Medical Genetics Commons^™

Efficacy And Safety Of Denileukin Diftitox-Cxdl, An Improved Purity Formulation Of Denileukin Diftitox, In Patients With Relapsed Or Refractory Cutaneous T-Cell Lymphoma, Francine M Foss, Youn H Kim, H Miles Prince, Oleg E Akilov, Christiane Querfeld, Lucia Seminario-Vidal, David C Fisher, Timothy M Kuzel, Costas K Yannakou, Larisa J Geskin, Tatyana Feldman, Lubomir Sokol, Pamela Blair Allen, Nam Hoang Dang, Fernando Cabanillas, Henry K Wong, Chean Eng Ooi, Dongyuan Xing, Nicholas Sauter, Preeti Singh, Myron Czuczman, Madeleine Duvic

Faculty, Staff and Student Publications

Purpose: Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL).

Patients and methods: In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. …

Evaluation Of A Comprehensive Set Of Normal Tissue Complication Probability Models For Patients With Head And Neck Cancer In An International Cohort, Suzanne P M De Vette, Maria I Van Rijn-Dekker, Lisa Van Den Bosch, Kylie Keijzer, Hendrike Neh, Hung Chu, Yan Li, Mark L Frederiks, Hans Paul Van Der Laan, Jolien Heukelom, Peter Van Luijk, Arjen Van Der Schaaf, Roel J H M Steenbakkers, Nanna M Sijtsema, Katherine A Hutcheson, Clifton D Fuller, Johannes A Langendijk, Amy C Moreno, Lisanne V Van Dijk

Faculty, Staff and Student Publications

Background/purpose: Normal tissue complication probability (NTCP) models can be used to guide radiation therapy (RT) decisions by estimating side-effect risks pretreatment to minimize (late) side-effects. Recently, a comprehensive individual toxicity risk (CITOR) profile of NTCP models addressing common side-effects in head and neck cancer (HNC) patients was developed. This study investigates the generalizability of these models in an international setting, with different treatment approaches and side-effect assessments, promoting their integration into more widespread clinical practice.

Materials/methods: From a prospective registry study, 407 HNC patients were included who were treated with definitive RT with or without systemic therapy between 2015 and …

Cytokine Storms In Covid-19, Hemophagocytic Lymphohistiocytosis, And Car-T Therapy, James P Long, Rishab Prakash, Paul Edelkamp, Mark Knafl, Anath C Lionel, Ranjit Nair, Sairah Ahmed, Paolo Strati, Luis E Malpica Castillo, Ajlan Al-Zaki, Kelly Chien, Dai Chihara, Jason Westin, Fareed Khawaja, Loretta J Nastoupil, Victor Mulanovich, Andrew Futreal, Scott E Woodman, Naval G Daver, Christopher R Flowers, Sattva Neelapu, Joanna-Grace Manzano, Swaminathan P Iyer

Faculty, Staff and Student Publications

Importance: Cytokine storm (CS) is a hyperinflammatory syndrome causing multiorgan dysfunction and high mortality, especially in patients with malignant hematologic neoplasms. Triggers include malignant neoplasm-associated hemophagocytic lymphohistiocytosis (MN-HLH), cytokine release syndrome from chimeric antigen receptor T-cell therapy (CAR-T CRS), and COVID-19, but the underlying mechanisms of inflammation and their impact on outcomes are poorly understood.

Objective: To delineate the inflammatory patterns characterizing different CS etiologies and their association with clinical outcomes.

Design, setting, and participants: This retrospective cohort study was conducted at the MD Anderson Cancer Center in Houston, Texas, between March 1, 2020, and November 20, 2022, using the …

Diet And Survival After A Diagnosis Of Ovarian Cancer: A Pooled Analysis From The Ovarian Cancer Association Consortium, Christina M Nagle, Torukiri I Ibiebele, Renhua Na, Elisa V Bandera, Daniel Cramer, Jennifer A Doherty, Graham G Giles, Marc T Goodman, Gillian E Hanley, Holly R Harris, Allan Jensen, Susanne K Kjaer, Alice Lee, Valerie Mcguire, Roger L Milne, Bo Qin, Jean Richardson, Naoko Sasamoto, Joellen M Schildkraut, Weiva Sieh, Kathryn L Terry, Linda Titus, Britton Trabert, Nicolas Wentzensen, Anna H Wu, Andrew Berchuck, Malcolm C Pike, Celeste Leigh Pearce, Penelope M Webb, Multidisciplinary Ovarian Cancer Outcomes Group And Ovarian Cancer Association Consortium

Faculty, Staff and Student Publications

Background: Prognosis after a diagnosis of invasive epithelial ovarian cancer is poor. Some studies have suggested modifiable behaviors, like diet, are associated with survival but the evidence is inconsistent.

Objectives: This study aims to pool data from studies conducted around the world to evaluate the relationships among dietary indices, foods, and nutrients from food sources and survival after a diagnosis of ovarian cancer.

Methods: This analysis from the Multidisciplinary Ovarian Cancer Outcomes Group within the Ovarian Cancer Association Consortium included 13 studies with 7700 individuals with ovarian cancer, who completed food-frequency questionnaires regarding their prediagnosis diet. Adjusted hazard ratios (aHRs) …

Nicotinic Acetylcholine Receptor Expression In Merkel Cell Carcinoma Is Associated With Clinical And Histopathologic Parameters, Christopher R Cunningham, Yiannis P Dimopoulos, Ian M García-Quiñones, Denái R Milton, Manuel Delgado-Vélez, Woo Cheal Cho, Victor G Prieto, José A Lasalde-Dominicci, Leomar Y Ballester, Phyu P Aung

Faculty, Staff and Student Publications

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow-up was 29.8 months (range, 2.7-234.1). We performed immunohistochemistry using antibodies against the …

Nicotinic Acetylcholine Receptor Expression In Merkel Cell Carcinoma Is Associated With Clinical And Histopathologic Parameters, Christopher R Cunningham, Yiannis P Dimopoulos, Ian M García-Quiñones, Denái R Milton, Manuel Delgado-Vélez, Woo Cheal Cho, Victor G Prieto, José A Lasalde-Dominicci, Leomar Y Ballester, Phyu P Aung

Faculty, Staff and Student Publications

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow-up was 29.8 months (range, 2.7-234.1). We performed immunohistochemistry using antibodies against the …

Comparison Of Six Handheld Ultrasound Devices By Pediatric Point Of Care Ultrasound (Pocus) Experts, Stephanie K Leung, Ria Dancel, Riya N Soni, Ariadna Perez-Sanchez, Michael J Mader, Haitham Al-Wahab, Thomas W Conlon, Maria V Fraga, Javier J Lasa, Andrea Matho, Hannah Smith, Nilam J Soni

Faculty, Staff and Student Publications

BACKGROUND: Point of care ultrasound (POCUS) use is increasing among pediatric clinicians, but lack of access to ultrasound devices is a major barrier. The availability of pocket-sized handheld ultrasound devices ("handhelds") has improved access. However, no head-to-head comparative studies of handhelds in children have been performed to guide purchasing decisions.

METHODS: This cross-sectional study compared six handhelds: Butterfly iQ+™ (Butterfly Network Inc.), Clarius® (Clarius Mobile Health™), Kosmos™(EchoNous), TE Air™ (Mindray®), Vscan Air™ SL (General Electric), and Lumify™ (Philips Healthcare). Eight pediatric POCUS experts acquired views showing the abdominal right upper quadrant (RUQ), cardiac apical 4-chamber, and superficial neck and lung …

Cell-Free Dna Results Indicating Mosaic Monosomy X Of Likely Maternal Origin: Impact On Genetic Counseling Practices And Patient Experiences, Audrey Mcbride, Ashley Cannon, Siddharth Prakash, Aaron W Roberts, Angela Seasely, Anna C E Hurst, Laura Hendon

Faculty, Staff and Student Publications

Objective: To investigate the current genetic counseling practices involving a cfDNA result indicating mosaic monosomy X of likely maternal origin, and to better understand the perspectives of patients who have received this result.

Method: A total of 60 prenatal genetic counselors completed surveys about their experiences with this result, cfDNA consenting practices, and management practices. In addition, qualitative interviews were conducted with 5 patients to gain insight into their experiences with result disclosure and follow-up care.

Results: 95% of genetic counselors reported feeling prepared to counsel on these results. However, responses to current practices varied. Of the genetic counselors surveyed, …

Daratumumab/Lenalidomide/Dexamethasone In Transplant-Ineligible Newly Diagnosed Myeloma: Maia Long-Term Outcomes, Thierry Facon, Philippe Moreau, Katja Weisel, Hartmut Goldschmidt, Saad Z Usmani, Ajai Chari, Torben Plesner, Robert Z Orlowski, Nizar Bahlis, Supratik Basu, Cyrille Hulin, Hang Quach, Michael O'Dwyer, Aurore Perrot, Caroline Jacquet, Christopher P Venner, Noopur Raje, Mourad Tiab, Margaret Macro, Laurent Frenzel, Xavier Leleu, Gordon Cook, George Wang, Huiling Pei, Maria Krevvata, Robin Carson, Fredrik Borgsten, Shaji K Kumar

Faculty, Staff and Student Publications

In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (< 70, ≥70 to < 75, ≥75, and ≥80 years). Overall, 737 transplant-ineligible patients with NDMM were randomized 1:1 to D-Rd or Rd. The primary endpoint, PFS, was improved with D-Rd versus Rd (median, 61.9 vs 34.4 months; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; P <  0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P <  0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.

In Vivo Antibody Labeling Route And Fluorophore Dictate Labeling Efficiency, Sensitivity, And Longevity, Natalie B Hagan, Charles Inaku, Nikesh Kunder, Tayleur White, Thierry Iraguha, Anna Meyer, Kristen E Pauken, Jason M Schenkel

Faculty, Staff and Student Publications

Leukocytes migrate through the blood and extravasate into organs to surveil the host for infection or cancer. Recently, we demonstrated that intravenous (IV) anti-CD45.2 antibody labeling allowed for precise tracking of leukocyte migration. However, the narrow labeling window can make this approach challenging for tracking rare migration events. Here, we show that altering antibody administration route and fluorophore can significantly extend the antibody active labeling time. We found that while both IV and intraperitoneal (IP) anti-CD45.2 antibody labeled circulating leukocytes after injection, they had different kinetic properties that impacted labeling time and intensity. Quantification of circulating antibody revealed that while …

Staged Screening Identifies People With Biomarkers Related To Neuronal Alpha-Synuclein Disease, Ethan G Brown, Lana M Chahine, Andrew Siderowf, Caroline Gochanour, Ryan Kurth, Micah J Marshall, Chelsea Caspell-Garcia, Michael C Brumm, Craig E Stanley, Monica Korell, Bridget Mcmahon, Maggie Kuhl, Kimberly Fabrizio, Laura Heathers, Luis Concha-Marambio, Claudio Soto, Sohini Chowdhury, Christopher S Coffey, Tatiana M Foroud, Tanya Simuni, Kenneth Marek, Caroline M Tanner

Faculty, Staff and Student Publications

Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation.

Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in …

Manual Therapy For Fibrosis-Related Late Effect Dysphagia In Head And Neck Cancer Survivors: The Mantle Nonrandomized Clinical Trial, Holly Mcmillan, Carla L Warneke, Sheila Buoy, Christine Porsche, Kiara Savage, Stephen Y Lai, Clifton D Fuller, Katherine A Hutcheson

Faculty, Staff and Student Publications

Importance: Late radiation-associated dysphagia (RAD) after head and neck cancer (HNC) treatment is challenging and commonly treatment refractory, with fibrosis stiffening connective tissues and compressing peripheral nerve tracts, contributing to diminished strength and possibly denervation of swallowing muscles. Manual therapy (MT), while common for cancer-related pain and other indications, remains largely unstudied for fibrosis-related late RAD.

Objective: To determine the feasibility and safety of MT, estimate effect size and durability of MT for associated improvements in cervical range of motion (CROM), and examine functional outcomes after MT in survivors of HNC with fibrosis-related late RAD.

Design, setting, and participants: This …

The Effect Of Alzheimer's Disease Genetic Factors On Limbic White Matter Microstructure, Anna Lorenz, Aditi Sathe, Dimitrios Zaras, Yisu Yang, Alaina Durant, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Praitayini Kanakaraj, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Yuankai Huo, Logan Dumitrescu, Niranjana Shashikumar, Kimberly R Pechman, Trevor Bryan Jackson, Abigail W Workmeister, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Mohamad Habes, Di Wang, Duygu Tosun, Arthur W Toga, Paul M Thompson, Elizabeth C Mormino, Panpan Zhang, Kurt Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Sterling C Johnson, Barbara Bendlin, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Timothy J Hohman, Derek B Archer

Faculty, Staff and Student Publications

Introduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.

Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores …

Pediatric Myeloid Neoplasms With Ubtf Tandem Duplications: Morphologic, Immunophenotypic, And Clinical Characterization, Mahsa Khanlari, Wei Wang, Yonghui Ni, Paul E Mead, Masayuki Umeda, Tami Westover, Jing Ma, Jeffrey E Rubnitz, Juan M Barajas, Stanley Pounds, Jeffery M Klco

Faculty, Staff and Student Publications

Tandem duplications (TDs) in exons of upstream binding transcription factor (UBTF-TD) are a rare recurrent alteration in pediatric and adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/neoplasm. Although recently identified, AML with UBTF-TD is now considered a distinct subtype of AML. To further our understanding of myeloid neoplasms with UBTF-TD, we analyzed clinical, morphologic, and immunophenotypic characteristics of 27 pediatric patients with UBTF-TD-positive myeloid neoplasm, including 21 diagnosed as AML and 6 as MDS. Our data demonstrated that UBTF-TD is frequently associated with cytopenia, hypercellular marrow with erythroid hyperplasia, and trilineage dysplasia. Blasts …

Real-World Effectiveness Of Chemoimmunotherapy And Novel Therapies For Patients With Relapsed/Refractory Aggressive Large B-Cell Lymphoma, Loretta J Nastoupil, Clark R Andersen, Amy Ayers, Yucai Wang, Thomas M Habermann, Dai Chihara, Brad S Kahl, Brian K Link, Jean L Koff, Jonathon B Cohen, Peter Martin, Izidore S Lossos, Michele Stanchina, Sara Haddadi, Carla Casulo, Sabarish Ayyappan, Ruitao Lin, Ziyi Li, Melissa A Larson, Matthew J Maurer, Lynn Huynh, Chi Gao, Ramya Ramasubramanian, Mei Sheng Duh, Alex Mutebi, Tongsheng Wang, Monika Jun, Anthony Wang, Rajesh Kamalakar, Anupama Kalsekar, James R Cerhan, Christopher R Flowers

Faculty, Staff and Student Publications

Introduction: Clinical trials provide meaningful data regarding the safety and efficacy of novel therapies but there is often a lag between the time of new drug approval and information on posttreatment clinical outcomes in real-world practice. This study evaluated clinical outcomes in a large real-world population of patients with relapsed and/or refractory large B-cell lymphoma (r/r LBCL) treated with chemoimmunotherapy or novel therapies in second or later lines of therapy (2L+).

Materials and methods: Data from the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real-World Evidence (CReWE) cohort (1/1/2015-2/15/2023) were analyzed. Patients' demographic and clinical characteristics were described and response …

Receptor Tyrosine Kinase Fusion-Mediated Resistance To Egfr Tki In Egfr-Mutant Nsclc: A Multi-Center Analysis And Literature Review, Yang Xia, Kaiwen Wang, Jing Zhao, Zhaohui Arter, Yongchang Zhang, Jiaqi Zhou, Yuefei Lu, Liang Zeng, Robyn Du, Jennifer A Owens, Yasir Y Elamin, Carl M Gay, Ferdinandos Skoulidis, Anne S Tsao, Charles Lu, Tina Cascone, Don L Gibbons, Jianjun Zhang, Olivia Chen, Kevin K S Mok, Misako Nagasaka, Wen Li, John V Heymach, Sai-Hong Ignatius Ou, Molly Li, Xiuning Le

Faculty, Staff and Student Publications

Introduction: Drug resistance remains a major clinical challenge in EGFR-mutant NSCLC tumors owing to pathway reactivation, pathway bypass, and pathway indifference resistance mechanisms to evade tyrosine kinase inhibitor (TKI) suppression. Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance. Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition.

Methods: We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from …

De Novo Variants In Rybp Are Associated With A Severe Neurodevelopmental Disorder And Congenital Anomalies, Monika Weisz-Hubshman, Lindsay C Burrage, Sharayu V Jangam, Jill A Rosenfeld, Sandra Von Hardenberg, Anke Bergmann, Manuela Friederike Richter, Malgorzata Rydzanicz, Rafal Ploski, Agnieszka Stembalska, Wendy K Chung, Rebecca R Hernan, Foong Y Lim, Theresa Brunet, Steffen Syrbe, Boris Keren, Solveig Heide, David R Murdock, Hongzheng Dai, Fan Xia, Shamika Ketkar, Brian Dawson, Vinodh Narayanan, Hillary K Graves, Undiagnosed Diseases Network, Michael F Wangler, Carlos Bacino, Brendan Lee

Duncan NRI Faculty and Staff Publications

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

Methods: Functional consequences of RYBP variants were assessed using in vitro cellular and in vivo Drosophila melanogaster studies.

Results: We described 7 individuals with heterozygous de novo variants of RYBP and their clinical findings, including severe developmental delay, dysmorphisms, and multiple congenital anomalies. We showed that all single-nucleotide variants in RYBP localize to the N-terminal domain of …

Oral Decitabine Cedazuridine With And Without Venetoclax In Higher-Risk Myelodysplastic Syndromes Or Chronic Myelomonocytic Leukemia: A Propensity Score-Matched Study, Alex Bataller, Koji Sasaki, Samuel Urrutia, Guillermo Montalban-Bravo, Alexandre Bazinet, Kelly Chien, Danielle Hammond, Ian M Bouligny, Mahesh Swaminathan, Ghayas Issa, Nicholas Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gail J Roboz, Michael Savona, Elizabeth A Griffiths, James Mccloskey, Olatoyosi Odenike, Aram Oganesian, Harold N Keer, Mohammad Azab, Hagop Kantarjian, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Hypomethylating agents (HMA) are indicated in the treatment of higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The combination of hypomethylating agents with venetoclax (Ven) has demonstrated promising results in these diseases, although randomized clinical trials are needed for validation. In this retrospective study, we compared two matched cohorts of patients with MDS or CMML: one receiving oral decitabine-cedazuridine (DEC-C, n = 73) and one receiving DEC-C and Ven (DEC-C-Ven, n = 51), in three contemporary clinical trials. The aim is to determine the impact of the addition of Ven to HMA in MDS and CMML. Individuals were matched …

Oral Decitabine Cedazuridine With And Without Venetoclax In Higher-Risk Myelodysplastic Syndromes Or Chronic Myelomonocytic Leukemia: A Propensity Score-Matched Study, Alex Bataller, Koji Sasaki, Samuel Urrutia, Guillermo Montalban-Bravo, Alexandre Bazinet, Kelly Chien, Danielle Hammond, Ian M Bouligny, Mahesh Swaminathan, Ghayas Issa, Nicholas Short, Naval Daver, Courtney D Dinardo, Tapan Kadia, Elias Jabbour, Farhad Ravandi, Gail J Roboz, Michael Savona, Elizabeth A Griffiths, James Mccloskey, Olatoyosi Odenike, Aram Oganesian, Harold N Keer, Mohammad Azab, Hagop Kantarjian, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Hypomethylating agents (HMA) are indicated in the treatment of higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The combination of hypomethylating agents with venetoclax (Ven) has demonstrated promising results in these diseases, although randomized clinical trials are needed for validation. In this retrospective study, we compared two matched cohorts of patients with MDS or CMML: one receiving oral decitabine-cedazuridine (DEC-C, n = 73) and one receiving DEC-C and Ven (DEC-C-Ven, n = 51), in three contemporary clinical trials. The aim is to determine the impact of the addition of Ven to HMA in MDS and CMML. Individuals were matched …

Effects Of Prebiotic Phytocompound Administration In Gestational Diabetic Dams And Its Influence On Offspring Cognitive Outcomes, Gayathri Jagadeesan, Tushar K Das, Jennifer M Mendoza, Ghalya Alrousan, Maria P Blasco-Conesa, Parimelazhagan Thangaraj, Bhanu Priya Ganesh

Faculty, Staff and Student Publications

Gestational diabetes mellitus (GD)-induced gut dysbiosis in pregnant mothers may increase the risk of cognitive impairment and neurological disorders in both the mother and offspring as they age. Restoring gut balance could improve cognitive outcomes for both. Despite advancements in GD treatment, side effects have increased, and long-term neurocognitive impacts on offspring born to GD mothers remain underexplored. This study uses a GD mouse model, inducing pancreatic dysfunction in 3-month-old pregnant C57BL/6J mice with Streptozotocin. The efficacy and mechanism of the prebiotic phytocompound green leaf extract (

Cigarette Smoke Induces Angiogenic Activation In The Cancer Field Through Dysregulation Of An Endothelial Microrna, Asawari Korde, Anuradha Ramaswamy, Seth Anderson, Lei Jin, Jian-Ge Zhang, Buqu Hu, Walter V Velasco, Lixia Diao, Jing Wang, Margaret A Pisani, Maor Sauler, Daniel J Boffa, Jonathan T Puchalski, Xiting Yan, Seyed Javad Moghaddam, Shervin S Takyar

Faculty, Staff and Student Publications

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial …

Distinct Patterns Of Pv And Sst Gabaergic Neuronal Activity In The Basal Forebrain During Olfactory-Guided Behavior In Mice, Elizabeth H Moss, Evelyne K Tantry, Elaine Le, Pey-Shyuan Chin, Priscilla Ambrosi, Katie L Brandel-Ankrapp, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Sensory perception relies on the flexible detection and interpretation of stimuli across variable contexts, conditions, and behavioral states. The basal forebrain (BF) is a hub for behavioral state regulation, supplying dense cholinergic and GABAergic projections to various brain regions involved in sensory processing. Of GABAergic neurons in the BF, parvalbumin (PV) and somatostatin (SST) subtypes serve opposing roles toward regulating behavioral states. To elucidate the role of BF circuits in sensory-guided behavior, we investigated GABAergic signaling dynamics during odor-guided decision-making in male and female mice. We used fiber photometry to record cell type-specific BF activity during an odor discrimination task …

Rare Damaging Ccr2 Variants Are Associated With Lower Lifetime Cardiovascular Risk, Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S De Vries, Martin Dichgans

Faculty, Staff and Student Publications

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested …

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 …

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 …

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 = …

Genetic Associations With C-Peptide Levels Before Type 1 Diabetes Diagnosis In At-Risk Relatives, Taylor M Triolo, Hemang M Parikh, Mustafa Tosur, Lauric A Ferrat, Lu You, Peter A Gottlieb, Richard A Oram, Suna Onengut-Gumuscu, Jeffrey P Krischer, Stephen S Rich, Andrea K Steck, Maria J Redondo

Children’s Nutrition Research Center Staff Publications

Objective: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms are associated with C-peptide preservation before type 1 diabetes diagnosis.

Methods: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known single nucleotide polymorphisms and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis.

Results: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before …

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 …