. Development and clinical application of an integrative genomic approach to personalized 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 4495.
Multicentre experience using daclatasvir and sofosbuvir to treat hepatitis C recurrence – The ANRS CUPILT study
Authors: Audrey Coilly, Claire Fougerou-Leurent, Victor de Ledinghen, Pauline Houssel-Debry, Christophe Duvoux, Vincent Di Martino, Sylvie Radenne, Nassim Kamar, Louis D’Alteroche, Vincent Leroy, Valérie Canva, Pascal Lebray, Christophe Moreno, Jérôme Dumortier, Christine Silvain, Camille Besch, Philippe Perre, Danielle Botta-Fridlund, Rodolphe Anty, Claire Francoz, Armando Abergel, Maryline Debette-Gratien, Filomena Conti, François Habersetzer, Alexandra Rohel, Emilie Rossignol, Hélène Danjou, Anne-Marie Roque-Afonso, Didier Samuel, Jean-Charles Duclos-Vallée, Georges-Philippe Pageaux
Journal: Journal of Hepatology (2016)
Early event status informs subsequent outcome in newly diagnosed follicular lymphoma
Authors: Matthew J. Maurer, Emmanuel Bachy, Hervé Ghesquières, Stephen M. Ansell, Grzegorz S. Nowakowski, Carrie A. Thompson, David J. Inwards, Cristine Allmer, Catherine Chassagne‐Clément, Emmanuelle Nicolas‐Virelizier, Catherine Sebban, Laure Lebras, Clementine Sarkozy, William R. Macon, Andrew L. Feldman, Sergei I. Syrbu, Alexandra Traverse‐Glehan, Bertrand Coiffier, Susan L. Slager, George J. Weiner, Thomas E. Witzig, Thomas M. Habermann, Gilles Salles, James R. Cerhan, Brian K. Link
Journal: American Journal of Hematology (2016)

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event-free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1-3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re-treatment, or death due to any cause. OS was compared to age-and-sex-matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78-4.88; Lyon SMR = 8.74, 95%CI: 5.41-13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56-0.94, Lyon SMR = 1.02, 95%CI: 0.58-1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97-25.02, Lyon SMR = 19.10, 95%CI:9.86-33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31-17.74, Lyon SMR = 7.22, 95%CI:4.13-11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096-1101, 2016. © 2016 Wiley Periodicals, Inc.