tbuckley/cabot-search huggingface dataset:
A New Surveillance Algorithm After Resection of Colorectal Liver Metastases Based on Changes in Recurrence Risk and RAS Mutation Status
Authors: Yoshikuni Kawaguchi, Scott Kopetz, Heather A. Lillemoe, Hyunsoo Hwang, Xuemei Wang, Ching-Wei D. Tzeng, Yun Shin Chun, Thomas A. Aloia, Jean-Nicolas Vauthey
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: The optimal surveillance strategy after resection of colorectal liver metastases (CLM) is unknown. We evaluated changes in recurrence risk after CLM resection and developed a surveillance algorithm. Methods: Patients undergoing CLM resection during 1998 to 2015 were identified from a prospectively compiled database and analyzed if they had the potential for follow-up longer than the longest observed time to recurrence in this cohort. Changes in recurrence risk and risk factors for recurrence were evaluated. All statistical tests were 2-sided. Results: Among 2,105 patients who were initially identified and underwent CLM resection, the latest recurrence was observed at 87 months; 1,221 consecutive patients from 1998 through 2011 with the potential for at least 87 months of follow-up were included. The risk of recurrence was highest at 0 to 2 years after CLM resection, lower at 2 to 4 years after CLM resection, and steadily lower after 4 years after CLM resection. Factors associated with increased recurrence risk at the time of surgery were primary lymph node metastasis (hazard ratio [HR], 1.54; 95% CI, 1.21–1.97; P &lt;.001), multiple CLM (HR, 1.31; 95% CI, 1.06–1.63; P =.015), largest liver metastasis diameter &gt;5 cm (HR, 1.64; 95% CI, 1.23–2.19; P &lt;.001), and RAS mutation (HR, 1.29; 95% CI, 1.04–1.59; P =.020). In patients without recurrence at 2 years, the only factor still associated with increased recurrence risk was RAS mutation. In those patients, the recurrence rate at 4 years was 59.3% in patients with RAS mutation versus 27.8% in patients with RAS wild-type ( P =.019). Conclusions: For patients who have undergone CLM resection, we propose surveillance every 3 to 4 months during years 0 to 2, every 3 to 4 months (if mutant RAS ) versus every 4 to 6 months (if RAS wild-type) during years 2 to 4, and every 6 to 12 months if recurrence-free at 4 years.
Development of a Hydrashift 2/4 Isatuximab Assay to Mitigate Interference with Monoclonal Protein Detection on Immunofixation Electrophoresis in Vitro Diagnostic Tests in Multiple Myeloma
Authors: Greg Finn, Sandrine Macé, Ruiyin Chu, Helgi van de Velde, Samia Menad, Marie-Thérèse Melki, Georges Nouadje
Journal: Blood (2020)
Hepcidin Peptidomimetics - Oral Efficacy in Pre-Clinical Disease Model of Iron Overload
Authors: Roopa Taranath, Gregory Bourne, Jie Zhang, Brian Frederick, Tran T Tran, Ashok Bhandari, Jayanthi Vengalam, Jaimee McMahon, Keith Huie, Grace A Ledet, Li Zhao, James Tovera, Larry Lee, Bo Yang, Celino Dion, Lucy Yuan, Genet Zemede, Michelle Nguyen, Mohammad Masjedizadeh, Xiaoli Cheng, Larry Mattheakis, David Liu, Mark L Smythe
Journal: Blood (2020)
Predictors of Tyrosine Kinase Inhibitor Use Among Older Patients with Chronic Myeloid Leukemia in the United States
Authors: Rong Wang, Rory M. Shallis, Jan Philipp Bewersdorf, Amer M. Zeidan, Scott F. Huntington, Xiaomei Ma, Nikolai A. Podoltsev
Journal: Blood (2020)
Comparison of Bone Marrow Versus Peripheral Blood in Haploidentical Transplantation Using Post-Transplant Cyclophosphamide- a Retrospective Analysis
Authors: Nidhi Sharma, Justin Jiang, Qiuhong Zhao, Patrick Elder, Don M. Benson, Ashley Rosko, Maria Chaudhry, Naresh Bumma, Abdullah Khan, Srinivas Devarakonda, Sumithira Vasu, Samantha Jaglowski, Basem M. William, Alice S. Mims, Hannah Choe, Jonathan E. Brammer, Sarah A Wall, Nicole Grieselhuber, Ayman Saad, Sam Penza, Audrey M. Sigmund, Yvonne A. Efebera
Journal: Blood (2020)
Alternative Donor Hematopoietic Cell Transplantation for Pediatric, Adolescent and Young Adult with Hematological Diseases
Authors: Nicole Karras, Ni-Chun Tsai, Ahmed Tahoun, Saloomeh Mokhtari, Haris Ali, Shukaib Arslan, Anna B Pawlowska, Chatchada Karanes, Joseph Rosenthal, David S Snyder, Stephen J. Forman, Ryotaro Nakamura, Monzr M. Al Malki
Journal: Blood (2020)
Abstract IA02: Slide-seq: A platform for understanding cellular circuits in tissue
Authors: Fei Chen
Journal: Cancer Research (2020)

Abstract The precise spatial localization of molecular signals within tissues richly informs the mechanisms of tissue formation and function. Here we introduce Slide-seq, a technology which enables transcriptome-wide measurements with near-single cell spatial resolution. We’ll describe recent experimental and computational advances to enable Slide-seq in biological contexts in biological contexts where high detection sensitivity is important. More broadly, we’ll discuss the promise and challenges of spatial transcriptomics for tissue genomics. Citation Format: Fei Chen. Slide-seq: A platform for understanding cellular circuits in tissue [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA02.
Abstract 316: Influence of Aging and Na Channels on Sinus Rhythm and Heart Rate Variability
Authors: Martina Comelli, Marianna Meo, Daniel O Cervantes, Emanuele Pizzo, Aaron Plosker, Thomas J Hund, Jason T Jacobson, olivier meste, Marcello Rota
Journal: Circulation Research (2020)

Heart rate variability (HRV) is an index of cardiovascular health and reflects the ability of the heart to adjust sinus rhythm in response to autonomic regulation, a process affected by age. Importantly, Na channels have emerged as key components of discharge and conduction of the sino-atrial node, but whether altered Na channels affect HRV remains to be established. Thus, we studied effects of aging and altered Na channels on heart rate and HRV using wild type (WT) mice and mice with phosphomimetic mutation of Na channel Nav1.5 at Ser571 (S571E mice). Electrocardiograms (ECG) were obtained in male conscious mice at ~4, ~12, ~18, and ~24 months of age (n=13-51). The mean RR interval of the ECG was similar in WT mice at ~4, ~12, and ~18 months (83±4, 81±2, 83±2 ms, respectively), but increased at ~24 months (85±5 ms). In contrast, mean RR interval in S571E mice was maximal at ~4 months (86±6 ms) and progressively decreased at ~12 (83±9 ms), ~18 (79±2 ms), and ~24 months (80±3 ms). Standard deviation of RR intervals (SDRR), an indicator of RR variability, was maximal in WT at ~4 months (3.8±1.6 ms) and was reduced at ~12, ~18, and ~24 months (2.1±0.9, 2.4±1, and 2.6±1.2 ms). Similarly, SDRR was maximal in S571 at ~4 (5.1±2.6 ms) and ~12 months (4.3±1.5 ms), and decreased at ~18 and ~24 months of age (2.6±1.0 and 3.1±1.1 ms). Standard deviation of instantaneous (SD1) and long-term (SD2) RR interval variability, indicative of parasympathetic and sympathetic influence, respectively, were derived from Poincaré plots of RR i and RR i+1 intervals. Overall, SD1 was preserved for the two groups of aging mice, whereas SD2 was maximal at ~4 months and decreased at ~18 and ~24 months. In the presence of complete autonomic block (propranolol and atropine), RR interval increased in young (~4 months, +10%) and old (~24 months, +16%) WT mice. Similarly, autonomic block increased RR interval in young (~4 months, +12%) and old (~24 months, +14%) S571E, but it abrogated RR interval differences between young and old. For the two genotypes, autonomic block reduced SDRR and SD2 exclusively in young animals, abolishing age-related differences in HRV. Overall, these data suggest that Na + channel function conditions heart rate and its age-related adaptations, but does not interfere with the decline of HRV occurring with age.
SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19
Authors: Peter Chen, Ajay Nirula, Barry Heller, Robert L Gottlieb, Joseph Boscia, Jason Morris, Gregory Huhn, Jose Cardona, Bharat Mocherla, Valentina Stosor, Imad Shawa, Andrew C Adams, Jacob Van Naarden, Kenneth L Custer, Lei Shen, Michael Durante, Gerard Oakley, Andrew E Schade, Janelle Sabo, Dipak R Patel, Paul Klekotka, Daniel M Skovronsky
Journal: New England Journal of Medicine (2020)

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization.MethodsIn this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here.ResultsAt the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group.ConclusionsIn this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501.)
Phase 1 Study of Axatilimab (SNDX-6352), a CSF-1R Humanized Antibody, for Chronic Graft-Versus-Host Disease after 2 or More Lines of Systemic Treatment
Authors: Mukta Arora, Madan Jagasia, Antonio Di Stasi, Michael L Meyers, Christine Quaranto, Aaron Schmitt, Serap Sankoh, Mohammad Issam Abu Zaid, Geoff R Hill, Daniel J. Weisdorf, Bruce R. Blazar, Peter Ordentlich, Stephanie J. Lee
Journal: Blood (2020)
Importance of Flow Cytometry in the Differential Diagnosis of Hairy Cell Leukemia in the State of Rio Grande Do Norte, Brazil
Authors: Aldair Sousa Paiva, Alessandra Suelen Jardim Silva, Victor lima Soares, Gustavo Henrique de Medeiros Oliveira, Lenilton Silva DA Silva Júnior, Hugo Henrique de Freitas Ferreira, Rodrigo Villar Freitas, Taissa Moura Oliveira, Dany GKC Silva, Valéria SF Sales, Rodolfo DA Soares, Hugo Diogenes De Oliveira Paiva, Geraldo Barroso Cavalcanti
Journal: Blood (2020)
Factors Associated with the Improvement of Outcomes of High-Risk Relapsed Hodgkin Lymphoma (HL) Patients Receiving High-Dose Chemotherapy (HDC) and Autologous Stem-Cell Transplantation (ASCT): The MD Anderson Cancer Center Experience
Authors: Yago Nieto, Stephen K. Gruschkus, Roy B. Jones, Benigno C. Valdez, Melissa Timmons, Chitra Hosing, Paolo Anderlini, Partow Kebriaei, Uday R. Popat, Muzaffar H. Qazilbash, Amin M. Alousi, Samer A. Srour, Neeraj Saini, Jeremy Ramdial, Jin S. Im, Elizabeth J. Shpall, Katayoun Rezvani, Alison Gulbis, Terri Lynn Shigle, Kris Michael Mahadeo, Sajad Khazal, Issa F. Khouri, Bouthaina S. Dabaja, Chelsea C. Pinnix, Jillian R. Gunther, Hun Lee, Sairah Ahmed, Raphael Eric Steiner, Swaminathan P Iyer, Ranjit Nair, Simrit Parmar, Branko Cuglievan, Farzaneh Maadani, Gabriela Rondon, Richard E. Champlin, Borje S. Andersson
Journal: Blood (2020)
A Clinical Practice Comparison of Overall Survival, Time-to-Next-Treatment, and Time-to-Treatment-Discontinuation Among CLL/SLL Patients Receiving First-Line Ibrutinib with and without a Del(17p) Mutation
Authors: Anthony Mato, Boxiong Tang, Soraya Azmi, Keri Yang, Jennifer C Stern, Eric Hedrick, Jane Huang, Jeff P Sharman
Journal: Blood (2020)
Gvhd and Relapse Free Survival (GRFS) after Allogeneic Transplantation for Idiopathic Severe Aplastic Anemia: An Analysis from the Saawp Data Quality Initiative Program of EBMT
Authors: Raynier Devillier, Dirk-Jan Eikema, Paul Bosman, Carlo Dufour, Mahmoud Aljurf, Depei Wu, Alexey Maschan, Boris V. Afanasyev, Constantijn Halkes, Matthew P. Collin, John A Snowden, Yves Bertrand, Arnold Ganser, Karl-Walter Sykora, Brenda Gibson, Johan Maertens, Maija Itälä-Remes, Corti Paola, Jan J. Cornelissen, Martin Bornhäuser, Mercedes Colorado Araujo, Hakan Ozdogu, Antonio Risitano, Regis Peffault De Latour
Journal: Blood (2020)
Somatic Mutations Associated with IgVH4-34 FR1 Region Unmutated QW and Avy Motifs in DLBCL Patients
Authors: Caitlin Coombes, Keisuke Horikawa, Sanjiv Jain, Jun Hee Lim, Sewa Rijal, Kartik Saxena, Dipti Talaulikar
Journal: Blood (2020)
Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients Enrolled in CPX-351-301, a Randomized Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, High-Risk and/or Secondary AML
Authors: Geoffrey L Uy, Laura F. Newell, Tara Lin, Stuart L. Goldberg, Matthew J. Wieduwilt, Robert J. Ryan, Stefan Faderl, Jeffrey E. Lancet
Journal: Blood (2020)
A Prospective Study and Identification of Genomewide Association Markers of Familial Predisposition to Plasma Cell Dyscrasias
Authors: Adam S Sperling, Rebecca Georgakopoulou, Mehmet Kemal Samur, Christine Ivy Liacos, Brittany E Sandoval, Flora Zagouri, Maria Gavriatopoulou, Evangelos Eleutherakis-Papaiakovou, Magdalini Migkou, Nikolaos Kanellias, Despina Fotiou, Ioannis Ntanasis-Stathopoulos, Evangelos Terpos, Efstathios Kastritis, Nikhil C. Munshi, Meletios A Dimopoulos
Journal: Blood (2020)
Low-Dose Triptolide Promotes MDM2 Inhibitor Nutlin3a to Induce Acute Myeloid Leukemia Cell Death Via p53-Dependent and -Independent Mechanisms
Authors: Qinwei Chen, Suqi Deng, Zhijuan Lin, Manman Deng, Lihong Ding, Jie Zha, Yong Zhou, Yuelong Jiang, Bing Z Carter, Bing Xu
Journal: Blood (2020)
Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice
Authors: Benson Chellakkan Selvanesan, Kiran Meena, Amanda Beck, Lydie Meheus, Olaya Lara, Ilse Rooman, Claudia Gravekamp
Journal: Journal for ImmunoTherapy of Cancer (2020)

Treatments for pancreatic ductal adenocarcinoma are poorly effective, at least partly due to the tumor's immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment (TME), compelled us to test the combination of gemcitabine (GEM), a standard chemotherapeutic for pancreatic cancer, with nicotinamide (NAM), the amide form of niacin (vitamin B3), in mice with pancreatic cancer. Various mouse tumor models of pancreatic cancer, that is, orthotopic Panc-02 and KPC (KrasG12D, p53R172H, Pdx1-Cre) grafts, were treated alternately with NAM and GEM for 2 weeks, and the effects on efficacy, survival, stromal architecture and tumor-infiltrating immune cells was examined by immunohistochemistry (IHC), flow cytometry, Enzyme-linked immunospot (ELISPOT), T cell depletions in vivo, Nanostring analysis and RNAscope. A significant reduction in tumor weight and number of metastases was found, as well as a significant improved survival of the NAM+GEM group compared with all control groups. IHC and flow cytometry showed a significant decrease in tumor-associated macrophages and myeloid-derived suppressor cells in the tumors of NAM+GEM-treated mice. This correlated with a significant increase in the number of CD4 and CD8 T cells of NAM+GEM-treated tumors, and CD4 and CD8 T cell responses to tumor-associated antigen survivin, most likely through epitope spreading. In vivo depletions of T cells demonstrated the involvement of CD4 T cells in the eradication of the tumor by NAM+GEM treatment. In addition, remodeling of the tumor stroma was observed with decreased collagen I and lower expression of hyaluronic acid binding protein, reorganization of the immune cells into lymph node like structures and CD31 positive vessels. Expression profiling for a panel of immuno-oncology genes revealed significant changes in genes involved in migration and activation of T cells, attraction of dendritic cells and epitope spreading. This study highlights the potential of NAM+GEM as immunotherapy for advanced pancreatic cancer.
Mutations of the <i>Exportin 1 (XPO1)</i> Gene Predict Shorter Time to First Treatment in 1092 Early Stage Chronic Lymphocytic Leukemia Patients. Α Training/Validation Study
Authors: Riccardo Moia, Chiara Favini, Valentina Ferri, Riccardo Bomben, Sruthi Sagiraju, Tamara Bittolo, Lydia Scarfo, Silvia Bonfiglio, Rossana Maffei, Stefano Baldoni, Sara Raponi, Valeria Spina, Alessio Bruscaggin, Lodovico Terzi di Bergamo, Lorenzo De Paoli, Gloria Margiotta Casaluci, Clara Deambrogi, Silvia Rasi, Adalgisa Condoluci, Ahad Ahmed Kodipad, Ramesh Adhinaveni, Katia Mokabari, Abdurraouf Mokhtar Mahmoud, Andrea Patriarca, Jacopo Olivieri, Giovanni D'Arena, Francesco Zaja, Annalisa Chiarenza, Giovanni Del Poeta, Antonella Zucchetto, Francesca Maria Rossi, Ilaria Del Giudice, Paolo Sportoletti, Roberto Marasca, Paolo Ghia, Robin Foà, Gianluca Gaidano, Davide Rossi, Valter Gattei
Journal: Blood (2020)
Racial Disparities and Their Impact on Knowledge, Behavioral Patterns, and Preferences Towards Participation in Clinical Trials Among Cancer Patients
Authors: Meghna Ailawadhi, Mays F Abdulazeez, Leyla Bojanini Molina, Victoria R. Alegria, Taimur Sher, Vivek Roy, Rami Manochakian, Aneel Paulus, Asher A. Chanan-Khan, Sikander Ailawadhi
Journal: Blood (2020)
Abstract 207: A Catalogue of the Pathogenic Mutations of LDL Receptor Gene in Japanese Familial Hypercholesterolemia
Authors: Hayato Tada, Soichiro Usui, Masa-aki Kawashiri, Masayuki Takamura, Mariko Harada-shiba
Journal: Circulation Research (2020)

Background: Familial hypercholesterolemia (FH), mainly caused by LDL receptor gene mutation is attracting a lot of attention associated with the development of novel therapies. However, rare mutations tend to be ethnicity-specific, hence, it is always difficult to determine pathogenicity of LDL receptor gene mutation in a single individual in a certain ethnicity. Currently, little data exist on the pathogenic mutations of LDL receptor in Japanese familial hypercholesterolemia (FH). Objective: We aimed to catalogue the pathogenic mutations of LDL receptor gene in the 2 major Japanese FH-care centers (Kanazawa University and National Cerebral and Cardiovascular Center Research Institute), where genetic testing of FH has been performed centrally upon requests from institutes all over Japan during more than past two decades. Methods: 796 FH subjects from 472 families who had nonsynonymous mutations in LDL receptor gene were included in this study. Genetic mutations were analyzed for mutations by Sanger sequencing as well as by multiplex ligation probe dependent amplification (MLPA) technique for large rearrangements. Pathogenic mutations were defined either as 1) protein truncated variants, 2) registered as pathogenic in Clinvar, or Human Gene Mutation Database (HGMD), or meet the criteria of American College of Medical Genetics and Genomics (ACMG) guideline, or 3) CADD-score &gt; 10. Results: We found 138 different mutations. Among them, 132 mutations were considered as pathogenic, including 19 large rearrangement mutations. Whereas, 6 missense mutations were classified as variants of unknown significance (VUS). A single mutation accounted for as much as 41 % of the FH subjects recruited from Kanazawa University mainly due to founder gene effect, whereas, many singleton mutations were found from National Cerebral and Cardiovascular Center Research Institute located in Osaka. Conclusions: We provided the largest catalogue of pathogenic mutations of LDL receptor gene in Japanese FH. This could aid to determine the pathogenicity of the LDL receptor genetic mutations not only in Japanese but also in other ethnicities.
Oncofetal Protein SALL4 Is Highly Expressed in Myelodysplastic Syndrome Alongside with NAT10 and P53
Authors: Hiro Tatetsu, Miho Watanabe, Emily F Mason, Scott B Lovitch, Kenji Tokunaga, Eisaku Iwanaga, Masao Matsuoka, Daniel G. Tenen, Li Chai
Journal: Blood (2020)
Comparison of Outcomes of Donor Lymphocyte Infusions with or without Lenalidomide in Patients with Hematological Malignancies Post Allogeneic Transplant
Authors: Sachin Punatar, Vinodhini Murugaiyan, Anant Gokarn, Akanksha Chichra, Sumeet Prakash Mirgh, Lingaraj Nayak, Avinash Bonda, Vijay Shirure, Bhausaheb Bagal, Libin J Mathew, Sadhana Kannan, Tapan Saikia, Navin Khattry
Journal: Blood (2020)
Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer
Authors: Denis M. Collins, Stephen F. Madden, Nicola Gaynor, Dalal AlSultan, Marion Le Gal, Alex J. Eustace, Kathy A. Gately, Clare Hughes, Anthony M. Davies, Thamir Mahgoub, Jo Ballot, Sinead Toomey, Darran P. O'Connor, William M. Gallagher, Frankie A. Holmes, Virginia Espina, Lance Liotta, Bryan T. Hennessy, Kenneth J. O'Byrne, Max Hasmann, Birgit Bossenmaier, Norma O'Donovan, John Crown
Journal: Clinical Cancer Research (2020)

Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action of the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined the impact of lapatinib on HER2/EGFR expression levels and natural killer (NK) cell gene signatures. We investigated the ability of three TKIs (lapatinib, afatinib, and neratinib) to alter HER2/immune-related protein levels in preclinical models of HER2-positive (HER2+) and HER2-low breast cancer, and the subsequent effects on trastuzumab/pertuzumab-mediated ADCC.Preclinical studies (proliferation assays, Western blotting, high content analysis, and flow cytometry) employed HER2+ (SKBR3 and HCC1954) and HER2-low (MCF-7, T47D, CAMA-1, and CAL-51) breast cancer cell lines. NCT00524303 provided reverse phase protein array-determined protein levels of HER2/pHER2/EGFR/pEGFR. RNA-based NK cell gene signatures (CIBERSORT/MCP-counter) post-neoadjuvant anti-HER2 therapy were assessed (NCT00769470/NCT01485926). ADCC assays utilized flow cytometry-based protocols.Lapatinib significantly increased membrane HER2 levels, while afatinib and neratinib significantly decreased levels in all preclinical models. Single-agent lapatinib increased HER2 or EGFR levels in 10 of 11 (91%) tumor samples. NK cell signatures increased posttherapy (P = 0.03) and associated with trastuzumab response (P = 0.01). TKI treatment altered mAb-induced NK cell-mediated ADCC in vitro, but it did not consistently correlate with HER2 expression in HER2+ or HER2-low models. The ADCC response to trastuzumab and pertuzumab combined did not exceed either mAb alone.TKIs differentially alter tumor cell phenotype which can impact NK cell-mediated response to coadministered antibody therapies. mAb-induced ADCC response is relevant when rationalizing combinations for clinical investigation.
Frontline HCVAD with Nelarabine and Peg-Asparaginase in T-Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LBL): Updated Results of a Phase II Trial
Authors: Abhishek Maiti, Elias Jabbour, Nitin Jain, Gautam Borthakur, Tapan M. Kadia, Jan A. Burger, William G. Wierda, Marina Konopleva, Yesid Alvarado, Nicholas J. Short, Stefan Faderl, Susan M. O'Brien, Alessandra Ferrajoli, Steven M. Kornblau, Naval Daver, Naveen Pemmaraju, Prithviraj Bose, Philip A. Thompson, Joseph D. Khoury, Hayley Balkin, Mary Kelly, Hind Azzawi, Rebecca Garris, Guillermo Garcia-Manero, Hagop M. Kantarjian, Farhad Ravandi
Journal: Blood (2020)