tbuckley/cabot-search huggingface dataset:
ACTR-18. A PHASE IB/II CLINICAL TRIAL OF DODECAFLUOROPENTANE EMULSION (DDFPE) AS A RADIOSENSITIZER IN GLIOBLASTOMA
Authors: Jason Lickliter, Jeremy Ruben, Ross Jennens, Ganessan Kichenadasse, Cecelia Gzell, Ralph Mason, Raymond Carmody, Jennifer Becker, Baldassarre Stea, Heling Zhou, Michael Sellenger, Olivia Longacre, Kaitlin Graham, Evan Unger
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Tumor hypoxia decreases the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). The purpose of this study was to evaluate the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. METHODS With ethics approval and informed consent, 11 adult GBM patients were enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) within 5–30 minutes prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) while breathing supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To evaluate the reversal of tumor hypoxia, patients underwent oxygen-sensitive (TOLD) MRI before and after DDFPe administration. Patients were also studied with serial MRI scans per standard of care and followed for survival. RESULTS The non-serious adverse events considered by the investigator to be possibly, probably, or definitely related to DDFPe administration included fatigue (n=4), headache (n=2) and decrease in platelet count (n=2). Serious adverse events included two patients with symptomatic radiation necrosis: one patient at each of dose levels 0.1 and 0.17 mL/kg. Enrollment continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. Historically, the average overall survival for GBM patients is about 14.6 months. The median overall survival for the study was 591 days, or 19.4 months. According to independent review of the serial MR images, the median time to progression was 555 days, or 18 months, compared to a historical control of 6.9 months. TOLD MRI showed a trend in improved tumor oxygenation. CONCLUSION Although small, this trial shows that DDFPe used as a radiosensitizer appears to be safe and may provide some survival benefit. The FDA has allowed a Phase II clinical trial to assess its effectiveness.
Adult Case Series of Extramedullary Relapsing Acute Myeloid Leukemia (AML) after Allogeneic Stem Cell Transplantation in Whom a Rapid Response and a Reasonably Long Remission Could be Achieved with Gemtuzumab Ozogamycin (GO)
Authors: Omur Gokmen Sevindik, Ali Ihsan Gemici, Furkan Selim Usta, Asli Çakır, Sevil Sadri, Hüseyin Beköz, Fatma Deniz Sargın
Journal: Blood (2019)
Response by Hu et al to Letter Regarding Article, “Impact of the 2017 ACC/AHA Guideline for High Blood Pressure on Evaluating Gestational Hypertension–Associated Risks for Newborns and Mothers: A Retrospective Birth Cohort Study”
Authors: Jie Hu, Yuanyuan Li, Kathryn M. Rexrode, Shunqing Xu
Journal: Circulation Research (2019)
Learning from the Dead
Authors: Kevin M. De Cock, Emily Zielinski-Gutiérrez, Sebastian B. Lucas
Journal: New England Journal of Medicine (2019)

Interview with Dr. Kevin De Cock on the research and public health benefits of autopsies and other forms of postmortem investigation. (10:34)Download A striking trend in medical education and practice over the past half century has been the decline in the rate of autopsies conducted throughout much of the world. But there is much we can learn from the dead, for both clinical and public health purposes.
Translational Study of Cell Surface Proteins in Non-Hodgkin Lymphoma Patients Treated with the First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Rituximab
Authors: Roy Louis Maute, James Y Chen, Kristopher David Marjon, Jiaqi Duan, Timothy Choi, Mark Chao, Chris H Takimoto, Balaji Agoram, Jens-Peter Volkmer
Journal: Blood (2019)
INNV-03. A MICROFLUIDIC CULTURE PARADIGM FOR THE EX VIVO MAINTENANCE OF HUMAN GLIOBLASTOMA TISSUE - A NEW GBM MODEL?
Authors: Farouk Olubajo, Shailendra Achawal, Chittoor Rajaraman, Gerry O’Reilly, John Greenman
Journal: Neuro-Oncology (2019)

Abstract The genetic and molecular variations that exist within Glioblastoma (GBM) determine treatment responses. One way to improve patient outcomes is to optimise treatment(s) pre-clinically by studying each tumour on an individual basis. Presented here are the results of a pilot study on the maintenance of human GBM tissue on a microfluidic platform. The device, fabricated using a photolithographic process, was composed of two layers of glass bonded together to contain a tissue chamber and a network of microchannels. A thin mesh layer was inserted to separate the tissue chamber from the microchannels and prevented blockage of the chip. Over an 18-month period, 33 patients were recruited, and 128 tissue sections were maintained in microfluidic devices for an average of 72 hours (h). Tissue viability as measured by Annexin V and Propidium Iodide staining showed that viability was 61.1 % in tissue maintained on chip after 72 h, compared with 68.9 % for fresh tissue analysed at the commencement of the experiment (P &lt; 0.05). Other biomarkers, including Lactate Dehydrogenase (LDH) release and Trypan Blue assay, supported the viability of the tissue maintained on chip. Histological appearances of the tissue remained unchanged during the maintenance period and immunohistochemical analysis of Ki67 and Caspase 3 also showed no statistically significant differences. Analysis has shown a trend with tumours associated with poorer prognoses (e.g. recurrent tumours and IDH wildtype) displaying higher viability on chip compared to tumours linked with better outcomes (Grade 1–3 gliomas, IDH mutants and primary tumours). This work has demonstrated for the first time that human GBM tissue can be maintained ex vivo within a microfluidic device with viability comparable to fresh tissue samples. The model has the potential to be developed as a new platform for studying the biology of brain tumours, with the aim of facilitating personalised treatments.
Early Experience Using Radiotherapy As a Salvage Treatment for Relapsed or Refractory Non-Hodgkin Lymphomas Following CD19 Chimeric Antigen Receptor Modified T-Cell Therapy
Authors: Brandon Imber, M. Lia Palomba, Carl DeSelm, Parastoo B. Dahi, Craig S. Sauter, Michael Scordo, Connie Lee Batlevi, Jae H. Park, Gunjan L. Shah, Sergio A. Giralt, Miguel-Angel Perales, Michel Sadelain, Joachim Yahalom
Journal: Blood (2019)
Prognostic Implication of Inflammatory Factor-Based Staging System in Multiple Myeloma in the New Agent Era
Authors: Ji Hyun Lee, Sung-Hyun Kim, Ho-Sup Lee, Sung-Soo Yoon, Dong-Yeop Shin, Ja Min Byun, Je-Jung Lee, Sung-Hoon Jung, Chang-Ki Min, Hyo Jung Kim, Byeong Seok Sohn, Sung Hwa Bae, Lee Gyeong-Won, Sungwoo Park, Young Rok Do, Hyun Jung Lee, Min Kyoung Kim, Yoo Jin Lee
Journal: Blood (2019)
Clinical Relevance of Individual Response to Iron Chelation Therapy (ICT) in Patients with Myelodysplastic Syndromes (MDS) and Transfusion Requirement
Authors: Roberto Latagliata, Pasquale Niscola, Esther Natalie Oliva, Marta Riva, Isabella Capodanno, Antonio Volpe, Federica Pilo, Claudia Baratè, Alessia Campagna, Anna Maria Pelizzari, Antonella Poloni, Chiara Sarlo, Giovanna Mansueto, Anna Lina Piccioni, Serena Rosati, Ida Carmosino, Antonella Carbone, Lucia Tognazzi, Prassede Salutari, Annalisa Mancini, Patrizia Cuffari, Elsa Pennese, Susanna Fenu, Maria Antonietta Aloe Spiriti, Sara Galimberti, Alfredo Molteni, Enrico Balleari, Massimo Breccia, Robin Foà, Luca Maurillo, Carlo Finelli
Journal: Blood (2019)
Ultrafast discrimination of Gram-positive bacteria and highly efficient photodynamic antibacterial therapy using near-infrared photosensitizer with aggregation-induced emission characteristics
Authors: Michelle M.S. Lee, Wenhan Xu, Liang Zheng, Bingran Yu, Anakin C.S. Leung, Ryan T.K. Kwok, Jacky W.Y. Lam, Fu-Jian Xu, Dong Wang, Ben Zhong Tang
Journal: Biomaterials (2019)
Overexpression and Targeted Activation of the Protein Phosphatases SHP-1 Abrogates Survival Pathways in Large Granular Lymphocyte Leukemia (LGLL)
Authors: Mario Angelo Pagano, Elena Tibaldi, Giulia Calabretto, Antonella Teramo, Luca Dell'Amico, Gabriella Donà, Gregorio Barilà, Cristina Vicenzetto, Vanessa Rebecca Gasparini, Valentina Trimarco, Monica Facco, Francesco Piazza, Gianpietro Semenzato, Anna Maria Brunati, Renato Zambello
Journal: Blood (2019)
Reduced Dose of Non-Pegylated Liposomal Doxorrubicin with Cyclophosphamide, Vincristine and Prednisone ± Rituximab for Elderly Patients with Aggressive Lymphoma Non Candidates to Standard Chemotherapy.
Authors: Eva Gimeno, Alberto Alvarez, Carme Pedro, Eugenia Abella, Miquel Gomez, Josep Comin, Carles Besses, Antonio Salar
Journal: Blood (2007)
Loop Ileostomy a Viable Alternative for <i>Clostridium Difficile</i> Colitis?—Reply
Authors: Yen-Yi Juo, Yas Sanaiha, Peyman Benharash
Journal: JAMA Surgery (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
RBTT-07. A PHASE 2 TRIAL OF PEMBROLIZUMAB AND BEVACIZUMAB IN MELANOMA BRAIN MET PATIENTS
Authors: Harriet M Kluger, Peter Forsyth, Nikhil Khushalani, Zeynep Eroglu, Mario Sznol, Thuy Tran, Lucia Jilaveanu, Justine V Cohen, Upendra Hegde, Wei Wei, Amit Mahajan, Sarah B Goldberg, Veronica Chiang, Sarah A Weiss
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Pembro monotherapy (NCT02085070) produces responses in 26% of (mel) BrM pts. VEGF inhibitors (VEGFi) enhance anti-PD-1 activity in preclinicals. Therefore, we initiated a phase 2 study (NCT02681549) of pembro plus bev in BrM pts. METHODS Eligibility includes advanced mel, &gt; 1 asymptomatic BrM, diameter 5-20mm, no steroids, no prior PD-1/PD-L1 or VEGFi. Pembro IV 200mg q3 wks for &lt; yrs with bev 7.5mg/kg for the first 4 cycles. Primary endpoint was BrM RR by modified RECIST. RESULTS Between 8/2016 - 1/2019, 20 mel pts were enrolled. 60% were male mdn age 62;ECOG PS was 0 in 16 and 1 in 4 pts; LDH &gt; ULN in 20%; 4 (20%); 10 were BRAFmt; 8 pts (40%) had &gt; 4 untreated BrM. 12 had a BrM response (7 CR, 5 PR); 1 each with SD, unevaluable and an unconfirmed PR, for an ORR BrM of 60% (12/20). All responses lasted 7+ to 30+ mths. 16 pts are alive. AEs attributable to bev include hypertension, microscopic diverticular perforation and wound dehiscence (1 pt each, all resolved). 1 had mucositis attributed to Pembro. Three d/c’d treatment for grade 3 ALT elevation. Cerebral edema decreased in all pts with baseline edema. CONCLUSIONS Pembro plus bev demonstrates promising activity in melanoma BrMs compared to pembro alone. The pre-specified primary endpoint (&gt; 4 BrM responses/20) was met, supporting further study. The toxicity profile was similar to pembro alone.
A Distinct Class of Bursting Neurons with Strong Gamma Synchronization and Stimulus Selectivity in Monkey V1
Authors: Irene Onorato, Sergio Neuenschwander, Jennifer Hoy, Bruss Lima, Katia-Simone Rocha, Ana Clara Broggini, Cem Uran, Georgios Spyropoulos, Johanna Klon-Lipok, Thilo Womelsdorf, Pascal Fries, Cristopher Niell, Wolf Singer, Martin Vinck
Journal: Neuron (2019)
An Exploratory Analysis of Brentuximab Vedotin Plus CHP (A+CHP) in the Frontline Treatment of Patients with CD30+ Peripheral T-Cell Lymphomas (ECHELON-2): Impact of Consolidative Stem Cell Transplant
Authors: Kerry J Savage, Steven M. Horwitz, Ranjana H Advani, Jacob H. Christensen, Eva Domingo-Domenech, Giuseppe Rossi, Franck Morschhauser, Onder Alpdogan, Cheolwon Suh, Kensei Tobinai, Andrei R Shustov, Marek Trneny, Sam Yuen, Pier Luigi Zinzani, Lorenz Truemper, Timothy Illidge, Owen O'Connor, Barbara Pro, Meredith Little, Veronica Bunn, Keenan Fenton, Thomas Manley, Swaminathan P. Iyer
Journal: Blood (2019)
Electrospinning Piezoelectric Fibers for Biocompatible Devices
Authors: Bahareh Azimi, Mario Milazzo, Andrea Lazzeri, Stefano Berrettini, Mohammed Jasim Uddin, Zhao Qin, Markus J. Buehler, Serena Danti
Journal: Advanced Healthcare Materials (2019)

The field of nanotechnology has been gaining great success due to its potential in developing new generations of nanoscale materials with unprecedented properties and enhanced biological responses. This is particularly exciting using nanofibers, as their mechanical and topographic characteristics can approach those found in naturally occurring biological materials. Electrospinning is a key technique to manufacture ultrafine fibers and fiber meshes with multifunctional features, such as piezoelectricity, to be available on a smaller length scale, thus comparable to subcellular scale, which makes their use increasingly appealing for biomedical applications. These include biocompatible fiber-based devices as smart scaffolds, biosensors, energy harvesters, and nanogenerators for the human body. This paper provides a comprehensive review of current studies focused on the fabrication of ultrafine polymeric and ceramic piezoelectric fibers specifically designed for, or with the potential to be translated toward, biomedical applications. It provides an applicative and technical overview of the biocompatible piezoelectric fibers, with actual and potential applications, an understanding of the electrospinning process, and the properties of nanostructured fibrous materials, including the available modeling approaches. Ultimately, this review aims at enabling a future vision on the impact of these nanomaterials as stimuli-responsive devices in the human body.
Subclinical and Device-Detected Atrial Fibrillation: Pondering the Knowledge Gap: A Scientific Statement From the American Heart Association
Authors: Peter A. Noseworthy, Elizabeth S. Kaufman, Lin Y. Chen, Mina K. Chung, Mitchell S.V. Elkind, José A. Joglar, Miguel A. Leal, Pamela J. McCabe, Sean D. Pokorney, Xiaoxi Yao
Journal: Circulation (2019)

The widespread use of cardiac implantable electronic devices and wearable monitors has led to the detection of subclinical atrial fibrillation in a substantial proportion of patients. There is evidence that these asymptomatic arrhythmias are associated with increased risk of stroke. Thus, detection of subclinical atrial fibrillation may offer an opportunity to reduce stroke risk by initiating anticoagulation. However, it is unknown whether long-term anticoagulation is warranted and in what populations. This scientific statement explores the existing data on the prevalence, clinical significance, and management of subclinical atrial fibrillation and identifies current gaps in knowledge and areas of controversy and consensus.
CXCR4 Blockade By BL-8040 in T Cell Acute Lymphoblastic Leukemia Decreases Mitochondrial Mass and Induces Non-Apoptotic Cell Death
Authors: Jun Xia, Stephanie Sun, Matthew RM Jotte, Geoffrey L. Uy, Osnat Bohana-Kashtan, Ella Sorani, Abi Vainstein, Amnon Peled, Daniel C. Link
Journal: Blood (2019)
Detection of Glaucoma
Authors: J. H. Austin
Journal: BMJ (1963)

Neutrophils are the first infiltrating cell population to appear within the CNS during infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). To determine whether neutrophils play a role in limiting acute JHMV infection, mice were depleted of neutrophils. Infection of neutropenic animals resulted in increased levels of virus replication and mortality compared with control mice. Furthermore, neutropenia resulted in significantly reduced mononuclear leukocyte infiltration possibly due to reduced loss of blood brain barrier integrity during acute JHMV infection. These data suggest that infiltrating neutrophils are crucial for limiting virus replication during acute JHMV infection, contribute to the loss of blood brain barrier integrity and play a role in shaping adaptive immunity within the CNS.
Direct Comparison of Long-Term Outcome of Allogeneic Transplantation for Myelofibrosis in Chronic and Leukemic Stage in a Single Institute
Authors: Shinsuke Takagi, Takashi Mitsuki, Mitsuhiro Yuasa, Kosei Kageyama, Daisuke Kaji, Yuki Taya, Aya Nishida, Kazuya Ishiwata, Hisashi Yamamoto, Go Yamamoto, Yuki Asano-Mori, Naoyuki Uchida, Atsushi Wake, Shuichi Taniguchi
Journal: Blood (2019)
The Choice of Treatment for Elderly AML-Patients: 7+3 or Low Doses ARA-C
Authors: Vera V. Troitskaya, Elena N. Parovichnikova, Andrey N. Sokolov, Alina V. Kokhno, Zalina T. Fidarova, Olga A. Gavrilina, Tatiana I. Lobanova, Elena O. Gribanova, Sergey K. Kravchenko, Gennadiy M. Galstyan, Sergei M. Kulikov, Julia A. Chabaeva, Valeriy G. Savchenko
Journal: Blood (2019)
Risk Factors and Different Therapeutic Patterns of Late-Onset Hemorrhagic Cystitis after Haploidentical Allogeneic Stem Cell Transplantation
Authors: Qiaozhu Zeng, Yun He, Xiaolu Zhu, Xiao Liu, Haixia Fu, Xiao-Dong Mo, Yu Wang, Xiangyu Zhao, Yuanyuan Zhang, Wei Han, Feifei Tang, Huan Chen, Yao Chen, Chenhua Yan, Jingzhi Wang, Ting-Ting Han, Yuhong Chen, Yifei Cheng, Ying-Jun Chang, Lan-Ping Xu, Kaiyan Liu, Xiaojun Huang, Xiao-Hui Zhang
Journal: Blood (2019)
SURG-18. 5-AMINOLEVULINIC ACID FLUORESCENCE (5-ALA) GUIDED RESECTION OF GLIOBLASTOMA, LESSON LEARNED FROM 19 CASES
Authors: Jinmo Cho
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND 5-ALA is known as useful tool for high grade glioma resection and the accumulation extent of 5-ALA is known as far beyond gadolinium enhancement. Extent of resection is key factor for favorable outcome and long-term survival for high grade glioma patients and 5-ALA might increase extent of resection. We present our experience of 5-ALA guided glioma surgeries METHODS Total 19 patients were performed 5-ALA guided surgery. They ingested 20mg/kg, four hours before craniotomy. We tried to perform supra-total resection rather than gross total resection according to the tumor consistency and if the tumor located relatively non-eloquent area, we tried to perform lobectomy rather than lesionectomy. After tumor resection, we inspect the tumor bed under 5-ALA fluorescence, and we confirmed the complete loss of fluorescence on the tumor resected bed. We check the MRI within 48 hour after operation and assess the extent of resection RESULTS Among the 19 patients, 15 patients were confirmed glioblastoma and 3 anaplastic astrocytoma and 1 anaplastic oligoastrocytoma. We confirmed all enhancing lesion was completely removed, however, 2 patients show residual non-enhancing lesion in post-operative MRI. Two patients suffered temporary hemiparesis and 2 patients show permanent visual field defect. CONCLUSION 5-ALA is useful tool for glioma surgery. Resection extent could be increased, however, non-enhancing lesion in the high grade gliomas, might be missed under 5-ALA guidance.
MSKCC Early Experience Using Radiotherapy As a Bridging Strategy for Relapsed Diffuse Large B Cell Lymphoma before CD19 CAR T Therapy
Authors: Brandon Imber, M. Lia Palomba, Carl DeSelm, Connie Lee Batlevi, Parastoo B. Dahi, Sergio A. Giralt, Ariela Noy, Jae H. Park, Craig S. Sauter, Michael Scordo, Gunjan L. Shah, Michel Sadelain, Miguel-Angel Perales, Joachim Yahalom
Journal: Blood (2019)
Age-Associated Myeloid Biased Hematopoiesis Depends on Relative Decrease of Short-Term Hematopoietic Stem Cell
Authors: Katsuyuki Nishi, Taro Sakamaki, Kevin Shuolong Kao, Kay Sadaoka, Momo Fujii, Akifumi Takaori-Kondo, Masanori Miyanishi
Journal: Blood (2019)
First-in-Human Study of ET019003, a Next Generation Anti-CD19 T-Cell Therapy, in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma (r/r DLBCL)
Authors: Pengcheng He, Hong Liu, Haibo Liu, Mina Luo, Hui Feng, Qijing Li, Qi Chang, Bingyi Shi, Cheng Liu
Journal: Blood (2019)
Injectable extracellular vesicle-released self-assembling peptide nanofiber hydrogel as an enhanced cell-free therapy for tissue regeneration
Authors: Yijie Zhou, Shuyun Liu, Meng Zhao, Chengshi Wang, Ling Li, Yujia Yuan, Lan Li, Guangneng Liao, William Bresette, Jie Zhang, Younan Chen, Jingqiu Cheng, Yanrong Lu, Jingping Liu
Journal: Journal of Controlled Release (2019)
Value of Pre-Procedural Lymphocyte-to-Monocyte Ratio for Predicting New Cerebral Ischemic and Haemorrhagic Lesions Observed after Transcatheter Aortic Valve Implantation: A Pilot Study
Authors: Tom Denimal, Fanny Lassalle, Nicolas Debry, Antoine Rauch, Flavien Vincent, Bart Staels, André Vincentelli, Sophie Susen, Eric Van Belle, Annabelle Dupont
Journal: Blood (2019)
Tumor-Associated Fibroblasts Promote HER2-Targeted Therapy Resistance through FGFR2 Activation
Authors: Patricia Fernández-Nogueira, Mario Mancino, Gemma Fuster, Anna López-Plana, Patricia Jauregui, Vanesa Almendro, Estel Enreig, Silvia Menéndez, Federico Rojo, Aleix Noguera-Castells, Anke Bill, L. Alex Gaither, Laia Serrano, Leire Recalde-Percaz, Núria Moragas, Raul Alonso, Elisabet Ametller, Ana Rovira, Ana Lluch, Joan Albanell, Pere Gascon, Paloma Bragado
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Despite the therapeutic success of existing HER2-targeted therapies, tumors invariably relapse. This study aimed at identifying new mechanisms responsible for HER2-targeted therapy resistance. Experimental Design: We have used a platform of HER2-targeted therapy–resistant cell lines and primary cultures of healthy and tumor-associated fibroblasts (TAF) to identify new potential targets related to tumor escape from anti-HER2 therapies. Results: We have shown that TAFs promote resistance to HER2-targeted therapies. TAFs produce and secrete high levels of FGF5, which induces FGFR2 activation in the surrounding breast cancer cells. FGFR2 transactivates HER2 via c-Src, leading to resistance to HER2-targeted therapies. In vivo, coinoculating nonresistant cell lines with TAFs results in more aggressive and resistant tumors. Resistant cells activate fibroblasts and secrete FGFR ligands, creating a positive feedback loop that fuels resistance. FGFR2 inhibition not only inhibits HER2 activation, but also induces apoptosis in cells resistant to HER2-targeted therapies. In vivo, inhibitors of FGFR2 reverse resistance and resensitize resistant cells to HER2-targeted therapies. In HER2 patients' samples, α-SMA, FGF5, and FGFR2 contribute to poor outcome and correlate with c-Src activation. Importantly, expression of FGF5 and phospho-HER2 correlated with a reduced pathologic complete response rate in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab, which highlights the significant role of TAFs/FGF5 in HER2 breast cancer progression and resistance. Conclusions: We have identified the TAF/FGF5/FGFR2/c-Src/HER2 axis as an escape pathway responsible for HER2-targeted therapy resistance in breast cancer, which can be reversed by FGFR inhibitors.
Characterization of Changes in the T-Cell Receptor Repertoire in Patients with Acute Myeloid Leukemia with Durable Remission Following Allogeneic Stem Cell Transplant
Authors: Ronald M. Paranal, Hagop M. Kantarjian, Alexandre Reuben, Celine Kerros, Priya Koppikar, Latasha Little, Curtis Gumbs, Nicholas J. Short, Jorge E. Cortes, Elias Jabbour, Jeffrey J. Molldrem, P. Andrew Futreal, Ghayas C. Issa
Journal: Blood (2019)