Biomedical Informatics Commons^™

Sitravatinib In Patients With Solid Tumors Selected By Molecular Alterations: Results From A Phase Ib Study, Lyudmila Bazhenova, Dong-Wan Kim, Byoung Chul Cho, Sanjay Goel, Rebecca Heist, Theresa L Werner, Keith D Eaton, Judy S Wang, Shubham Pant, Douglas R Adkins, Collin M Blakely, Xiaohong Yan, Saskia Neuteboom, James G Christensen, Richard Chao, Todd Bauer

Faculty, Staff and Student Publications

No abstract provided.

Assessment Of Gender Differences In Letters Of Recommendation For Physical Therapy Residency Applications, Darren Q Calley, Sunyang Fu, Marissa D Hamilton, Austin W Kalla, Christopher K Lee, Veronica A Rasmussen, John H Hollman, Hongfang Liu

Faculty, Staff and Student Publications

Introduction: Letters of recommendation (LOR) are an integral component of physical therapy residency applications. Identifying the influence of applicant and writer gender in LOR will help identify whether potential implicit gender bias exists in physical therapy residency application processes.

Review of literature: Several medical and surgical residency education programs have reported positive, neutral, or negative LOR female gender bias among applicants and writers. Little research exists on gender differences in LOR to physical therapy education programs or physical therapy residency programs.

Subjects: Seven hundred sixty-eight LOR were analyzed from 256 applications to 3 physical therapy residency programs (neurologic, orthopaedic, sports) …

Imipridones Inhibit Tumor Growth And Improve Survival In An Orthotopic Liver Metastasis Mouse Model Of Human Uveal Melanoma, Chandrani Chattopadhyay, Janos Roszik, Rajat Bhattacharya, Md Alauddin, Iqbal Mahmud, Sirisha Yadugiri, Mir Mustafa Ali, Fatima S Khan, Varun Vijay Prabhu, Philip L Lorenzi, Bo Wei, Elizabeth Burton, Rohini R Morey, Rossana Lazcano, Michael A Davies, Sapna P Patel, Elizabeth A Grimm

Faculty, Staff and Student Publications

Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.

Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.

Results: CLPP expression was detected in primary …

Gravity- Vs Wall Suction-Driven Large-Volume Thoracentesis: A Randomized Controlled Study, Samira Shojaee, Jasleen Pannu, Lonny Yarmus, Alberto Fantin, Christina Macrosty, Roland Bassett, Labib Debiane, Zachary S Depew, Saadia A Faiz, Carlos A Jimenez, Sameer K Avasarala, Erik Vakil, Andrew Demaio, Lara Bashoura, Keerthana Keshava, Travis Ferguson, Roberto Adachi, George A Eapen, David E Ost, Sami Bashour, Asad Khan, Vickie Shannon, Ajay Sheshadri, Roberto F Casal, Scott E Evans, Krystle Pew, Nadia Castaldo, Diwakar D Balachandran, Vincenzo Patruno, Robert Lentz, Cheryl Pai, Fabien Maldonado, Lance Roller, Junsheng Ma, Jhankruti Zaveri, Jenna Los, Luis Vaquero, Eva Ordonez, Gulmira Yermakhanova, Jason Akulian, Cole Burks, Roel-Rolando Almario, Marie Sauve, Jackson Pettee, Laila Z Noor, Muhammad H Arain, Horiana B Grosu

Faculty, Staff and Student Publications

Background: Prior studies have found no differences in procedural chest discomfort for patients undergoing manual syringe aspiration or drainage with gravity after thoracentesis. However, whether gravity drainage could protect against chest pain due to the larger negative-pressure gradient generated by wall suction has not been investigated.

Research question: Does wall suction drainage result in more chest discomfort compared with gravity drainage in patients undergoing large-volume thoracentesis?

Study design and methods: In this multicenter, single-blinded, randomized controlled trial, patients with large free-flowing effusions of ≥ 500 mL were assigned at a 1:1 ratio to wall suction or gravity drainage. Wall suction …

Adjuvant Rituximab And Elevated Intratumoural Cd8 Expression Are Associated With Sustained Disease Control After Radiotherapy In A Randomised Trial Of Systemic Therapy In Early-Stage Follicular Lymphoma, Michael P Macmanus, John F Seymour, Hennes Tsang, Richard Fisher, Colm Keane, Muhammed B Sabdia, Soi C Law, Jay Gunawardana, Karthik Nath, Stephen H Kazakoff, Mario L Marques-Piubelli, Daniela E Duenas, Michael R Green, Daniel Roos, Peter O'Brien, Andrew Mccann, Richard Tsang, Sidney Davis, David Christie, Chan Cheah, Benhur Amanuel, Tara Cochrane, Jason Butler, Anna Johnston, Mohamed Shanavas, Li Li, Claire Vajdic, Robert Kridel, Victoria Shelton, Samantha Hershenfield, Tara Baetz, David Lebrun, Nathalie Johnson, Marianne Brodtkorb, Maja Ludvigsen, Francesco D'Amore, Ella R Thompson, Piers Blombery, Maher K Gandhi, Joshua W D Tobin

Faculty, Staff and Student Publications

Background: We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies.

Methods: Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT + CVP). From 2006 rituximab was added to IFRT + CVP (IFRT + R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively).

Findings: Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at …

The Prognostic Impact Of Tumor Deposits In Colorectal Cancer: More Than Just N1c, Neal Bhutiani, Oliver Peacock, Abhineet Uppal, Chung-Yuan Hu, Brian K Bednarski, Melissa W Taggart, Arvind Dasari, Van K Morris, Harmeet Kaur, Scott Kopetz, Emma B Holliday, Prajnan Das, Y Nancy You, George J Chang

Faculty, Staff and Student Publications

Background: The identification of tumor deposits (TD) currently plays a limited role in staging for colorectal cancer (CRC) aside from N1c lymph node designation. The objective of this study was to determine the prognostic impact, beyond American Joint Committee on Cancer N1c designation, of TDs among patients with primary CRC.

Methods: Patients who had resected stage I-III primary CRC diagnosed between 2010 and 2019 were identified from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer-specific survival (CSS) stratified by TD status and lymph node (N) status was calculated using the Kaplan-Meier method and multivariable Cox proportional hazards …

Normal Breast Tissues Harbour Rare Populations Of Aneuploid Epithelial Cells, Yiyun Lin, Junke Wang, Kaile Wang, Shanshan Bai, Aatish Thennavan, Runmin Wei, Yun Yan, Jianzhuo Li, Heba Elgamal, Emi Sei, Anna Casasent, Mitchell Rao, Chenling Tang, Asha S Multani, Jin Ma, Jessica Montalvan, Chandandeep Nagi, Sebastian Winocour, Bora Lim, Alastair Thompson, Nicholas Navin

Faculty, Staff and Student Publications

Aneuploid epithelial cells are common in breast cancer

Individual Dynamic Prediction For Cure And Survival Based On Longitudinal Biomarkers, Can Xie, Xuelin Huang, Ruosha Li, Alexander Tsodikov, Kapil Bhalla

Faculty, Staff and Student Publications

To optimize personalized treatment strategies and extend patients' survival times, it is critical to accurately predict patients' prognoses at all stages, from disease diagnosis to follow-up visits. The longitudinal biomarker measurements during visits are essential for this prediction purpose. Patients' ultimate concerns are cure and survival. However, in many situations, there is no clear biomarker indicator for cure. We propose a comprehensive joint model of longitudinal and survival data and a landmark cure model, incorporating proportions of potentially cured patients. The survival distributions in the joint and landmark models are specified through flexible hazard functions with the proportional hazards as …

A Proteome-Wide Association Study Identifies Putative Causal Proteins For Breast Cancer Risk, Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Jill E Henry, Bing Zhang, Xingyi Guo, Michele L Cote, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long

Faculty, Staff and Students Publications

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 200 breast cancer risk-associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue related to breast cancer risk.

METHODS: We profiled the proteome in fresh frozen breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank (KTB). Protein expression levels were log2-transformed then normalized via quantile and inverse-rank transformations. GWAS data were also generated for …

Efficacy Of Letermovir For Cytomegalovirus Prophylaxis Following Alemtuzumab T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplant, Ibrahim N Muhsen, Kristen E Shaver, Tao Wang, Mengfen Wu, Premal Lulla, Carlos A Ramos, Rammurti T Kamble, Helen E Heslop, George Carrum, Laquisa C Hill

Faculty, Staff and Students Publications

In vivo T-cell depletion (TCD) using alemtuzumab decreases the risk of Graft vs Host Disease (GvHD) in recipients of allogeneic hematopoietic stem cell transplant (allo-HSCT). However, this approach increases the risk of infections post-allo-HSCT, including Cytomegalovirus (CMV). Letermovir is approved for the use in CMV prophylaxis post-allo-HSCT. Few studies have investigated the efficacy of letermovir in patients receiving alemtuzumab. This is a single-center retrospective study describing our institutional experience using letermovir in recipients of alemtuzumab TCD allo-HSCT from unrelated donors (URD). The primary outcome was the cumulative incidence of significant CMV infection (defined as viremia leading to preemptive antiviral therapy …

Blood Matters: The Hematological Signatures Of Coronavirus Infection, Ayelen Toro, Ana P Arévalo, Marianoel Pereira-Gómez, Agustina Sabater, Eric A Zizzi, Paula Perbolianachis, Gaston Pascual, Sofia Lage-Vickers, Jorge L Pórfido, Ines Achinelli, Rocio Seniuk, Juan Bizzotto, Pablo Sanchis, Alvaro Olivera, Alejandro Leyva, Pilar Moreno, Alicia Costábile, Alvaro Fajardo, Federico Carrión, Martín Fló, Natalia Olivero-Deibe, Fernando Rodriguez, Nicolas Nin, Nicolas Anselmino, Estefania Labanca, Elba Vazquez, Javier Cotignola, Daniel F Alonso, Maria P Valacco, Marcelo Marti, Francesco Gentile, Artem Cherkasov, Martina Crispo, Gonzalo Moratorio, Geraldine Gueron

Faculty, Staff and Student Publications

Recent developments have broadened our perception of SARS-CoV-2, indicating its capability to affect the body systemically beyond its initial recognition as a mere respiratory pathogen. However, the pathways of its widespread are not well understood. Employing a dual-modality approach, we integrated findings from a Murine Hepatitis Virus (MHV) infection model with corroborative clinical data to investigate the pervasive reach of Coronaviruses. The novel presence of viral particles within red blood cells (RBCs) was demonstrated via high-resolution transmission electron microscopy, with computational modeling elucidating a potential heme-mediated viral entry mechanism via Spike protein affinity. Our data affirm viral localization in RBCs, …

Comparing Neoantigen Cancer Vaccines And Immune Checkpoint Therapy Unveils An Effective Vaccine And Anti-Trem2 Macrophage-Targeting Dual Therapy, Sunita Keshari, Alexander S Shavkunov, Qi Miao, Akata Saha, Tomoyuki Minowa, Martina Molgora, Charmelle D Williams, Mehdi Chaib, Anna M Highsmith, Josué E Pineda, Sayan Alekseev, Elise Alspach, Kenneth H Hu, Marco Colonna, Kristen E Pauken, Ken Chen, Matthew M Gubin

Faculty, Staff and Student Publications

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines …

Identification Of Lrp1+Cd13+ Human Periosteal Stem Cells That Require Lrp1 For Bone Repair, Youngjae Jeong, Lorenzo Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Faculty, Staff and Students Publications

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, podoplanin (PDPN) and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs, selectively expressed identified markers low density lipoprotein receptor-related protein 1 (LRP1) and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential …

Clc-Kb Pore Mutation Disrupts Glycosylation And Triggers Distal Tubular Remodeling, Yogita Sharma, Robin Lo, Viktor N Tomilin, Kotdaji Ha, Holly Deremo, Aishwarya V Pareek, Wuxing Dong, Xiaohui Liao, Svetlana Lebedeva, Vivek Charu, Neeraja Kambham, Kerim Mutig, Oleh Pochynyuk, Vivek Bhalla

Faculty, Staff and Student Publications

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole-exome sequencing. Compared with wild-type ClC-Kb, the Gly167Cys mutant conducted less current and exhibited impaired complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Genetic Risk Stratification And Outcomes Among Treatment-Naive Patients With Aml Treated With Venetoclax And Azacitidine, Hartmut Döhner, Keith W Pratz, Courtney D Dinardo, Andrew H Wei, Brian A Jonas, Vinod A Pullarkat, Michael J Thirman, Christian Récher, Andre C Schuh, Sunil Babu, Xiaotong Li, Grace Ku, Zihuan Liu, Yan Sun, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea

Faculty, Staff and Student Publications

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most …

Genotype-Specific Effects Of Elamipretide In Patients With Primary Mitochondrial Myopathy: A Post Hoc Analysis Of The Mmpower-3 Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce Cohen, Gregory M Ennes, Marni J Falk, Amy Goldstein, Gráinne Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russekk Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, Anthony Abbruscato, David A Brown, Alana Sullivan, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Students Publications

BACKGROUND: As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those …

Phase I Dose Escalation Study Of Io-108, An Anti-Lilrb2 Antibody, In Patients With Advanced Solid Tumors, Matthew H Taylor, Aung Naing, John Powderly, Paul Woodard, Luke Chung, Wen Hong Lin, Hongyu Tian, Nathan Siemers, Hong Xiang, Rong Deng, Kyu Hong, Donna Valencia, Tao Huang, Ying Zhu, X Charlene Liao, Xiao Min Schebye, Manish R Patel

Faculty, Staff and Student Publications

Purpose: In this first-in-human dose escalation study, the safety and efficacy of IO-108, a fully human monoclonal antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), was investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody.

Methods: The study included patients with histologically or cytologically confirmed advanced and relapsed solid tumors, with measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Patients were treated with escalating doses of IO-108 every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. Safety and tolerability were the primary objectives. …

Long-Term Follow-Up Of Levonorgestrel Intrauterine Device For Atypical Hyperplasia And Early Endometrial Cancer Reveals Relapse Characterized By Immune Exhaustion, Mikayla B Bowen, Brenda Melendez, Qian Zhang, Richard K Yang, Bryan M Fellman, Barrett C Lawson, Naomi N Adjei, Joseph Celestino, Khalida M Wani, Bhavana Singh, Diana L Urbauer, Alexander J Lazar, Karen H Lu, Jennifer A Wargo, Shannon N Westin, Melinda S Yates

Faculty, Staff and Student Publications

Purpose: Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited.

Materials and methods: Follow-up data from patients in our prospective phase II trial of levonorgestrel intrauterine device (LIUD) for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse.

Results: Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen …

Association Of Clonal Hematopoiesis And Mosaic Chromosomal Alterations With Solid Malignancy Incidence And Mortality, Pinkal Desai, Ying Zhou, Justin Grenet, Samuel K Handelman, Cynthia M Crispino, Laura N Tarbay, Eric A Whitsel, Gail Roboz, Ana Barac, Michael Honigberg, Alexander Bick, Garnet Anderson, Jean Wactawski-Wende, Yasminka A Jakubek Swartzlander, Jason Bacon, Justin Wong, Xiaolong Ma, Paul Scheet, Zichan Li, Pashtoon Kasi, Ross Prentice, Paul Auer, Joann E Manson, Alexander Reiner, Michael Simon

Faculty, Staff and Student Publications

Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways.

Methods: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers.

Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or …

Disease Site Specialization In The Academic Radiation Oncology Workforce: Evidence Of Gender Differences, Kelsey L Corrigan, Mikaela E Bankston, Emma B Holliday, Simona F Shaitelman, Anna Lee, Chelain R Goodman, C David Fuller, Fumiko L Chino, Charles R Thomas, Reshma Jagsi, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: Because some stakeholders within medicine seek to diversify and attain greater workforce equity, it is critical to understand gender-based divisions within specialization. Radiation oncology (RO) has one of the smallest proportions of women representation of all specialties, and to our knowledge, no prior studies have investigated gender differences in all the disease site specializations within RO. Thus, we analyzed the relationship between gender and disease site(s) treated in academic RO (ARO).

Methods and materials: Faculty gender and disease site(s) treated by faculty from ARO departments were collected via publicly available department websites in January 2020. X2 analyses were conducted …

Outcomes Of Patients With Acute Myeloid Leukemia And Bone Marrow Fibrosis, Samuel Urrutia, Hagop M Kantarjian, Farhad Ravandi-Kashani, Carlos Bueso-Ramos, Rashmi Kanagal-Shamanna, Elias Jabbour, Guillermo Montalban-Bravo, Nicholas J Short, Naval Daver, Gautam Borthakur, Courtney D Dinardo, Tapan M Kadia, Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Guillermo Garcia-Manero, Koji Sasaki

Faculty, Staff and Student Publications

The outcomes of patients with acute myeloid leukemia (AML) and bone marrow fibrosis (MF) are not well defined. The study objectives were to evaluate the degrees of MF in AML, and corresponding response rates and outcomes. We performed a retrospective review of 2302 patients with AML. We annotated the clinical and molecular characteristics, response to therapy, and survival outcomes of patients with bone marrow fibrosis. Overall, 492 patients (21.4%) had a reported microscopic evaluation of MF: 344 (69.9%) had MF grade 0-1 and 148 (30.1%) had MF grade 2-3. Patients with MF 2-3 had a higher proportion of complex cytogenetics …

Low-Molecular Weight Cyclin E Confers A Vulnerability To Pkmyt1 Inhibition In Triple-Negative Breast Cancer, Mi Li, Amriti R Lulla, Yan Wang, Spyros Tsavaschidis, Fuchenchu Wang, Cansu Karakas, Tuyen D T Nguyen, Tuyen N Bui, Marc A Pina, Mei-Kuang Chen, Sofia Mastoraki, Asha S Multani, Natalie W Fowlkes, Aysegul Sahin, C Gary Marshall, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low-molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1-S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 …

What Do Cancer Genetic Providers Want Us To Know About Variant Reclassification And Recontact That We Are Not Asking? A Thematic Analysis Of Open-Ended Survey Responses, Kerri Brown, Marisel Ponton, Elenita Davidson, Banu Arun, Robert J Volk, Sanjay Shete, Susan K Peterson, Sukh Makhnoon

Faculty, Staff and Student Publications

BACKGROUND: Accurate variant classification and relaying reclassified results to patients is critical for hereditary cancer care delivery. Over a 5- to 10-year period, 6%-15% of variants undergo reclassification. As the frequency of reclassifications increases, the issue of whether, how, when, and which providers should recontact patients becomes important but remains contentious.

METHODS: The authors used inductive thematic analysis to analyze open-ended comments offered by oncologists and genetic counselors (GCs) from a large national survey.

RESULTS: Of the 634 oncologists and cancer GCs, 126 (20%) offered substantive free-text comments. Four thematic areas emerged: 1) ambiguity over professional responsibility to recontact, 2) …

Personalized Composite Dosimetric Score-Based Machine Learning Model Of Severe Radiation-Induced Lymphopenia Among Patients With Esophageal Cancer, Yan Chu, Cong Zhu, Brian P Hobbs, Yiqing Chen, Peter S N Van Rossum, Clemens Grassberger, Degui Zhi, Steven H Lin, Radhe Mohan

Faculty, Staff and Student Publications

Purpose: Radiation-induced lymphopenia (RIL) is common among patients undergoing radiation therapy (RT)' Severe RIL has been linked to adverse outcomes. The severity and risk of RIL can be predicted from baseline clinical characteristics and dosimetric parameters. However, dosimetric parameters, e.g. dose-volume (DV) indices, are highly correlated with one another and are only weakly associated with RIL. Here we introduce the novel concept of "composite dosimetric score" (CDS) as the index that condenses the dose distribution in immune tissues of interest to study the dosimetric dependence of RIL. We derived an improved multivariate classification scheme for risk of grade 4 RIL …

Evidence That Crispr-Cas9 Y537s-Mutant Expressing Breast Cancer Cells Activate Yes-Associated Protein 1 To Driving The Conversion Of Normal Fibroblasts Into Cancer-Associated Fibroblasts, Luca Gelsomino, Amanda Caruso, Emine Tasan, Adele Elisabetta Leonetti, Rocco Malivindi, Giuseppina Daniela Naimo, Francesca Giordano, Salvatore Panza, Guowei Gu, Benedetta Perrone, Cinzia Giordano, Loredana Mauro, Bruno Nardo, Gianfranco Filippelli, Daniela Bonofiglio, Ines Barone, Suzanne A W Fuqua, Stefania Catalano, Sebastiano Andò

Faculty, Staff and Students Publications

BACKGROUND: Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME.

METHODS: We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from …

The Il-1Β Inhibitor Canakinumab In Previously Treated Lower-Risk Myelodysplastic Syndromes: A Phase 2 Clinical Trial, Juan Jose Rodriguez-Sevilla, Vera Adema, Kelly S Chien, Sanam Loghavi, Feiyang Ma, Hui Yang, Guillermo Montalban-Bravo, Xuelin Huang, Xavier Calvo, Joby Joseph, Kristy Bodden, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had …

Addition Of Metastasis-Directed Therapy To Systemic Therapy For Oligometastatic Pancreatic Ductal Adenocarcinoma (Extend): A Multicenter, Randomized Phase Ii Trial, Ethan B Ludmir, Alexander D Sherry, Bryan M Fellman, Suyu Liu, Tharakeswara Bathala, Cara Haymaker, Marina N Medina-Rosales, Alexandre Reuben, Emma B Holliday, Grace L Smith, Sonal S Noticewala, Sarah Nicholas, Tracy R Price, Rachael M Martin-Paulpeter, Luis A Perles, Sunyoung S Lee, Michael S Lee, Brandon G Smaglo, Ryan W Huey, Jason Willis, Dan Zhao, Lorenzo Cohen, Cullen M Taniguchi, Eugene J Koay, Matthew H G Katz, Robert A Wolff, Prajnan Das, Shubham Pant, Albert C Koong, Chad Tang

Faculty, Staff and Student Publications

Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response …

Dna Methylation Classifier To Diagnose Pancreatic Ductal Adenocarcinoma Metastases From Different Anatomical Sites, Teodor G Calina, Eilís Perez, Elena Grafenhorst, Jamal Benhamida, Simon Schallenberg, Adrian Popescu, Ines Koch, Tobias Janik, Baoqing Chen, Jana Ihlow, Stephanie Roessler, Benjamin Goeppert, Bruno Sinn, Marcus Bahra, George A Calin, Eliane T Taube, Uwe Pelzer, Christopher C M Neumann, David Horst, Erik Knutsen, David Capper, Mihnea P Dragomir

Faculty, Staff and Student Publications

Background: We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites.

Methods: For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the …

The Rna Receptor Rig-I Binding Synthetic Oligodeoxynucleotide Promotes Pneumonia Survival, Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleóngarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans

Faculty, Staff and Student Publications

Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, …