Medical Genetics Commons^™

Intra-Tumoral And Peripheral Blood Tigit And Pd-1 As Immune Biomarkers In Nodular Lymphocyte Predominant Hodgkin Lymphoma, Jay Gunawardana, Soi C Law, Muhammed B Sabdia, Éanna Fennell, Aoife Hennessy, Ciara I Leahy, Paul G Murray, Karolina Bednarska, Sandra Brosda, Judith Trotman, Leanne Berkahn, Andreea Zaharia, Simone Birch, Melinda Burgess, Dipti Talaulikar, Justina N Lee, Emily Jude, Eliza A Hawkes, Sanjiv Jain, Karthik Nath, Cameron Snell, Fiona Swain, Joshua W D Tobin, Colm Keane, Mohamed Shanavas, Emily Blyth, Christian Steidl, Kerry Savage, Pedro Farinha, Merrill Boyle, Barbara Meissner, Michael R Green, Francisco Vega, Maher K Gandhi

Faculty, Staff and Student Publications

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or …

Hu8f4-Car T Cells With Mutated Fc Spacer Segment Improve Target Specificity And Mediate Anti-Leukemia Activity In Vivo, Hong He, Rolando A Vedia, Sijie Lu, Qiaochuan Li, Kathryn R Cox, Lisa St John, Anna Sergeeva, Karen Clise-Dwyer, Gheath Alatrash, Elizabeth J Shpall, Qing Ma, Jeffrey J Molldrem

Faculty, Staff and Student Publications

Background aims: Hu8F4 is a T-cell receptor-like antibody with high affinity for the leukemia-associated antigen PR1/HLA-A2 epitope. Adapted into a chimeric antigen receptor (CAR) format, Hu8F4-CAR is composed of the Hu8F4 single-chain variable fragment, the human IgG1 CH2CH3 extracellular spacer domain, a human CD28 costimulatory domain and the human CD3ζ signaling domain. We have demonstrated high efficacy of Hu8F4-CAR-T cells against PR1/HLA-A2-expressing cell lines and leukemic blasts from patients with acute myeloid leukemia in vitro. Previous studies have shown that modification of the Fc domains of IgG4 CH2CH3 spacer regions can eliminate activation-induced cell death and off-target killing mediated by …

Genomic Alterations In Dna Mismatch Repair Genes Across Different Cancer Types, Vijaykumar R Holla, Michael P Kahle, Sun-Hee Kim, Arash Ronaghy, Richard K Yang, Keyur P Patel, Mark J Routbort, Michael J Overman, Ecaterina E Dumbrava, Kenna R Mills Shaw, Daniel D Karp, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 …

A Complementary Metaproteomic Approach To Interrogate Microbiome Cultivated From Clinical Colon Biopsies, Van-An Duong, Altai Enkhbayar, Nobel Bhasin, Lakmini Senavirathna, Eva C Preisner, Kristi L Hoffman, Richa Shukla, Robert R Jenq, Kai Cheng, Mary P Bronner, Daniel Figeys, Robert A Britton, Sheng Pan, Ru Chen

Faculty, Staff and Student Publications

The human gut microbiome plays a vital role in preserving individual health and is intricately involved in essential functions. Imbalances or dysbiosis within the microbiome can significantly impact human health and are associated with many diseases. Several metaproteomics platforms are currently available to study microbial proteins within complex microbial communities. In this study, we attempted to develop an integrated pipeline to provide deeper insights into both the taxonomic and functional aspects of the cultivated human gut microbiomes derived from clinical colon biopsies. We combined a rapid peptide search by MSFragger against the Unified Human Gastrointestinal Protein database and the taxonomic …

Self-Management Intervention Improves Patient Adherence To Swallowing Exercises During Radiation For Head And Neck Cancer, Eileen H Shinn, Adam S Garden, Minxing Chen, Karen Basen-Engquist, Bryan Fellman, Kate Hutcheson, William H Morrison, Susan Peterson, Liang Li

Faculty, Staff and Student Publications

Background: While preventive swallowing exercises reduce the risk of radiation-associated dysphagia in patients with head and neck cancer, strategies are needed to improve patient adherence.

Methods: Before radiation, all participants were taught preventive swallowing exercises and randomized to either an adherence intervention or enhanced usual care. During radiation, all participants met twice with a speech pathologist for swallowing assessment and reinforcement of exercises. Intervention participants met weekly with a counselor in-person or by phone. At 6-week post-radiation follow-up, all participants completed a follow-up assessment of self-reported adherence, which was then corroborated with medical record documentation.

Results: Newly diagnosed pharyngeal and …

Boosting Acetylcholine Signaling By Cannabidiol In A Murine Model Of Alzheimer's Disease, Hesam Khodadadi, Évila Lopes Salles, Sahar Emami Naeini, Bidhan Bhandari, Hannah M Rogers, Jules Gouron, William Meeks, Alvin V Terry, Anilkumar Pillai, Jack C Yu, John C Morgan, Kumar Vaibhav, David C Hess, Krishnan M Dhandapani, Lei P Wang, Babak Baban

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a challenging medical issue that requires efficacious treatment options to improve long-term quality of life. Cannabidiol (CBD) is a cannabis-derived phytocannabinoid with potential health benefits, including reports from our laboratory and others showing a therapeutic role in the pre-clinical treatment of AD; however, the mechanisms whereby CBD affects AD progression remain undefined. Innate lymphoid cells (ILCs) are recently discovered immune cells that initiate and orchestrate inflammatory responses. ILC2, a sub-class of ILCs, is proposed to have a role in cognitive function via unknown mechanisms. In this present study, we explored whether CBD ameliorates AD symptoms via …

Secondary Acquisition Of The Philadelphia Chromosome In Acute Lymphoblastic Leukemia, Qiudan Shen, Elias J Jabbour, Guilin Tang, Hong Fang, Wei Wang, Nicholas J Short, M James You, L Jeffrey Medeiros, Shimin Hu

Faculty, Staff and Student Publications

No abstract provided.

Role Of The Crosstalk B:Neoplastic T Follicular Helper Cells In The Pathobiology Of Nodal T Follicular Helper Cell Lymphomas, Tania P Sainz, Vishal Sahu, Javier A Gomez, Nicholas J Dcunha, Akshay V Basi, Claudia Kettlun, Iman Sarami, Jared K Burks, Deepa Sampath, Francisco Vega

Faculty, Staff and Student Publications

Angioimmunoblastic T-cell lymphoma (AITL), the most common form of peripheral T-cell lymphoma, originates from follicular helper T (Tfh) cells and is notably resistant to current treatments. The disease progression and maintenance, at least in early stages, are driven by a complex interplay between neoplastic Tfh and clusters of B-cells within the tumor microenvironment, mirroring the functional crosstalk observed inside germinal centers. This interaction is further complicated by recurrent mutations, such as TET2 and DNMT3A, which are present in both Tfh cells and B-cells. These findings suggest that the symbiotic relationship between these 2 cell types could represent a therapeutic vulnerability. …

Molecular, Socioeconomic, And Clinical Factors Affecting Racial And Ethnic Disparities In Colorectal Cancer Survival, Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Mohammad M Fanaeian, Mark Knafl, Jennifer Peterson, Mohammad Zeineddine, Kristin Alfaro, Fadl Zeineddine, Drew Goldstein, Nicholas Hornstein, Arvind Dasari, Ryan Huey, Benny Johnson, Victoria Higbie, Alisha Bent, Bryan Kee, Michael Lee, Maria Pia Morelli, Van Karlyle Morris, Daniel Halperin, Michael J Overman, Christine Parseghian, Eduardo Vilar, Robert Wolff, Kanwal P Raghav, Michael G White, Abhineet Uppal, Ryan Sun, Wenyi Wang, Scott Kopetz, Jason Willis, John Paul Shen

Faculty, Staff and Student Publications

Importance: Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown.

Objective: To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer.

Design, setting, and participants: This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables …

Genome-Wide Study Of Gene-By-Sex Interactions Identifies Risks For Cleft Palate, Kelsey Robinson, Randy Parrish, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Lord J J Gowans, Jacqueline T Hecht, Lina Moreno Uribe, Jeffrey C Murray, Gary M Shaw, Seth M Weinberg, Harrison Brand, Mary L Marazita, David J Cutler, Michael P Epstein, Jingjing Yang, Elizabeth J Leslie

Faculty, Staff and Student Publications

Structural birth defects affect 3–4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified …

Allosteric Competition And Inhibition In Ampa Receptors, W Dylan Hale, Alejandra Montaño Romero, Cuauhtemoc U Gonzalez, Vasanthi Jayaraman, Albert Y Lau, Richard L Huganir, Edward C Twomey

Faculty, Staff and Student Publications

Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the …

Translating Biological Insights Into Improved Management Of Endometrial Cancer, Jeffrey A How, Amir A Jazaeri, Shannon N Westin, Barrett C Lawson, Ann H Klopp, Pamela T Soliman, Karen H Lu

Faculty, Staff and Student Publications

Endometrial cancer (EC) is the most common gynaecological cancer among women in high-income countries, with both incidence and mortality continuing to increase. The complexity of the management of patients with EC has evolved with greater comprehension of the underlying biology and heterogeneity of this disease. With a growing number of novel therapeutic agents available, emerging treatment regimens seem to have the potential to help to address the concerning trends in EC-related mortality. In this Review, we describe the epidemiology, histopathology and molecular classification of EC as well as the role of the new (2023) International Federation of Gynecologists and Obstetricians …

Mechanisms Of Response And Tolerance To Active Ras Inhibition In Kras-Mutant Non-Small Cell Lung Cancer, Haniel A Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R Rojas Alvarez, Maria E Salvatierra, Heladio P Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M Solis Soto, Marcelo V Negrao, Don L Gibbons, David S Hong, Jack A Roth, John V Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh, Jacqueline A M Smith, Elsa Quintana, Ferdinandos Skoulidis

Faculty, Staff and Student Publications

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition …

Brca-Mutated Breast Cancer: The Unmet Need, Challenges And Therapeutic Benefits Of Genetic Testing, Banu Arun, Fergus J Couch, Jean Abraham, Nadine Tung, Peter A Fasching

Faculty, Staff and Student Publications

Mutations in the BRCA1 and/or BRCA2 genes (BRCAm) increase the risk of developing breast cancer (BC) and are found in ~5% of unselected patients with the disease. BC resulting from a germline BRCAm (gBRCAm) has distinct clinical characteristics along with increased sensitivity to DNA-damaging agents such as poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies, and potentially decreased sensitivity to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. Given the evolving treatment landscape for gBRCAm BC in early and advanced disease settings, timely determination of gBRCAm status is fundamental to facilitate the most effective treatment strategy for patients. However, many patients with …

Efficacy Of Trastuzumab Deruxtecan In Her2-Expressing Solid Tumors By Enrollment Her2 Ihc Status: Post Hoc Analysis Of Destiny-Pantumor02, Ana Oaknin, Jung-Yun Lee, Vicky Makker, Do-Youn Oh, Susana Banerjee, Antonio González-Martín, Kyung Hae Jung, Iwona Ługowska, Luis Manso, Aránzazu Manzano, Bohuslav Melichar, Salvatore Siena, Daniil Stroyakovskiy, Anitra Fielding, Soham Puvvada, Ann Smith, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Introduction: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results …

Fractionated Photoimmunotherapy Stimulates An Anti-Tumour Immune Response: An Integrated Mathematical And In Vitro Study, Mohammad U Zahid, Matthew Waguespack, Rebecca C Harman, Eric M Kercher, Shubhankar Nath, Tayyaba Hasan, Imran Rizvi, Bryan Q Spring, Heiko Enderling

Faculty, Staff and Student Publications

Background: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery.

Methods: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control.

Results: In vitro measurements of PIT dose …

Enriched G4 Forming Repeats In The Human Genome Are Associated With Robust Well-Coordinated Transcription And Reduced Cancer Transcriptome Variation, Ruth B De-Paula, Albino Bacolla, Aleem Syed, John A Tainer

Faculty, Staff and Student Publications

Non-B DNA G-quadruplex (G4) structures with guanine (G) runs of 2 to 4 repeats can trigger opposing experimental transcriptional impacts. Here, we used bioinformatic algorithms to comprehensively assess correlations of steady-state RNA transcript levels with all putative G4 sequence (pG4) locations genome-wide in three mammalian genomes and in normal and tumor human tissues. The human pG4-containing gene set displays higher expression levels than the set without pG4, supporting and extending some prior observations. pG4 enrichment at transcription start sites (TSSs) in human, but not chimpanzee and mouse genomes, suggests possible positive selection pressure for pG4 at human TSS, potentially driving …

Molecular Profiling Of Braf-V600e-Mutant Metastatic Colorectal Cancer In The Phase 3 Beacon Crc Trial, Scott Kopetz, Danielle A Murphy, Jie Pu, Fortunato Ciardiello, Jayesh Desai, Eric Van Cutsem, Harpreet Singh Wasan, Takayuki Yoshino, Hedieh Saffari, Xiaosong Zhang, Phineas Hamilton, Tao Xie, Rona Yaeger, Josep Tabernero

Faculty, Staff and Student Publications

The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic …

Mature Microrna-Binding Protein Qki Suppresses Extracellular Microrna Let-7b Release, Kyung-Won Min, Kyoung-Min Choi, Hyejin Mun, Seungbeom Ko, Ji Won Lee, Cari A Sagum, Mark T Bedford, Young-Kook Kim, Joe R Delaney, Jung-Hyun Cho, Ted M Dawson, Valina L Dawson, Waleed Twal, Dong-Chan Kim, Clarisse H Panganiban, Hainan Lang, Xin Zhou, Seula Shin, Jian Hu, Tilman Heise, Sang-Ho Kwon, Dongsan Kim, Young Hwa Kim, Sung-Ung Kang, Kyungmin Kim, Sydney Lewis, Ahmet Eroglu, Seonghyun Ryu, Dongin Kim, Jeong Ho Chang, Junyang Jung, Je-Hyun Yoon

Faculty, Staff and Student Publications

Argonaute (AGO), a component of RNA-induced silencing complexes (RISCs), is a representative RNA-binding protein (RBP) known to bind with mature microRNAs (miRNAs) and is directly involved in post-transcriptional gene silencing. However, despite the biological significance of miRNAs, the roles of other miRNA-binding proteins (miRBPs) remain unclear in the regulation of miRNA loading, dissociation from RISCs and extracellular release. In this study, we performed protein arrays to profile miRBPs and identify 118 RBPs that directly bind to miRNAs. Among those proteins, the RBP quaking (QKI) inhibits extracellular release of the mature microRNA let-7b by controlling the loading of let-7b into extracellular …

Mechanisms Of Resistance To Oncogenic Kras Inhibition In Pancreatic Cancer, Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre

Faculty, Staff and Student Publications

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. …

Therapeutic Targeting Of Hypoxia Inducible Factor In Acute Respiratory Distress Syndrome, Thu T Tran, Holger K Eltzschig, Xiaoyi Yuan

Faculty, Staff and Student Publications

Acute respiratory distress syndrome (ARDS) is characterized by bilateral chest infiltration and acute hypoxic respiratory failure. ARDS carries significant morbidity and mortality despite advancements in medical management, calling for the development of novel therapeutic targets. Hypoxia-inducible factor (HIF) is a heterodimeric protein involved in various essential pathways, including metabolic reprogramming, immune modulation, angiogenesis and cell cycle regulation. HIF is routinely degraded in homeostasis conditions via the prolyl hydroxylase domain/von Hippel-Lindau protein pathway. However, HIF is stabilized in ARDS via various mechanisms (oxygen-dependent and independent) as an endogenous protective pathway and plays multifaceted roles in different cell populations. This review focuses …

Intraoperative Methadone Administration For Total Mastectomy: A Single Center Retrospective Study, Juan P Cata, Yusuf Zaidi, Juan Jose Guerra-Londono, Evan D Kharasch, Matthew Piotrowski, Spencer Kee, Nicolas A Cortes-Mejia, Jose Miguel Gloria-Escobar, Peter F Thall, Ruitao Lin

Faculty, Staff and Student Publications

Background: Breast cancer is the most frequent type of cancer and the second leading cause of cancer-related mortality in women. Mastectomies remain a key component of the treatment of non-metastatic breast cancer, and strategies to treat acute postoperative pain, a complication affecting nearly all patients undergoing surgery, continues to be an important clinical challenge. This study aimed to determine the impact of intraoperative methadone administration compared to conventional short-acting opioids on pain-related perioperative outcomes in women undergoing a mastectomy.

Methods: This single-center retrospective study included adult women undergoing total mastectomy. The primary outcome of this study was postoperative pain intensity …

Consensus Molecular Subtyping Of Metastatic Colorectal Cancer Expands Biomarker-Directed Therapeutic Benefit For Patients With Cms1 And Cms2 Tumors, Saikat Chowdhury, Joanne Xiu, Jennifer R Ribeiro, Theodore Nicolaides, Jian Zhang, W Michael Korn, Kelsey A Poorman, Heinz-Josef Lenz, John L Marshall, Matthew J Oberley, George W Sledge, David Spetzler, Scott Kopetz, John Paul Shen

Faculty, Staff and Student Publications

Background: We developed a whole transcriptome sequencing (WTS)-based Consensus Molecular Subtypes (CMS) classifier using FFPE tissue and investigated its prognostic and predictive utility in a large clinico-genomic database of CRC patients (n = 24,939).

Methods: The classifier was trained against the original CMS datasets using an SVM model and validated in an independent blinded TCGA dataset (88.0% accuracy). Kaplan-Meier estimates of overall survival (OS) and time-on-treatment (TOT) were calculated for each CMS (p < 0.05 considered significant).

Results: CMS2 tumors were enriched on left-side of colon and conferred the longest median OS. In RAS-wildtype mCRC, left-sided tumors and CMS2 classification were associated with longer …

Localized Intratumoral Delivery Of Immunomodulators For Oral Cancer And Oral Potentially Malignant Disorders, Nourhan I Hussein, Andrea H Molina, Gemalene M Sunga, Moran Amit, Yu Leo Lei, Xiao Zhao, Jeffrey D Hartgerink, Andrew G Sikora, Simon Young

Faculty, Staff and Student Publications

Immunotherapy has developed into an important modality of modern cancer treatment. Unfortunately, checkpoint inhibitor immunotherapies are currently delivered systemically and require frequent administration, which can result in toxicity and severe, sometimes fatal, adverse events. Localized delivery of immunomodulators for oral cancer and oral potentially malignant disorders offers the promise of maximum therapeutic potential and reduced systemic adverse effects. This review will discuss the limitations of current standard-of-care systemic therapies and highlight research advances in localized, intratumoral delivery platforms for immunotherapy for oral cancer and oral potentially malignant disorders.

Association Analysis Of Mitochondrial Dna Heteroplasmic Variants: Methods And Application, Xianbang Sun, Katia Bulekova, Jian Yang, Meng Lai, Achilleas N Pitsillides, Xue Liu, Yuankai Zhang, Xiuqing Guo, Qian Yong, Laura M Raffield, Jerome I Rotter, Stephen S Rich, Goncalo Abecasis, April P Carson, Ramachandran S Vasan, Joshua C Bis, Bruce M Psaty, Eric Boerwinkle, Annette L Fitzpatrick, Claudia L Satizabal, Dan E Arking, Jun Ding, Daniel Levy, Chunyu Liu

Faculty, Staff and Student Publications

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α = 0.001. Notably, when 5 % or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden …

Decitabine, Venetoclax, And Ponatinib For Advanced Phase Chronic Myeloid Leukaemia And Philadelphia Chromosome-Positive Acute Myeloid Leukaemia: A Single-Arm, Single-Centre Phase 2 Trial, Nicholas J Short, Daniel Nguyen, Elias Jabbour, Jayastu Senapati, Zhihong Zeng, Ghayas C Issa, Hussein Abbas, Cedric Nasnas, Wei Qiao, Xuelin Huang, Gautam Borthakur, Kelly Chien, Fadi G Haddad, Naveen Pemmaraju, Omer S Karrar, Danielle Nguyen, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi

Faculty, Staff and Student Publications

BACKGROUND: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, …

Surgical Predictors Of Clinical Outcome 6 Years After Revision Acl Reconstruction, Rick W Wright, Laura J Huston, Amanda K Haas, Jacquelyn S Pennings, Christina R Allen, Daniel E Cooper, Thomas M Deberardino, Warren R Dunn, Brett Brick A Lantz, Kurt P Spindler, Michael J Stuart, Annunziato Ned Amendola, Christopher C Annunziata, Robert A Arciero, Bernard R Bach, Champ L Baker, Arthur R Bartolozzi, Keith M Baumgarten, Jeffrey H Berg, Geoffrey A Bernas, Stephen F Brockmeier, Robert H Brophy, Charles A Bush-Joseph, J Brad Butler, James L Carey, James E Carpenter, Brian J Cole, Jonathan M Cooper, Charles L Cox, R Alexander Creighton, Tal S David, David C Flanigan, Robert W Frederick, Theodore J Ganley, Charles J Gatt, Steven R Gecha, James Robert Giffin, Sharon L Hame, Jo A Hannafin, Christopher D Harner, Norman Lindsay Harris, Keith S Hechtman, Elliott B Hershman, Rudolf G Hoellrich, David C Johnson, Timothy S Johnson, Morgan H Jones, Christopher C Kaeding, Ganesh V Kamath, Thomas E Klootwyk, Bruce A Levy, C Benjamin Ma, G Peter Maiers, Robert G Marx, Matthew J Matava, Gregory M Mathien, David R Mcallister, Eric C Mccarty, Robert G Mccormack, Bruce S Miller, Carl W Nissen, Daniel F O'Neill, Brett D Owens, Richard D Parker, Mark L Purnell, Arun J Ramappa, Michael A Rauh, Arthur C Rettig, Jon K Sekiya, Kevin G Shea, Orrin H Sherman, James R Slauterbeck, Matthew V Smith, Jeffrey T Spang, Steven J Svoboda, Timothy N Taft, Joachim J Tenuta, Edwin M Tingstad, Armando F Vidal, Darius G Viskontas, Richard A White, James S Williams, Michelle L Wolcott, Brian R Wolf, James J York

Faculty, Staff and Student Publications

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown.

Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient's outcome at 6-year follow-up.

Study design: Cohort study; Level of evidence, 2.

Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) …

Results Of A Randomized Phase Ii Trial Of Paclitaxel And Carboplatin Versus Bleomycin, Etoposide And Cisplatin For Newly Diagnosed And Recurrent Chemonaive Stromal Ovarian Tumors: An Nrg Oncology/Gynecologic Oncology Group Study14, Jubilee Brown, Austin Miller, Laura L Holman, Floor Backes, Christa Nagel, David Bender, David S Miller, Matthew A Powell, Shannon N Westin, Albert Bonebrake, Carolyn Y Muller, Angeles Alvarez Secord, Erin Crane, John Schorge, William P Tew, Anil K Sood, Michael A Bookman, Carol Aghajanian, David M Gershenson

Faculty, Staff and Student Publications

Objectives: To assess the efficacy and toxicity of paclitaxel and carboplatin (PC) compared to bleomycin, etoposide, and cisplatin (BEP) for treatment of newly diagnosed Stage IIA-IV or recurrent chemotherapy-naive ovarian sex cord-stromal tumors (SCST).

Methods: This phase II noninferiority trial randomly assigned patients to receive PC (6 cycles P 175 mg/m2 and C AUC = 6 IV every 3 weeks), or BEP (4 cycles B 20 units/m2 IV push day 1, E 75 mg/m2 IV days 1-5, and cisplatin 20 mg/m2 IV days 1-5 every 3 weeks). The primary endpoint was progression- free survival (PFS). This trial is registered with …

Uterine-Conserving Treatment Options For Atypical Endometrial Hyperplasia And Early Endometrial Cancer, Naomi N Adjei, Mikayla Borthwick Bowen, Roni Nitecki Wilke, Melinda S Yates, Shannon N Westin

Faculty, Staff and Student Publications

Purpose of review: This review aims to synthesize available literature on uterine-conserving treatment options for atypical endometrial hyperplasia and grade 1 endometrial carcinoma while highlighting remaining unanswered questions.

Recent findings: The need for uterine-conserving treatment options for atypical endometrial hyperplasia and grade 1 endometrial carcinoma is growing with the increasing number of cases in younger patients or those who cannot undergo surgery. We reviewed the oncological and reproductive outcomes associated with endocrine therapies used for atypical endometrial hyperplasia and grade 1 endometrial carcinoma. The rising prevalence of delayed childbearing, obesity, and diabetes in reproductive-age individuals and of medical comorbidities associated …

Increased Expression Of Cd70 In Relapsed Acute Myeloid Leukemia After Hypomethylating Agents, Mario L Marques-Piubelli, Bijender Kumar, Rafet Basar, Siler Panowski, Surabhi Srinivasan, Kevin Norwood, Sacha Prashad, Victoria Szenes, Arun Balakumaran, Akanksha Arandhya, Wei Lu, Khaja Khan, Daniela Duenas, Salome Mcallen, Javier A Gomez, Jared K Burks, Sunil Acharyal, Gautam Borthakur, Wei-Lien Wang, Wei Wang, Sa Wang, Luisa M Solis, David Marin, Katayoun Rezvani, May Daher, Francisco Vega

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While induction chemotherapy leads to remission in most patients, a significant number will experience relapse. Therefore, there is a need for novel therapies that can improve remission rates in patients with relapsed and refractory AML. CD70 is the natural ligand for CD27 (a member of the TNF superfamily) and appears to be a promising therapeutic target. Consequently, there is considerable interest in developing chimeric antigen receptor (CAR) T-cell therapy products that can specifically target CD70 in various neoplasms, including AML. In this study, we employed routine diagnostic techniques, …