Medical Specialties Commons^™

Rapid Laser Ablation-Based Fabrication Of High-Density Polymer Microwell Arrays For High-Throughput Cellular Studies, Desh Deepak Dixit, Kavya L Singampalli, Amit S Niyogi, Amanda Montoya, Alexandre Reuben, Peter B Lillehoj

Faculty, Staff and Student Publications

Polymer-based microwell platforms have garnered much interest due to their usefulness in culturing and analyzing small quantities of biological cells and spheroids. Existing methods for fabricating polymer microwell arrays involve complex fabrication processes and/or are limited in their ability to create dense arrays of very small (< 50 μm in diameter) microwells. Here, we present a simple and rapid technique for fabricating high-density arrays of microwells ranging from 20 to 160 μm in diameter on a variety of polymer substrates. In this approach, a polymer surface is ablated using a CO2 laser that is rastered over a stainless steel mesh, which serves as a shadow mask. A theoretical laser-polymer interaction model was developed for predicting the microwell volume based on the substrate properties and laser settings. Microwell volumes predicted by the model were within 5.4% of fabricated microwell volumes determined experimentally. Cellulose acetate microwell arrays fabricated using this technique were used to culture Lewis lung carcinoma cells expressing ovalbumin (LLC-OVA), which were maintained for up to 72 h with a negligible (< 5%) loss in viability. As a second proof of principle demonstration, LLC-OVA cells grown in microwell arrays were co-cultured with OT-I T cells and measurements of interferon gamma (IFN-γ), a marker for T cell activation, were performed which revealed a positive correlation between LLC-OVA cell-T cell interaction time and T cell activation. These two in vitro demonstrations showcase the capability of this technique in generating polymer microwell arrays for high-throughput cellular studies, including cell growth dynamics studies and cell interaction studies. Furthermore, we envision that these platforms can be used with different cell types and for other biological applications, such as spheroid formation and single cell analysis, …

Treatment Group-Specific Inferences In Phase Iii Randomized Oncology Trials, Alexander D Sherry, Adina H Passy, Joseph Abi Jaoude, Timothy A Lin, Ramez Kouzy, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Background: Estimation of comparative treatment effects between randomized groups is well-supported in randomized trials. By contrast, treatment group-specific inferences are challenging, as patients are selectively chosen for enrollment, and such inferences are formally discouraged by the CONSORT guidelines. The present study is the first-large scale assessment of the proportion of phase III oncology trials that present treatment group-specific inferences.

Methods: Published phase III randomized oncology trials were screened from ClinicalTrials.gov. Treatment group-specific inferences were defined by the presence of 95% CI or standard error for treatment-specific outcomes.

Results: A total of 774 phase III trials enrolling 568,080 patients were included. …

Lower Cytoplasmic Expression Of Ddit4 Is Associated With Poor Prognosis In Gastric Cancer Patients, Masoumeh Dehghan Manshadi, Fatemeh Tajik, Leili Saeednejad Zanjani, Farideh Hashemi, Mandana Rahimi, Fahimeh Fattahi, Sadegh Safaei, Zahra Madjd, Roya Ghods

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

INTRODUCTION: DNA damage-inducible transcript 4 (DDIT4), also known as Redd1, Dig2, and RTP801 was identified to be upregulated in response to a variety of cellular stresses, including DNA damage, endoplasmic reticulum stress, and energy stress. Several studies have discovered that dysregulation of DDIT4 involved in various cancers with paradoxical expression and roles. Hence, this study was designed to investigate the clinical significance and prognostic value of DDIT4 in different subtypes of gastric cancer (GC).

MATERIALS AND METHODS: To evaluate the expression pattern of DDIT4 in GC tissues as well as adjacent normal tissue, we utilized immunohistochemistry on tissue microarray (TMA) …

Evaluation Of The Distress Thermometer In Older Patients With Cancer, Charlotte Zuber, Kristine Swartz, Andrew Chapman, Lora Rhodes, Tingting Zhan, Kuang-Yi Wen

Kimmel Cancer Center Faculty Papers

INTRODUCTION: The Geriatric Depression Scale is a useful tool in screening for depression in older adults, a particularly vulnerable population in oncology. The National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT) has been validated as a fast and effective screening tool for psychological distress in general oncology populations, and it could possibly be used as a surrogate for the longer Geriatric Depression Scale (GDS) test in older adults with cancer.

MATERIALS AND METHODS: In this retrospective cross-sectional study in older adults prior to starting cancer treatment, we evaluated the relationship between the DT and GDS by comparing 242 older adults …

Gene Expression Profiling Of Pancreatic Ductal Adenocarcinoma Cells In Hypercapnia Identifies Siah3 As A Novel Prognostic Biomarker, Nitzan Zohar, Ryan Maguire, Saed Khalilieh, Aditi Jain, Dmitriy Bosykh, Wilbur B. Bowne, Harish Lavu, Charles J. Yeo, Avinoam Nevler

Department of Surgery Faculty Papers

Hypercapnia is a key feature of the respiratory microenvironment in many pathologic conditions. It occurs both as a regional and as a systemic process, and it is associated with multiple metabolic changes such as mitochondrial dysfunction, decreased ATP production, and metabolic shift from glycolytic energy production to fatty acid metabolism. In the cancer tumor microenvironment, hypercapnia has been linked at times to enhanced cell migration, invasion, and chemoresistance. Our previous work has shown that hypercapnia-associated gene signatures can be used as prognostic biomarkers. However, unlike the hypoxia-inducible factor pathway, there are no validated targets to quantify hypercapnia. In this study, …

Dna-Pk Inhibition Sustains The Antitumor Innate Immune Response In Small Cell Lung Cancer, Caterina De Rosa, Floriana Morgillo, Luisa Amato, Francesca Iommelli, Viviana De Rosa, Virginia Tirino, Federica Papaccio, Concetta Tuccillo, Gaetano Di Guida, Domenico Michele D'Angiolella, Alessandra Di Liello, Silvia Zappavigna, Michele Caraglia, Antonio Gambardella, Valerio Nardone, Kavya Ramkumar, Qi Wang, Jing Wang, Ferdinando De Vita, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Stefania Napolitano, Giulia Martini, Alberto Servetto, Lauren Averett Byers, Fortunato Ciardiello, Carminia Maria Della Corte

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with limited treatment options. Patients often respond well to initial chemo-immunotherapy but relapse quickly, necessitating new strategies to enhance immune responsiveness. Recent research explores combining DNA-damaging therapies with immunotherapy to activate the STING pathway and improve the antitumor immune response. The addition of DNA Damage Repair (DDR) inhibitors, such as DNA-PKcs inhibitors, after chemotherapy has shown promise in activating innate immune sensors and enhancing CD8

Evaluation And Surgical Management Of Pediatric Cutaneous Melanoma And Atypical Spitz And Non-Spitz Melanocytic Tumors (Melanocytomas): A Report From Children's Oncology Group, Michael R Sargen, Raymond L Barnhill, David E Elder, Susan M Swetter, Victor G Prieto, Jennifer S Ko, Armita Bahrami, Pedram Gerami, Arivarasan Karunamurthy, Alberto S Pappo, Lynn M Schuchter, Philip E Leboit, Iwei Yeh, John M Kirkwood, Melinda Jen, Ira J Dunkel, Megan M Durham, Emily R Christison-Lagay, Mary T Austin, Jennifer H Aldrink, Casey Mehrhoff, Elena B Hawryluk, Emily Y Chu, Klaus J Busam, Vernon Sondak, Jane Messina, Susana Puig, Andrew J Colebatch, Carrie C Coughlin, Kristen G Berrebi, Theodore W Laetsch, Sarah G Mitchell, Brittani Seynnaeve

Faculty, Staff and Student Publications

Purpose: The purpose of this study was to develop recommendations for the diagnostic evaluation and surgical management of cutaneous melanoma (CM) and atypical Spitz tumors (AST) and non-Spitz melanocytic tumors (melanocytomas) in pediatric (age 0-10 years) and adolescent (age 11-18 years) patients.

Methods: A Children's Oncology Group-led panel with external, multidisciplinary CM specialists convened to develop recommendations on the basis of available data and expertise.

Results: Thirty-three experts from multiple specialties (cutaneous/medical/surgical oncology, dermatology, and dermatopathology) established recommendations with supporting data from 87 peer-reviewed publications.

Recommendations: (1) Excisional biopsies with 1-3 mm margins should be performed when feasible for clinically …

Sap30, A Novel Autophagy Regulatory Gene In Neuroblastoma, Anup S Pathania, Anjana Murugan, Areem Zahid, Haritha Chava, Don W Coulter, George A Calin, Kishore B Challagundla

Faculty, Staff and Student Publications

Neuroblastoma (NB), a devastating pediatric cancer originating from neural crest cells crucial for nervous system development, poses a significant therapeutic challenge. Despite chemotherapy being the primary treatment, approximately 70% of high-risk NB cases develop resistance. Autophagy is vital for neuronal development, balance, and differentiation of neural stem cells into mature neurons. However, the intricate mechanisms governing autophagy and the pivotal genes orchestrating its regulation in NB remain largely elusive. In this study, we first identified Sin3A Associated Protein 30 (SAP30) as a novel regulator of autophagy in NB. Silencing SAP30 inhibits autophagy and disrupts starvation-induced physiological autophagy in NB cells. …

Do We Need To Add The Type Of Treatment Planning System, Dose Calculation Grid Size, And Ct Density Curve To Predictive Models?, Reza Reiazi, Surendra Prajapati, Leonardo Che Fru, Dongyeon Lee, Mohammad Salehpour

Faculty, Staff and Student Publications

Background: Generalizability and domain dependency are critical challenges in developing predictive models for healthcare, particularly in medical diagnostics and radiation oncology. Predictive models designed to assess tumor recurrence rely on comprehensive and high-quality datasets, encompassing treatment planning parameters, imaging protocols, and patient-specific data. However, domain dependency, arising from variations in dose calculation algorithms, computed tomography (CT) density conversion curves, imaging modalities, and institutional protocols, can significantly undermine model reliability and clinical utility.

Methods: This study evaluated dose calculation differences in the head and neck cancer treatment plans of 19 patients using two treatment planning systems, Pinnacle 9.10 and RayStation 11, …

Dna Damage Response Signatures Are Associated With Frontline Chemotherapy Response And Routes Of Tumor Evolution In Extensive Stage Small Cell Lung Cancer, Benjamin B Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R Tyson, Kyle Concannon, Kavya Ramkumar, C Allison Stewart, Robert J Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V Heymach, Barzin Y Nabet, David S Shames, Carl M Gay, Lauren A Byers

Faculty, Staff and Student Publications

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.

Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is …

Do We Need To Add The Type Of Treatment Planning System, Dose Calculation Grid Size, And Ct Density Curve To Predictive Models?, Reza Reiazi, Surendra Prajapati, Leonardo Che Fru, Dongyeon Lee, Mohammad Salehpour

Faculty, Staff and Student Publications

Background: Generalizability and domain dependency are critical challenges in developing predictive models for healthcare, particularly in medical diagnostics and radiation oncology. Predictive models designed to assess tumor recurrence rely on comprehensive and high-quality datasets, encompassing treatment planning parameters, imaging protocols, and patient-specific data. However, domain dependency, arising from variations in dose calculation algorithms, computed tomography (CT) density conversion curves, imaging modalities, and institutional protocols, can significantly undermine model reliability and clinical utility.

Methods: This study evaluated dose calculation differences in the head and neck cancer treatment plans of 19 patients using two treatment planning systems, Pinnacle 9.10 and RayStation 11, …

Mathematical Modeling To Address Questions In Breast Cancer Screening: An Overview Of The Breast Cancer Models Of The Cancer Intervention And Surveillance Modeling Network, Oguzhan Alagoz, Jennifer L Caswell-Jin, Harry J De Koning, Hui Huang, Xuelin Huang, Sandra J Lee, Yisheng Li, Sylvia K Plevritis, Swarnavo Sarkar, Clyde B Schechter, Natasha K Stout, Amy Trentham-Dietz, Nicolien Van Ravesteyn, Kathryn P Lowry

Faculty, Staff and Student Publications

The National Cancer Institute-funded Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer mathematical models have been increasingly utilized by policymakers to address breast cancer screening policy decisions and influence clinical practice. These well-established and validated models have a successful track record of use in collaborations spanning over 2 decades. While mathematical modeling is a valuable approach to translate short-term screening performance data into long-term breast cancer outcomes, it is inherently complex and requires numerous inputs to approximate the impacts of breast cancer screening. This review article describes the 6 independently developed CISNET breast cancer models, with a particular focus …

Near-Infrared Fluorescence Imaging With An Met-Targeting Probe For Biopsy Site Selection In Patients With Oral Potentially Malignant Disorders, Jingbo Wang, Xuemin Shen, Qifan Ma, Lin Yang, Xiaoyu Zhou, Luting Wang, Junqi Cui, Chunye Zhang, Guojun Li, Neil Gross, Siyi Li, Ruimin Huang, Changyou Zhan, Zhen Cheng, Kun Wang, Jie Tian, Ying Yuan, Xiaofeng Tao

Faculty, Staff and Student Publications

Accurate detection of malignant transformation in oral potentially malignant disorders (OPMDs) is crucial for guiding effective treatment and improving patient management. This study evaluates the potential of MET-binding peptide-indocyanine green (cMBP-ICG), a mesenchymal-epithelial transition factor (MET)-targeted near-infrared fluorescence imaging (NIRFI) probe, for biopsy site selection in OPMDs. Preclinical results demonstrate the superior accuracy of NIRFI-assisted biopsy over conventional oral examination (COE)-based biopsy in detecting high-grade dysplasia (HGD) or squamous cell carcinoma (SCC) and reducing missed detection rates. In a clinical trial with 50 patients, NIRFI-assisted biopsy achieves significantly higher diagnostic accuracy compared to COE-based biopsy (91% vs. 72%, p = …

Icos-Expressing Car-T Cells Mediate Durable Eradication Of Triple-Negative Breast Cancer And Metastasis, Shelley Herbrich, Mehdi Chaib, Padmanee Sharma

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes. In their recent study, Cao et al introduced a B7H3-specific chimeric antigen receptor (CAR)-T cell with constitutive inducible co-stimulator (ICOS) expression (ICOS-B7H3-CAR-T), which demonstrated eradication of TNBC, including metastases, in preclinical models. These CAR-T cells exploit the expression of ICOS ligand on TNBC cells, enhancing antitumor cytotoxicity through ICOS signaling. Compared with conventional B7H3-CAR-T cells, the ICOS-B7H3-CAR-T cells exhibited superior antitumor efficacy, increased cytokine secretion, and prolonged survival in xenograft murine models. This study highlights ICOS as a promising co-stimulatory molecule for improving CAR-T …

Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation And Sensitizes Leukemias To Menin Inhibition, Xiangguo Shi, Minhua Li, Zian Liu, Jonathan Tiessen, Yuan Li, Jing Zhou, Yudan Zhu, Swetha Mahesula, Qing Ding, Lin Tan, Mengdie Feng, Yuki Kageyama, Yusuke Hara, Jacob J Tao, Xuan Luo, Kathryn A Patras, Philip L Lorenzi, Suming Huang, Alexandra M Stevens, Koichi Takahashi, Ghayas C Issa, Md Abul Hassan Samee, Michalis Agathocleous, Daisuke Nakada

Faculty, Staff and Student Publications

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding …

Neural Correlates Of Opioid-Induced Risk-Taking Behavior In The Prelimbic Prefrontal Cortex, Cana B Quave, Andres M Vasquez, Guillermo Aquino-Miranda, Milagros Marín, Esha P Bora, Chinenye L Chidomere, Xu O Zhang, Douglas S Engelke, Fabricio H Do-Monte

Faculty, Staff and Student Publications

Opioid use disorder occurs alongside impaired risk-related decision-making, but the underlying neural correlates are unclear. We developed an approach-avoidance conflict task using a modified conditioned place preference procedure to study neural signals of risky opioid seeking in the prefrontal cortex, a region implicated in executive decision-making. Following morphine conditioned place preference, rats underwent a conflict test in which fear-inducing cat odor was introduced in the previously drug-paired side of the apparatus. While the saline-exposed control group avoided cat odor, the morphine group included two subsets of rats that either maintained a preference for the paired side despite the presence of …

An Exosome-Based Liquid Biopsy Predicts Depth Of Response And Survival Outcomes To Cetuximab And Panitumumab In Metastatic Colorectal Cancer: The Exonerate Study, Caiming Xu, Alessandro Mannucci, Francis Esposito, Helena Oliveres, Vicente Alonso-Orduña, Alfonso Yubero, Carlos Fernández-Martos, Antonieta Salud, Javier Gallego, Marta Martín-Richard, Julen Fernández-Plana, Mónica Guillot, Jorge Aparicio, Marwan Fakih, Scott Kopetz, Jaime Feliu, Joan Maurel, Ajay Goel

Faculty, Staff and Student Publications

Purpose: The EXOsome and cell-free miRNAs of anti-EGFR ResistAnce (EXONERATE) study was an open-label, biomarker interventional study designed to develop, test, and validate a liquid biopsy predictive of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) for first-line EGFR inhibitors in metastatic colorectal cancer (mCRC).

Patients and methods: Patients with newly diagnosed RAS wild-type, chemotherapy-naïve mCRC, both right- and left-sided, were enrolled in two nationwide trials to receive cetuximab or panitumumab along with chemotherapy. The primary endpoint was 12-month PFS, which was hierarchically tested in left- and right-sided mCRCs to predict PFS, OS, and ORR.

Results: Genome-wide …

Impact Of Co-Mutations And Transcriptional Signatures In Non-Small Cell Lung Cancer Patients Treated With Adagrasib In The Krystal-1 Trial, Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach

Faculty, Staff and Student Publications

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: …

Phase I Trial Of Tti-101, A First-In-Class Oral Inhibitor Of Stat3, In Patients With Advanced Solid Tumors, Apostolia M Tsimberidou, David J Vining, Sukeshi P Arora, Sofia De Achaval, Jeffrey Larson, John Kauh, Carrie Cartwright, Rony Avritscher, Imran Alibhai, David J Tweardy, Ahmed O Kaseb

Faculty, Staff and Student Publications

Purpose: Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer.

Patients and methods: Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day ("3+3" design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699).

Results: Sixty-four patients were treated (median …

Ca-125 As A Biomarker In Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, And Prospective Clinical Validation, Sandra L Grimm, Menuka Karki, Kyle A Blum, Jean-Philippe Bertocchio, Rong He, Durga N Tripathi, Niki M Zacharias, Justin M Lebenthal, Rahul A Sheth, Priya Rao, Giannicola Genovese, Zhen Lu, Robert C Bast, Davis R Ingram, Rossana Lazcano, Khalida M Wani, Wei-Lien Wang, Alexander J Lazar, Nizar M Tannir, Cheryl L Walker, Cristian Coarfa, Pavlos Msaouel

Faculty, Staff and Student Publications

Purpose: Renal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC.

Experimental design: Integrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA sequencing and histone chromatin immunoprecipitation sequencing. The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. …

Inflammation And Gut Barrier Function-Related Genes And Colorectal Cancer Risk In Western European Populations, Hannah B Mandle, Mazda Jenab, Marc J Gunter, Anne Tjønneland, Anja Olsen, Christina C Dahm, Jie Zhang, Pierre-Emmanuel Sugier, Joseph Rothwell, Gianluca Severi, Rudolf Kaaks, Verena A Katzke, Matthias B Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Carlotta Sacerdote, Catalina Bonet, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Marcela Guevara, Richard Palmqvist, Thyra Löwenmark, Aurora Perez-Cornago, Elisabete Weiderpass, Alicia K Heath, Amanda J Cross, Paolo Vineis, David J Hughes, Veronika Fedirko

Faculty, Staff and Student Publications

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set …

Adding Metastasis-Directed Therapy To Standard-Of-Care Systemic Therapy For Oligometastatic Breast Cancer (Extend): A Multicenter, Randomized Phase 2 Trial, Jay P Reddy, Alexander D Sherry, Bryan Fellman, Suyu Liu, Tharakeswara Bathala, Cara Haymaker, Lorenzo Cohen, Benjamin D Smith, David Ramirez, Simona F Shaitelman, Stephen G Chun, Marina Medina-Rosales, Mediget Teshome, Abenaa Brewster, Carlos H Barcenas, Alexandre Reuben, Amol J Ghia, Ethan B Ludmir, Daniel Weed, Shalin J Shah, Melissa P Mitchell, Wendy A Woodward, Daniel R Gomez, Chad Tang

Faculty, Staff and Student Publications

PURPOSE: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer.

METHODS AND MATERIALS: External Beam Radiation to Eliminate Nominal Metastatic Disease is a multicenter phase 2 randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomly assigned 1:1 to MDT (definitive local treatment …

Superior Preclinical Efficacy Of Co-Treatment With Brg1/Brm And Flt3 Inhibitor Against Aml Cells With Flt3 Mutations, Warren Fiskus, Christopher P Mill, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Lauren B Flores, Sanam Loghavi, Xiaoping Su, Courtney D Dinardo, Kapil N Bhalla

Faculty, Staff and Student Publications

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells. Findings of present studies demonstrate that treatment with FHD-286 induces lethality in AML cells, regardless of sensitivity or resistance to …

Tunneling Nanotube-Like Structures Regulate Distant Cellular Interactions During Heart Formation, Lianjie Miao, Yangyang Lu, Anika Nusrat, Guizhen Fan, Shaohua Zhang, Luqi Zhao, Chia-Ling Wu, Hongyan Guo, Trang Le Nu Huyen, Yi Zheng, Zhen-Chuan Fan, Weinian Shou, Robert J Schwartz, Yu Liu, Ashok Kumar, Haixin Sui, Irina I Serysheva, Alan R Burns, Leo Q Wan, Bin Zhou, Sylvia M Evans, Mingfu Wu

Faculty, Staff and Student Publications

In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube-like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and …

Efficacy And Safety Of Venetoclax Plus Azacitidine For Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes, Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). …

Deep Learning Models Based On Pretreatment Mri And Clinicopathological Data To Predict Responses To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Zhan Xu, Zijian Zhou, Jong Bum Son, Haonan Feng, Beatriz E Adrada, Tanya W Moseley, Rosalind P Candelaria, Mary S Guirguis, Miral M Patel, Gary J Whitman, Jessica W T Leung, Huong T C Le-Petross, Rania M Mohamed, Bikash Panthi, Deanna L Lane, Huiqin Chen, Peng Wei, Debu Tripathy, Jennifer K Litton, Vicente Valero, Lei Huo, Kelly K Hunt, Anil Korkut, Alastair Thompson, Wei Yang, Clinton Yam, Gaiane M Rauch, Jingfei Ma

Faculty, Staff and Student Publications

Purpose: To develop deep learning models for predicting the pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in patients with triple-negative breast cancer (TNBC) based on pretreatment multiparametric breast MRI and clinicopathological data.

Methods: The prospective institutional review board-approved study [NCT02276443] included 282 patients with stage I-III TNBC who had multiparametric breast MRI at baseline and underwent NAST and surgery during 2016-2021. Dynamic contrast-enhanced MRI (DCE), diffusion-weighted imaging (DWI), and clinicopathological data were used for the model development and internal testing. Data from the I-SPY 2 trial (2010-2016) were used for external testing. Four variables with a …

Efficacy And Safety Of Venetoclax Plus Azacitidine For Patients With Treatment-Naive High-Risk Myelodysplastic Syndromes, Jacqueline S Garcia, Uwe Platzbecker, Olatoyosi Odenike, Shaun Fleming, Chun Yew Fong, Uma Borate, Meagan A Jacoby, Daniel Nowak, Maria R Baer, Pierre Peterlin, Brenda Chyla, Huipei Wang, Grace Ku, David Hoffman, Jalaja Potluri, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Outcomes are poor in patients with higher-risk myelodysplastic syndromes (HR MDS) and frontline treatment options are limited. This phase 1b study investigated safety and efficacy of venetoclax, a selective B-cell lymphoma 2 inhibitor, at the recommended phase 2 dose (RP2D; 400 mg for 14 days per 28-day cycle), in combination with azacitidine (75 mg/m2 for 7 days per 28-day cycle) for treatment-naive HR MDS. Safety was the primary outcome, and complete remission (CR) rate was the primary efficacy outcome. Secondary outcomes included rates of modified overall response (mOR), hematologic improvement (HI), overall survival (OS), and time to next treatment (TTNT). …

Cranial Radiation Disrupts Dopaminergic Signaling And Connectivity In The Mammalian Brain, Die Zhang, Riya Thomas, Thanh Thai Lam, Ines Veselinovic, David R Grosshans

Faculty, Staff and Student Publications

Cognitive impairment is a common and challenging side effect of cranial radiation therapy for brain tumors, though its precise mechanisms remain unclear. The mesocortical dopaminergic pathway, known to play a key role in cognitive function, is implicated in several neuropsychiatric disorders, yet its involvement in radiation-induced cognitive dysfunction is unexplored. Here, with using in vivo multi-electrode array recordings of both anesthetized and free-moving rats to monitor the firing activities of dopamine neurons in the ventral tegmental area (VTA) and local field potentials in both the prefrontal cortex (PFC) and VTA, as well as the immunofluorescence assays and western blotting, we …

Alpha-Frequency Stimulation Strengthens Coupling Between Temporal Fluctuations In Alpha Oscillation Power And Default Mode Network Connectivity, Yijia Ma, Joshua A Brown, Chaowen Chen, Mingzhou Ding, Wei Wu, Wen Li

Faculty, Staff and Student Publications

Alpha (8–12 Hz) oscillations and default mode network (DMN) activity dominate the brain's intrinsic activity in the temporal and spatial domains, respectively. They are thought to play crucial roles in the spatiotemporal organization of the complex brain system. Relatedly, both have been implicated, often concurrently, in diverse neuropsychiatric disorders, with accruing electroencephalogram (EEG)/magnetoencephalogram and functional magnetic resonance imaging (fMRI) data linking these two neural activities both at rest and during key cognitive operations. Prominent theories and extant findings thus converge to suggest a mechanistic relationship between alpha oscillations and the DMN. Here, we leveraged simultaneous EEG–fMRI data acquired before and …

Advancing Drug Development In Myelodysplastic Syndromes, Alain Mina, Kathy L Mcgraw, Lea Cunningham, Nina Kim, Emily Y Jen, Katherine R Calvo, Lori A Ehrlich, Peter D Aplan, Guillermo Garcia-Manero, James M Foran, Jacqueline S Garcia, Amer M Zeidan, Amy E Dezern, Rami Komrokji, Mikkael A Sekeres, Bart Scott, Rena Buckstein, Sara Tinsley-Vance, Amit Verma, Tanya Wroblewski, Steven Pavletic, Kelly Norsworthy

Faculty, Staff and Student Publications

Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges …