tbuckley/cabot-search huggingface dataset:
First results of safety profile of nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in II and III line of patients (pts) with metastatic renal cell carcinoma (mRCC) in NIVES study
Authors: C. Masini, P. Ciammella, G. Timon, R. Gnoni, U.F.F. De Giorgi, S.R. Bellia, S. Buti, F. Salaroli, M. Milella, R. Mazzarotto, C. Mucciarini, M.G. Vitale, A. Bruni, G. Procopio, S. Kinspergher, F. Nole, F. Morelli, G. Pappagallo, C. buttigliero, C. Pinto
Journal: Annals of Oncology (2019)
Inducible T cell costimulatory (ICOS) receptor agonist, GSK3359609 (GSK609) alone and in combination with pembrolizumab (pembro): Preliminary results from INDUCE-1 expansion cohorts (EC) in head and neck squamous cell carcinoma (HNSCC)
Authors: D. Rischin, S.L. Groenland, A.M.L. Lim, J. Martin-Liberal, V. Moreno, J.M. Trigo Perez, C. Le Tourneau, M. Mathew, D.C. Cho, A.R. Hansen, D. Vincente-Baz, M. Maio, A. Italiano, J.R. Bauman, M. Chisamore, H. Zhou, C. Ellis, M. Ballas, A. Hoos, E. Angevin
Journal: Annals of Oncology (2019)
A retrospective gene expression analysis of surgically-removed breast cancer brain metastasis (BCBM)
Authors: M. Mallafré-Larrosa, T. Pascual, N. Chic, O. Martínez, P. Galvan, B. Gonzalez-Farre, M. Vidal, M. Muñoz, B. Adamo, A. Prat
Journal: Annals of Oncology (2019)
Trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy in resectable HER2+ esophageal adenocarcinoma patients: An update on survival and predictive biomarkers in the TRAP study
Authors: C.I. Stroes, A. Creemers, R.J. Bennink, S. Schokker, R.H.A. Verhoeven, S.L. Meijer, K.K. Krisnadath, M. van Oijen, G.-J. Creemers, M.J.C. van der Sangen, L.V. Beerepoot, J. Heisterkamp, M. Los, M. Slingerland, A. Cats, G.A.P. Hospers, M. Bijlsma, M.I. van Berge Henegouwen, M. Hulshof, H.W.M. van Laarhoven
Journal: Annals of Oncology (2019)
IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC
Authors: D. Spigel, F. de Marinis, G. Giaccone, N. Reinmuth, A. Vergnenegre, C.H. Barrios, M. Morise, E. Felip, Z.G. Andric, S. Geater, M. Özgüroğlu, S. Mocci, M. McCleland, I. Enquist, K.M. Komatsubara, Y. Deng, H. Kuriki, X. Wen, J. Jassem, R.S. Herbst
Journal: Annals of Oncology (2019)
Screening for psychosocial distress in recently diagnosed cancer patients
Authors: E. Baillès, P. Romero, G. Simo, M. Rosdevall, S. Echavarria, M. Riu, E. Mahia, A. Berenguer, C. Royo, J. Pujadas Olano, F. Cobo, G. Garcia-Pares, S. Albiol Rodriguez
Journal: Annals of Oncology (2019)
High-sensitivity troponin as a cardiotoxicity biomarker in breast cancer treatment
Authors: J. Simões, N.T. Tavares, C. Borges, R. Pinto, M. Silva, M. Paiva, C. Sousa, I. Sousa, D. Almeida, I. Augusto, C. Caeiro, S.R. Meireles
Journal: Annals of Oncology (2019)
OncotypeDX® predictive nomogram for recurrence score output: A machine learning system based on quantitative immunochemistry analysis - ADAPTED01
Authors: F. Marazzi, V. Masiello, R. Barone, V. Magri, A. Mulé, A. Santoro, F. Cacciatori, L. Boldrini, G. Franceschini, F. Moschella, G. Naso, S. Tomao, G. Mantini, R. Masetti, D. Smaniotto, V. Valentini
Journal: Annals of Oncology (2019)
Frequency of epidermal growth factor receptor (EGFR) mutations in stage IB–IIIA EGFR mutation positive non-small cell lung cancer (NSCLC) after complete tumour resection
Authors: M. Tsuboi, R.S. Herbst, T. John, C. Grohe, M. Majem, J.W. Goldman, S.-W. Kim, C.-J. Yu, J.E.A. Miziara, S. Novello, D. Urban, C. Akewanlop, A. Öztürk, B.V. Quang, D. Kowalski, D. Marmol, M. Marotti, G. Laus, Y.-L. Wu
Journal: Annals of Oncology (2019)
Characterization of atypical dMMR (deficient MisMatch Repair) tumors: A study from a large cohort of 4948 cases
Authors: M. Jaffrelot, J. Selves, N. Fares, A. Staub, A.P. Laurenty, M. Danjoux, J. Meilleroux, E. Chipoulet, C. Toulas, R. Guimbaud
Journal: Annals of Oncology (2019)
Cell-free tumour-DNA (cfDNA) as a very early predictor of therapeutic outcome in pancreatic ductal adenocarcinoma (PDAC)
Authors: S. Payr, J. Bergelin, J. Beck, T. Dragovich, A. Azizian, M. Brunner, U. König, B. Naraev, V. Ellenrieder, J. Gaedcke, E. Schütz, M.N. Kundranda, A.-O. König
Journal: Annals of Oncology (2019)
Effectiveness of sequencing TKIs in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC): A French national medical-administrative claim database analysis
Authors: N. Girard, S. Bouee, D. Moro-Sibilot, C. Emery, K Le Lay, L. Luciani, C. Maritaz, C. Chouaid
Journal: Annals of Oncology (2019)
Hypomethylation of Tumor Suppressor Genes in Acute Myeloid Leukemia: Characteristic of Cell Lines with MLL Abnormalities?.
Authors: Hilmar Quentmeier, Sonja Röhrs, Wilhelm G Dirks, Claus Meyer, Rolf Marschalek, Michaela Scherr, Robert K. Slany, Andrew Wallace, Hans G. Drexler
Journal: Blood (2009)
Differences in multikinase inhibitors (MKI) toxicity profile according to gender. A pooled analysis of three phase II trials with lenvatinib, pazopanib and sorafenib in patients (pts) with advanced gastroenteropancreatic (GEP) neuroendocrine tumours (NETs)
Authors: J. Hernando Cubero, E. Grande, D. Castellano Gauna, T. Ibrahim, N. Fazio, C. Lopez, A. Teulé, J.W. Valle, V. Alonso, J. Molina-Cerrillo, S. Tafuto, A. Custodio, L. Trejo, A. Casteras, R. Manneh Kopp, C. Miqueo, M. Roca Herrera, R. Garcia-Carbonero, R. Salazar, J. Capdevila
Journal: Annals of Oncology (2019)
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study
Authors: M.A. Barbera, J. Corbelli, G. Papiani, E. Grassi, G. Ugolini, I. Montroni, M Di Bartolomeo, S. Cascinu, M. Marzola, A. Bonetti, G.L. Frassineti, O. Nanni, D. Zattoni, F. Ghignone, G. Taffurelli, C. Pinto, C Carli Moretti, G. Rossi, S. Palazzi, S. Tamberi
Journal: Annals of Oncology (2019)
High Frequency of CD74 Expression in B-Cell Non-Hodgkin's Lymphoma (NHL) and Targeting with SΤRO-001, a Novel Anti-CD74 Antibody Drug Conjugate (ADC) with Potent I n Vitro Cytotoxicty and In Vivo Anti-Tumor Activity
Authors: Abigail Yu, Cristina Abrahams, Millicent Embry, Xiaofan Li, Shuchun Zhao, Robert Henningsen, Venita DeAlmeida, Shannon Matheny, Toni Kline, Alice Yam, Ryan Stafford, Yasodha Natkunam, Trevor Hallam, Mark Lupher, Arturo Molina
Journal: Blood (2017)
A crosslinked polymer skin barrier film for moderate to severe atopic dermatitis: A pilot study in adults
Authors: Melaney Bouthillette, Daniela Beccati, Ariya Akthakul, Nithin Ramadurai, Amir Nashat, Robert Langer, R. Rox Anderson, Fernanda H. Sakamoto
Journal: Journal of the American Academy of Dermatology (2019)
A clonal expression biomarker associates with lung cancer mortality
Authors: Dhruva Biswas, Nicolai J. Birkbak, Rachel Rosenthal, Crispin T. Hiley, Emilia L. Lim, Krisztian Papp, Stefan Boeing, Marcin Krzystanek, Dijana Djureinovic, Linnea La Fleur, Maria Greco, Balázs Döme, János Fillinger, Hans Brunnström, Yin Wu, David A. Moore, Marcin Skrzypski, Christopher Abbosh, Kevin Litchfield, Maise Al Bakir, Thomas B. K. Watkins, Selvaraju Veeriah, Gareth A. Wilson, Mariam Jamal-Hanjani, Judit Moldvay, Johan Botling, Arul M. Chinnaiyan, Patrick Micke, Allan Hackshaw, Jiri Bartek, Istvan Csabai, Zoltan Szallasi, Javier Herrero, Nicholas McGranahan, Charles Swanton
Journal: Nature Medicine (2019)
Abstract 17056: High-Throughput Physiological Assay for Force and Stiffness Quantification in IPS Derived Cardiomyocytes
Authors: Ricardo Serrano, Wesley L McKeithan, Mark Mercola, Juan C del Álamo
Journal: Circulation (2018)

Introduction: Cardiovascular disease persists as one of the leading causes of death in the U.S. Physiological assays with iPSC-cardiomyocytes have been quickly adopted for cardiac drug discovery, and the study of cardiac disease in vitro. Whereas most of these assays focus on the kinematics of voltage and calcium, assays that quantify contraction forces are less common. Moreover, there is no current high-throughput method to characterize the passive elastic properties of cardyomyocytes that contribute to dyastolic function. Methods and Results: We have developed a method to measure and characterize force of contraction and stiffness of beating cardiomyocytes, solely based on optical measurements. First, we created a device consisting of 96 well plates with soft deformable polyacrylamide gels, doped with fluorescent beads (A). IPSc cardiomyocytes are seeded on the gels and stained with Wheat Germ Agluttining (WGA). We then acquire videos of both membrane and beads (B). Our algorithm processes the videos with Particle Image Velocimetry to obtain instantaneous deformation fields on the cells (C) and the gel. Next, the traction stresses at the cell-substrate interface (D) are computed using Traction Force Microscopy, and the intracellular monolayer stress using Monolayer Stress Microscopy. Our algorithm computes temporal traces of strain on the cells (E), traction forces on the gel (F), and retrieve relevant parameters that characterize the signal (G). The elastic modulus of the cells is inferred by fitting the relationship between the measured intracellular stress and strain maps. We have validated our analysis by performing dose response curves on cardiomyocytes treated with isoproterenol, mavacamten, and omecamtiv mecarbil (H). Conclusions: To our knowledge, we present the first method that measures force and elasticity of cardiomyocytes in a high-throughput set-up, as well as a novel device that allows for the execution of such experiments.
A pilot study of oral paclitaxel (ORAXOL) in subjects with cutaneous angiosarcomas (KX-ORAX-010)
Authors: H H-F Loong, R. Mennel, M. Wagner, T. Tse, Y.-M. Lau, C.S.F. Yuen, R. Moore, M-F R Kwan, D. Cutler, D. Kramer, W.-K. Chan, V. Ravi
Journal: Annals of Oncology (2019)
Hypertension and incident cardiovascular events following ibrutinib initiation
Authors: Tyler Dickerson, Tracy Wiczer, Allyson Waller, Jennifer Philippon, Kyle Porter, Devin Haddad, Avirup Guha, Kerry A. Rogers, Seema Bhat, John C. Byrd, Jennifer A. Woyach, Farrukh Awan, Daniel Addison
Journal: Blood (2019)
Filamentation initiated by Cas2 and its association with the acquisition process in cells
Authors: Lei Wang, Xin Yu, Mengjie Li, Guiqin Sun, Lin Zou, Tiansheng Li, Linlin Hou, Yameng Guo, Danfeng Shen, Di Qu, Xunjia Cheng, Li Chen
Journal: International Journal of Oral Science (2019)

Abstract Cas1-and-Cas2-mediated new spacer acquisition is an essential process for bacterial adaptive immunity. The process is critical for the ecology of the oral microflora and oral health. Although molecular mechanisms for spacer acquisition are known, it has never been established if this process is associated with the morphological changes of bacteria. In this study, we demonstrated a novel Cas2-induced filamentation phenotype in E. coli that was regulated by co-expression of the Cas1 protein. A 30 amino acid motif at the carboxyl terminus of Cas2 is necessary for this function. By imaging analysis, we provided evidence to argue that Cas-induced filamentation is a step coupled with new spacer acquisition during which filaments are characterised by polyploidy with asymmetric cell division. This work may open new opportunities to investigate the adaptive immune response and microbial balance for oral health.
Real-world 1-year survival analysis of patients with metastatic breast cancer with liver or lung metastasis treated with eribulin, gemcitabine or capecitabine
Authors: S.M. Kazmi, D. Chatterjee, K. Alexis, D. Raju, E. Wang, R.L. Knoth, R.S. Hauser, P.A. Kaufman
Journal: Annals of Oncology (2019)
Oral Dosing of the Novel Proteasome Inhibitor CEP-18770 Shows Marked Anti-Myeloma Effects in SCID-Hu Models of Multiple Myeloma.
Authors: Eric Sanchez, Mingjie Li, Jeffrey A Steinberg, Cathy S Wang, Jing Shen, Benjamin Bonavida, Zhi-Wei Li, Haiming Chen, James R. Berenson
Journal: Blood (2009)
Monoallelic Deletion of the Whole Locus of Immunoglobulin Heavy Chain Gene [Del(IGH)] Is Associated with a Better Prognosis in Newly Diagnosed Multiple Myeloma
Authors: Luba Trakhtenbrot, Adrian Duek, Ninette Amariglio, Abraham Avigdor, Noam Benyamini, Izhar Hardan, Itay Zilbershatz, Chezi Ganzel, Olga Shvetz, Ronit Leiba, Marina Izak, Cohen Ziv, Gabriela Rozic, Arnon Nagler, Merav Leiba
Journal: Blood (2017)
Abstract 1647: RAGE & HMBG1: Key Roles in Dendritic and T Cell Activation
Authors: Bernhard Moser, Shi Fang Yan, Dharmesh Desai, Yali Chen, Georg Roth, Jan Ankersmit, Rosa H Rosario, Timothy M Lightner, Kevan Herold, Ann Marie Schmidt, Raphael Clynes
Journal: Circulation (2006)
Impact of primary tumour side on 3-year survival outcomes of first-line (1L) FOLFOX-4 ± cetuximab in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase III TAILOR trial
Authors: S. Qin, T. Liu, J. Xu, Q. Li, Y. Cheng, J. Nippgen, W. Chen, J. Li
Journal: Annals of Oncology (2019)
Immune-related adverse events (irAEs) and outcome in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts) treated by immune-checkpoints inhibitors (ICI)
Authors: N. Baste Rotllan, A. Auperin, M. Iacob, A. Sampetrean, D. Bouguetta, L. Mayache Badis, F.R. Ferrand, O. Casiraghi, P. Blanchard, F. Bidault, P. Gorphe, S. Temam, S. Champiat, C. Even, A. Marabelle
Journal: Annals of Oncology (2019)
Interfacility Transfer of Medicare Beneficiaries With Acute Type A Aortic Dissection and Regionalization of Care in the United States
Authors: Andrew B. Goldstone, Peter Chiu, Michael Baiocchi, Bharathi Lingala, Justin Lee, Joseph Rigdon, Michael P. Fischbein, Y. Joseph Woo
Journal: Circulation (2019)

The feasibility and effectiveness of delaying surgery to transfer patients with acute type A aortic dissection-a catastrophic disease that requires prompt intervention-to higher-volume aortic surgery hospitals is unknown. We investigated the hypothesis that regionalizing care at high-volume hospitals for acute type A aortic dissections will lower mortality. We further decomposed this hypothesis into subparts, investigating the isolated effect of transfer and the isolated effect of receiving care at a high-volume versus a low-volume facility.
Raman microscopy for the identification of an aggressive variant of prostate cancer, intraductal carcinoma of the prostate
Authors: D. Trudel, A.-A. Grosset, F. Dallaire, T. Nguyen, A. Kougioumoutzakis, F. Azzi, K. Aubertin, F. Saad, M. Latour, R. Albadine, P. Boutros, M. Fraser, R. Bristow, T. Van der Kwast, N. Benzerdjeb, H. Hovington, A. Bergeron, Y. Fradet, H. Brisson, F. Leblond
Journal: Annals of Oncology (2019)
Bevacizumab plus trifluridine/tipiracil in elderly patients with previously untreated metastatic colorectal cancer (KSCC 1602): A single-arm, phase II study
Authors: A. Makiyama, E. Oki, Y. Miyamoto, M. Kotaka, H. Kawanaka, K. Miwa, A. Kabashima, T. Noguchi, K. Yuge, T. Kashiwada, M. Shimokawa, H. Saeki, Y. Akagi, H. Baba, M. Mori
Journal: Annals of Oncology (2019)
Association between PIK3CA mutation status and development of brain metastases in HR+/HER2- metastatic breast cancer
Authors: D.M. Fitzgerald, A. Muzikansky, C. Pinto, L. Henderson, C. Walmsley, R. Allen, G.B. Ferraro, S. Isakoff, B. Moy, K. Oh, H.A. Shih, D. Dias-Santagata, A.J. Iafrate, A. Bardia, P.K. Brastianos, D. Juric
Journal: Annals of Oncology (2019)
Abstract 14913: Difference of Tissue Characteristics in In-stent Re-restenosis Lesions: a Comparison Between Paclitaxel-eluting Balloon Dilatation and Plain Old Balloon Angioplasty for In-stent Restenosis Lesions After Drug-eluting Stent Implantation
Authors: Takeshi Tada, Kazushige Kadota, Shunsuke kubo, Masatomo Ozaki, Misturu Yoshino, Koshi Miyake, Haruki Eguchi, Noriyuki Ohashi, Yuki Hayakawa, Naoki Saito, Suguru Otsuru, Daiji Hasegawa, Yoshikazu Shigemoto, Seiji habara, Hiroyuki Tanaka, Yasushi Fuku, Naoki Oka, Harumi Kato, Hiroyuki Yamamoto, Tsuyoshi Goto, kazuaki Mitsudo
Journal: Circulation (2011)

Background: The morphological assessment of neointimal tissue is highly significant to clarify the pathophysiology of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation. Recently...
Interim results from CompLEEment-1 (A phase IIIb study of ribociclib and letrozole as first-line therapy for advanced breast cancer in an expanded population): Spanish cohort results
Authors: J. Salvador, E.M. Ciruelos, B. Jiménez-Rodríguez, L. De La Cruz, R. Villanueva Vázquez, R. De Toro, A. Antón, F. Moreno, I. Álvarez, V. Quiroga, J. de la Haba, S. González-Santiago, N. Díaz, A. Barnadas, B. Cantos, I. Delgado Mingorance, M. Bellet Ezquerra, M. Martín, N. Martínez, E. Vicente
Journal: Annals of Oncology (2019)
A phase III study comparing SB8, a proposed bevacizumab biosimilar, and reference bevacizumab in patients with metastatic or recurrent non-squamous NSCLC
Authors: M. Reck, A. Luft, I. Bondarenko, S. Shevnia, D. Trukhin, N.V. Kovalenko, K. Vacharadze, F. Andrea, A. Hontsa, J. Choi, D. Shin
Journal: Annals of Oncology (2019)
An analysis of colorectal cancer (CRC) following a diagnosis of prostate cancer (CaP): Is it due to earlier diagnosis or increased incidence?
Authors: S. Bae, M. Asadi, J. L. Millar, I. Jones, S. McLaughlin, A. Bui, M. Steele, M. W. Chao, D. English, P. Gibbs
Journal: Journal of Clinical Oncology (2011)

1560 Background: Treatment for CaP is reported to be associated with a subsequent diagnosis of CRC, based on studies of large series of CaP patients (pts), often with short follow-up and limited detail of the CRC diagnosis. Radiation and hormonal therapy for CaP are suggested factors. Methods: Examining a comprehensive prospective CRC database, where previous cancer history is routinely recorded, we performed a detailed analysis of CRC pts with a prior diagnosis of CaP. Contemporary treatment strategies for CaP were derived from a CaP database and practice surveys. Victorian cancer registry data was also examined for expected CaP incidence. Results: Of 3935 cases of CRC diagnosed at 4 hospitals between 1998 and 2010, 2256 were male, median age 68 years (yrs) (range 16 – 96), with 69 (3.1%, median age 73) having a history of CaP, consistent with the expected rate based on registry data. Median age at diagnosis of CRC varied with CaP treatment modality, 71 yrs for pts managed with observation (n = 10), 72 yrs for hormonal therapy (n = 26), 63yrs (n = 10) for prostatectomy and 67 yrs (n = 24) for radiotherapy. This age distribution was consistent with contemporary treatment strategies for CaP. Time from diagnosis of CaP to CRC diagnosis ranged from 0.2 – 20.7 yrs, median ranged from 4.1 yrs (observation) to 6.1 yrs (surgery). There was a trend for a lower rate of metastatic CRC at presentation (8.7% vs 16.8%, p = NS) in pts with a CaP history than for all males with CRC, and a trend for an increased rate of screen detected CRC (6.2% vs 3.3%, p = NS). There was no excess of rectal cancer in pts treated with radiotherapy for their CaP (2/24 = 8.3%) compared to other modalities (18/69 = 26.1%). Stage specific survival was as expected. Conclusions: We found no evidence for an overall increased risk of CRC following a diagnosis of CaP, and no impact of individual CaP treatment modality on CRC diagnosis or outcome. Previous findings of an increased rate of CRC may be due to earlier diagnosis, rather than an increased risk of CRC, possibly due to increased participation in screening, or early investigation of symptoms or incidental findings in pts with regular medical contact. Risk of CRC should not influence treatment selection for CaP.
Bacteria and fungi in acute cholecystitis. A prospective study comparing next generation sequencing to culture
Authors: Ruben Dyrhovden, Kjell Kåre Øvrebø, Magnus Vie Nordahl, Randi M. Nygaard, Elling Ulvestad, Øyvind Kommedal
Journal: Journal of Infection (2019)

ObjectivesGuidelines for antibiotic treatment of acute cholecystitis are based on studies using culture techniques for microbial identification. Microbial culture has well described limitations and more comprehensive data on the microbial spectrum may support adjustments of these recommendations. We used next generation sequencing to conduct a thorough microbiological characterization of bile-samples from patients with moderate and severe acute cholecystitis.MethodsWe prospectively included patients with moderate and severe acute cholecystitis, undergoing percutaneous or perioperative drainage of the gall bladder. Bile samples were analyzed using both culture and deep sequencing of bacterial 16S rRNA and rpoB genes and the fungal ITS2-segment. Clinical details were evaluated by medical record review.ResultsThirty-six patients with moderate and severe acute cholecystitis were included. Bile from 31 (86%) of these contained bacteria (29) and/or fungi (5) as determined by sequencing. Culture identified only 40 (38%) of the 106 microbes identified by sequencing. In none of the 15 polymicrobial samples did culture detect all present microbes. Frequently identified bacteria often missed by culture included oral streptococci, anaerobic bacteria, enterococci and Enterobacteriaceae other than Klebsiella spp. and Escherichia coli.ConclusionsCulture techniques display decreased sensitivity for the microbial diagnostics of acute cholecystitis leaving possible pathogens undetected.
Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Authors: J.J. Grob, V.G. Atkinson, C. Robert, D. Schadendorf, P. Nathan, M.A. Davies, R. Kefford, R. Dummer, J.M. Kirkwood, K.T. Flaherty, A. Ribas, P. Burgess, E. Gasal, G.V. Long, A. Hauschild
Journal: Annals of Oncology (2019)
Molecular Imaging of Extracellular Tumor pH to Reveal Effects of Locoregional Therapy on Liver Cancer Microenvironment
Authors: Lynn Jeanette Savic, Isabel Theresa Schobert, Dana Peters, John J. Walsh, Fabian Max Laage-Gaupp, Charlie Alexander Hamm, Nina Tritz, Luzie A. Doemel, MingDe Lin, Albert Sinusas, Todd Schlachter, James S. Duncan, Fahmeed Hyder, Daniel Coman, Julius Chapiro
Journal: Clinical Cancer Research (2019)

To establish magnetic resonance (MR)-based molecular imaging paradigms for the noninvasive monitoring of extracellular pH (pHe) as a functional surrogate biomarker for metabolic changes induced by locoregional therapy of liver cancer.Thirty-two VX2 tumor-bearing New Zealand white rabbits underwent longitudinal imaging on clinical 3T-MRI and CT scanners before and up to 2 weeks after complete conventional transarterial chemoembolization (cTACE) using ethiodized oil (lipiodol) and doxorubicin. MR-spectroscopic imaging (MRSI) was employed for pHe mapping. Multiparametric MRI and CT were performed to quantify tumor enhancement, diffusion, and lipiodol coverage of the tumor posttherapy. In addition, incomplete cTACE with reduced chemoembolic doses was applied to mimic undertreatment and exploit pHe mapping to detect viable tumor residuals. Imaging findings were correlated with histopathologic markers indicative of metabolic state (HIF-1α, GLUT-1, and LAMP-2) and viability (proliferating cell nuclear antigen and terminal deoxynucleotidyl-transferase dUTP nick-end labeling).Untreated VX2 tumors demonstrated a significantly lower pHe (6.80 ± 0.09) than liver parenchyma (7.19 ± 0.03, P < 0.001). Upregulation of HIF-1α, GLUT-1, and LAMP-2 confirmed a hyperglycolytic tumor phenotype and acidosis. A gradual tumor pHe increase toward normalization similar to parenchyma was revealed within 2 weeks after complete cTACE, which correlated with decreasing detectability of metabolic markers. In contrast, pHe mapping after incomplete cTACE indicated both acidic viable residuals and increased tumor pHe of treated regions. Multimodal imaging revealed durable tumor devascularization immediately after complete cTACE, gradually increasing necrosis, and sustained lipiodol coverage of the tumor.MRSI-based pHe mapping can serve as a longitudinal monitoring tool for viable tumors. As most liver tumors are hyperglycolytic creating microenvironmental acidosis, therapy-induced normalization of tumor pHe may be used as a functional biomarker for positive therapeutic outcome.