A Phase Ii, Multicenter, Open-Label, Randomized Trial Of Pegfilgrastim For Patients With Alcohol-Associated Hepatitis, John A Tayek, Andrew A Stolz, Danh V Nguyen, M Wayne Fleischman, John A Donovan, Joseph M Alcorn, Daniel C-K Chao, Aliya Asghar, Timothy R Morgan, Southern California Alcoholic Hepatitis (Scah) Consortium

Faculty, Staff and Student Publications

BACKGROUND: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States.

METHODS: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, …

Spinal Metastases And The Evolving Role Of Molecular Targeted Therapy, Chemotherapy, And Immunotherapy, Elena I Fomchenko, James C Bayley, Christopher Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved; however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved …

Germline Variants Associated With Toxicity To Immune Checkpoint Blockade, Stefan Groha, Sarah Abou Alaiwi, Wenxin Xu, Vivek Naranbhai, Amin H Nassar, Ziad Bakouny, Talal El Zarif, Renee Maria Saliby, Guihong Wan, Ahmad Rajeh, Elio Adib, Pier V Nuzzo, Andrew L Schmidt, Chris Labaki, Biagio Ricciuti, Joao Victor Alessi, David A Braun, Sachet A Shukla, Tanya E Keenan, Eliezer Van Allen, Mark M Awad, Michael Manos, Osama Rahma, Leyre Zubiri, Alexandra-Chloe Villani, Benjamin Fairfax, Christian Hammer, Zia Khan, Kerry Reynolds, Yevgeniy Semenov, Deborah Schrag, Kenneth L Kehl, Matthew L Freedman, Toni K Choueiri, Alexander Gusev

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.

Quantification Of Manipulation Forces Needed For Robot-Assisted Reduction Of The Ankle Syndesmosis: An Initial Cadaveric Study, Mikias Gebremeskel, Babar Shafiq, Ali Uneri, Niral Sheth, Corey Simmerer, Wojciech Zbijewski, Jeffrey H Siewerdsen, Kevin Cleary, Gang Li

Faculty, Staff and Student Publications

PURPOSE: Manual surgical manipulation of the tibia and fibula is necessary to properly align and reduce the space in ankle fractures involving sprain of the distal tibiofibular syndesmosis. However, manual reduction is highly variable and can result in malreduction in about half of the cases. Therefore, we are developing an image-guided robotic assistant to improve reduction accuracy. The purpose of this study is to quantify the forces associated with reduction of the ankle syndesmosis to define the requirements for our robot design.

METHODS: Using a cadaveric specimen, we designed a fixture jig to fix the tibia securely on the operating …

Mildly Dysplastic Oral Lesions With Optically-Detectable Abnormalities Share Genetic Similarities With Severely Dysplastic Lesions, David R Brenes, Allison J Nipper, Melody T Tan, Frederico O Gleber-Netto, Richard A Schwarz, Curtis R Pickering, Michelle D Williams, Nadarajah Vigneswaran, Ann M Gillenwater, Andrew G Sikora, Rebecca R Richards-Kortum

Faculty, Staff and Student Publications

OBJECTIVE: Optical imaging studies of oral premalignant lesions have shown that optical markers, including loss of autofluorescence and altered morphology of epithelial cell nuclei, are predictive of high-grade pathology. While these optical markers are consistently positive in lesions with moderate/severe dysplasia or cancer, they are positive only in a subset of lesions with mild dysplasia. This study compared the gene expression profiles of lesions with mild dysplasia (stratified by optical marker status) to lesions with severe dysplasia and without dysplasia.

MATERIALS AND METHODS: Forty oral lesions imaged in patients undergoing oral surgery were analyzed: nine without dysplasia, nine with severe …

Learning From The Past: A Century Of Accuracy, Aspirations, And Aspersions In Brachytherapy, Christopher S Melhus, Samantha J Simiele, Manik Aima, Susan Richardson

Faculty, Staff and Student Publications

The oldest form of radiation therapy, brachytherapy, has been investigated and reported in the scientific and medical literature for well over a century. Known by many names over the years, radium-based, empirical practices evolved over decades to contemporary practice. This includes treatment at various dose rates using multiple radionuclides or even electrically generated photon sources. Predictions or prognostications of what may happen in the future enjoy a history that spans centuries, e.g. those by Nostradamus in the 1500s. In this review article, publications from several eras of past practice between the early 1900s and the late 2010s where the authors …

Biobehavioral Factors Predict An Exosome Biomarker Of Ovarian Carcinoma Disease Progression, Susan K Lutgendorf, Premal H Thaker, Michael J Goodheart, Jesusa M G Arevalo, Mamur A Chowdhury, Alyssa E Noble, Laila Dahmoush, George M Slavich, Frank J Penedo, Anil K Sood, Steven W Cole

Faculty, Staff and Student Publications

BACKGROUND: Biobehavioral factors such as social isolation and depression have been associated with disease progression in ovarian and other cancers. Here, the authors developed a noninvasive, exosomal RNA profile for predicting ovarian cancer disease progression and subsequently tested whether it increased in association with biobehavioral risk factors.

METHODS: Exosomes were isolated from plasma samples from 100 women taken before primary surgical resection or neoadjuvant (NACT) treatment of ovarian carcinoma and 6 and 12 months later. Biobehavioral measures were sampled at all time points. Plasma from 76 patients was allocated to discovery analyses in which morning presurgical/NACT exosomal RNA profiles were …

Distinct Germline Genetic Susceptibility Profiles Identified For Common Non-Hodgkin Lymphoma Subtypes, Sonja I Berndt, Joseph Vijai, Yolanda Benavente, Nicola J Camp, Alexandra Nieters, Zhaoming Wang, Karin E Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F Skibola, Lindsay M Morton, Angela R Brooks-Wilson, Lauren R Teras, Charles Breeze, Joshua Arias, Hans-Olov Adami, Demetrius Albanes, Kenneth C Anderson, Stephen M Ansell, Bryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M Birmann, Paolo Boffetta, Paige M Bracci, Paul Brennan, Elizabeth E Brown, Laurie Burdett, Lisa A Cannon-Albright, Ellen T Chang, Brian C H Chiu, Charles C Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V Conti, David G Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, Arjan Diepstra, W Ryan Diver, Ahmet Dogan, Christopher K Edlund, Lenka Foretova, Joseph F Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M Habermann, Christopher A Haiman, Corinne Haioun, Jonathan N Hofmann, Theodore R Holford, Elizabeth A Holly, Amy Hutchinson, Aalin Izhar, Rebecca D Jackson, Ruth F Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K Link, Corrado Magnani, Marc Maynadie, James Mckay, Mads Melbye, Lucia Miligi, Roger L Milne, Thierry J Molina, Alain Monnereau, Rebecca Montalvan, Kari E North, Anne J Novak, Kenan Onel, Mark P Purdue, Kristin A Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W Sborov, Richard K Severson, Tait D Shanafelt, Martyn T Smith, Alexandra Smith, Kevin W Song, Lei Song, Melissa C Southey, John J Spinelli, Anthony Staines, Deborah Stephens, Heather J Sutherland, Kaitlyn Tkachuk, Carrie A Thompson, Hervé Tilly, Lesley F Tinker, Ruth C Travis, Jenny Turner, Celine M Vachon, Claire M Vajdic, Anke Van Den Berg, David J Van Den Berg, Roel C H Vermeulen, Paolo Vineis, Sophia S Wang, Elisabete Weiderpass, George J Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R Cerhan, Stephen J Chanock, Susan L Slager, Nathaniel Rothman

Faculty, Staff and Student Publications

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9,505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P<5 >× 10−8) for subsets of NHL subtypes, …

Tilsotolimod Exploits The Tlr9 Pathway To Promote Antigen Presentation And Type 1 Ifn Signaling In Solid Tumors: A Multicenter International Phase I/Ii Trial (Illuminate-101), Hani Babiker, Erkut Borazanci, Vivek Subbiah, Sanjiv Agarwala, Alain Algazi, Jacob Schachter, Michael Lotem, Corinne Maurice-Dror, Daniel Hendler, Shah Rahimian, Hans Minderman, Cara Haymaker, Daruka Mahadevan, Chantale Bernatchez, Ravi Murthy, Rolf Hultsch, Nadia Kaplan, Gregory Woodhead, Charles Hennemeyer, Srinivas Chunduru, Peter M Anderson, Adi Diab, Igor Puzanov

Faculty, Staff and Student Publications

PURPOSE: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors.

PATIENTS AND METHODS: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the …

An Outbreak Of A Novel Recombinant Coxsackievirus A4 In A Kindergarten, Shandong Province, China, 2021, Juan Li, Nan Ni, Yanan Cui, Shuai Zong, Xue Yao, Tao Hu, Mengyuan Cao, Yong Zhang, Peiqiang Hou, Michael J Carr, Weijia Xing, Hong Zhou, Weifeng Shi

Faculty, Staff and Student Publications

In 2021, twenty children exhibiting influenza-like illnesses were reported from a kindergarten in Shandong Province, China. Eleven genomes of Coxsackievirus A4 (CV-A4) were obtained from the pediatric cases, sharing <93% genome sequence identities with known CV-A4 strains. Further analyses suggested potential genetic recombination in the P3 region of the novel strains.

Adjuvant Therapy In Women With Early Stage Uterine Serous Carcinoma: A Multi-Institutional Study, Katherine C Kurnit, Silvana Pedra Nobre, Bryan M Fellman, David A Iglesias, Kristina Lindemann, Anuja Jhingran, Ane Gerda Z Eriksson, Beyhan Ataseven, Gretchen E Glaser, Jennifer J Mueller, Shannon N Westin, Pamela T Soliman

Faculty, Staff and Student Publications

OBJECTIVE: Uterine serous carcinoma is a rare but aggressive subtype of endometrial adenocarcinoma. Our objective was to compare adjuvant treatment strategies for patients with early stage uterine serous carcinoma.

METHODS: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or any mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher's exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free and overall …

Targeting The Pi3k Pathway In Gynecologic Malignancies, Monica Avila, Michaela Onstad Grinsfelder, Melissa Pham, Shannon N Westin

Faculty, Staff and Student Publications

Purpose of review: This review explores the PI3K pathway aberrations common in gynecologic malignancies, the relevant therapeutic targets that have been explored to date particularly given their success in endometrial cancers, and predictive biomarkers of response to therapy.

Recent findings: Landmark trials have been noted involving this pathway, particularly in endometrial cancers. One phase II trial of the potent orally bioavailable mTOR inhibitor, everolimus, in combination with letrozole demonstrated an unprecedented clinical benefit rate (CBR) of 40% and high objective response rate (RR) of 32% in hormone agnostic endometrial cancers. This was followed by GOG 3007 that compared everolimus and …

A Randomized, Phase Iii Trial To Evaluate Rucaparib Monotherapy As Maintenance Treatment In Patients With Newly Diagnosed Ovarian Cancer (Athena-Mono/Gog-3020/Engot-Ov45), Bradley J Monk, Christine Parkinson, Myong Cheol Lim, David M O'Malley, Ana Oaknin, Michelle K Wilson, Robert L Coleman, Domenica Lorusso, Paul Bessette, Sharad Ghamande, Athina Christopoulou, Diane Provencher, Emily Prendergast, Fuat Demirkiran, Olga Mikheeva, Oladapo Yeku, Anita Chudecka-Glaz, Michael Schenker, Ramey D Littell, Tamar Safra, Hung-Hsueh Chou, Mark A Morgan, Vít Drochýtek, Joyce N Barlin, Toon Van Gorp, Fred Ueland, Gabriel Lindahl, Charles Anderson, Dearbhaile C Collins, Kathleen Moore, Frederik Marme, Shannon N Westin, Iain A Mcneish, Danny Shih, Kevin K Lin, Sandra Goble, Stephanie Hume, Keiichi Fujiwara, Rebecca S Kristeleit

Faculty, Staff and Student Publications

PURPOSE: ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo.

METHODS: Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and …

Physician-Reported Perspectives On Myasthenia Gravis In The United States: A Real-World Survey, Milada Mahic, Ali M Bozorg, Jonathan J Decourcy, Keisha J Golden, Gregor A Gibson, Christian F Taylor, Angela Ting, Tyler J Story, Anna Scowcroft

Faculty, Staff and Student Publications

INTRODUCTION: Myasthenia gravis (MG) is a rare, debilitating, chronic disorder caused by the production of pathogenic immunoglobulin G autoantibodies against the neuromuscular junction. A lack of real-world studies in rare diseases reflects a relatively limited understanding of the significant unmet needs and burden of disease for patients. We aimed to provide comprehensive real-world insights into the management and burden of MG from treating physicians in the United States (US).

METHODS: Data were collected using the Adelphi Real World MG Disease Specific Programme™, a point-in-time survey of physicians and their patients with MG, in the US between March and July 2020. …

Soy Isoflavones Decrease Fibroglandular Breast Tissue Measured By Magnetic Resonance Imaging In Premenopausal Women: A 2-Year Randomized Double-Blind Placebo Controlled Clinical Trial, Lee-Jane W Lu, Nai-Wei Chen, Donald G Brunder, Fatima Nayeem, Manubai Nagamani, Thomas K Nishino, Karl E Anderson, Tuenchit Khamapirad

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Populations consuming soy have reduced risk for breast cancer, but the mechanisms are unclear. We tested the hypothesis that soy isoflavones, which have ovarian hormone-like effects, can reduce fibroglandular breast tissue (FGBT, 'breast density'), a strong risk marker for breast cancer.

METHODS: Premenopausal women (age 30-42 years) were randomized to consume isoflavones (136.6 mg as aglycone equivalents, n = 99) or placebo (n = 98) for 5 days per week up to 2 years, and changes in breast composition measured by magnetic resonance imaging at baseline and yearly intervals were compared after square root transformation using linear …

Cell-Free Dna Screening Positive For Monosomy X: Clinical Evaluation And Management Of Suspected Maternal Or Fetal Turner Syndrome, Tazim Dowlut-Mcelroy, Shanlee Davis, Susan Howell, Iris Gutmark-Little, Vaneeta Bamba, Siddharth Prakash, Sheetal Patel, Doris Fadoju, Nandini Vijayakanthi, Mary Haag, Deborrah Hennerich, Lorraine Dugoff, Roopa Kanakatti Shankar

Faculty, Staff and Student Publications

Initially provided as an alternative to evaluation of serum analytes and nuchal translucency for the assessment of pregnancies at high risk of trisomy 21, cell-free DNA screening for fetal aneuploidy, also referred to as noninvasive prenatal screening, can now also screen for fetal sex chromosome anomalies such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a sex chromosome anomaly resulting from the complete or partial absence of the second X chromosome, allows medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility preservation and support, and improved neurocognitive outcomes. However, …

Targeted Ablation Of Fn14 Receptor Improves Exercise Capacity And Inhibits Neurogenic Muscle Atrophy, Meiricris Tomaz Da Silva, Aniket S Joshi, Tatiana E Koike, Anirban Roy, Kavya Mathukumalli, Danesh H Sopariwala, Vihang A Narkar, Ashok Kumar

Faculty, Staff and Student Publications

Skeletal muscle atrophy is a prevalent complication in multiple chronic diseases and disuse conditions. Fibroblast growth factor-inducible 14 (Fn14) is a member of the TNF receptor superfamily and a bona fide receptor of the TWEAK cytokine. Accumulating evidence suggests that Fn14 levels are increased in catabolic conditions as well as during exercise. However, the role of Fn14 in the regulation of skeletal muscle mass and function remains poorly understood. In this study, through the generation of novel skeletal muscle-specific Fn14-knockout mice, we have investigated the muscle role of Fn14 in the regulation of exercise capacity and denervation-induced muscle atrophy. Our …

Low-Molecular-Weight Cyclin E Deregulates Dna Replication And Damage Repair To Promote Genomic Instability In Breast Cancer, Mi Li, Spiridon Tsavachidis, Fuchenchu Wang, Tuyen Bui, Tuyen Duong Thanh Nguyen, Linjie Luo, Asha S Multani, Melissa L Bondy, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors (n = 725) and promoted genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibited the proliferation of hMECs by replication stress and DNA …

Data-Driven Biomarker Panel Discovery In Ovarian Cancer Using Heterogenous Data Fusion On Exosomal And Non-Exosomal Microrna Expression Data, Paritra Mandal

All Dissertations

Ovarian cancer (OC) is an aggressive gynecological cancer and is currently the 5th leading cause of deaths due to cancer in women. High mortality rates are attributable to the vague pathogenesis and asymptomatic nature of the early stages. The development of a liquid biopsy for routine OC screening could help identify the disease at an earlier stage, making treatments more likely to be effective thereby increasing survival rates. Exosomes, small (~100nm) extracellular vesicles present in body fluids, have been shown to contain cancer-progression, onset, and related factors, making them good candidates for use in liquid biopsies. However, to date, only …

Clinical And Molecular Profiling Of Aml Patients With Chromosome 7 Or 7q Deletions In The Context Of Tp53 Alterations And Venetoclax Treatment, Hussein A Abbas, Edward Ayoub, Hanxiao Sun, Rashmi Kanagal-Shamanna, Nicholas J Short, Ghayas Issa, Musa Yilmaz, Sherry Pierce, Daniel Rivera, Brent Cham, Shane Wing, Ziyi Li, Danielle Hammond, Elias Jabbour, Gautam Borthakur, Guillermo Garcia-Manero, Michael Andreeff, Naval Daver, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Farhad Ravandi

Faculty, Staff and Student Publications

Deletions in chromosome 7 (del(7)) or its long arm (del(7q)) constitute the most common adverse cytogenetic events in acute myeloid leukemia (AML). We retrospectively analyzed 243 treatment-naive patients with AML and del(7) (168/243; 69%) or del(7q) (75/243; 31%) who did not receive any myeloid-directed therapy prior to AML diagnosis. This is the largest comprehensive clinical and molecular analysis of AML patients with del(7) and del(7q). Our results show that relapse-free survival was significantly longer for AML patients with del(7q) compared to del(7), but the overall survival and remission duration were similar. TP53 mutations and del5/5q were the most frequent co-occurring …

Inclusion Of Premenopausal Women In Breast Cancer Clinical Trials, Kelsey L Corrigan, Ramez Kouzy, Joseph Abi Jaoude, Roshal R Patel, Rachel M Layman, Sharon H Giordano, Wendy A Woodward, Benjamin D Smith, Simona F Shaitelman, Ethan B Ludmir

Faculty, Staff and Student Publications

BACKGROUND: Patients with premenopausal breast cancer (PMBC) have been historically excluded from some clinical trials because of the limitations of using endocrine therapy (ET) in this population. We analyzed breast cancer randomized clinical trials (RCTs) to determine the rates of and factors associated with inclusion of PMBC patients to provide a benchmark for PMBC inclusion in RCTs moving forward.

METHODS: Using ClinicalTrials.Gov, we identified breast cancer phase III RCTs and extracted inclusion criteria and patient enrollment information. Multiple binary logistic regression modeling was used to assess trial-related factors that were associated with PMBC patient inclusion.

RESULTS: Of 170 breast …

Obstetric And Neonatal Outcomes 1 Or More Years After A Diagnosis Of Breast Cancer, Kirsten Jorgensen, Roni Nitecki, Hazel B Nichols, Shuangshuang Fu, Chi-Fang Wu, Alexander Melamed, Paula Brady, Mariana Chavez Mac Gregor, Mark A Clapp, Sharon Giordano, J Alejandro Rauh-Hain

Faculty, Staff and Student Publications

OBJECTIVE: To evaluate obstetric and neonatal outcomes of the first live birth conceived 1 or more years after breast cancer diagnosis.

METHODS: We performed a population-based study to compare live births between women with a history of breast cancer (case group) and matched women with no cancer history (control group). Individuals in the case and control groups were identified using linked data from the California Cancer Registry and California Office of Statewide Health Planning and Development data sets. Individuals in the case group were diagnosed with stage I-III breast cancer at age 18-45 years between January 1, 2000, and December …

Small Molecule Targeting Nav17 Via Inhibition Of The Crmp2-Ubc9 Interaction Reduces Pain In Chronic Constriction Injury (Cci) Rats, Jiahe Li, Harrison J Stratton, Sabina A Lorca, Peter M Grace, Rajesh Khanna

Faculty, Staff and Student Publications

The voltage-gated sodium channel isoform NaV1.7 is a critical player in the transmission of nociceptive information. This channel has been heavily implicated in human genetic pain disorders and is a validated pain target. However, targeting this channel directly has failed, and an indirect approach - disruption of interactions with accessory protein partners - has emerged as a viable alternative strategy. We recently reported that a small-molecule inhibitor of CRMP2 SUMOylation, compound

Effects Of Gabapentin And Pregabalin On Calcium Homeostasis: Implications For Physical Rehabilitation Of Musculoskeletal Tissues, Perla C Reyes Fernandez, Christian S Wright, Stuart J Warden, Julia Hum, Mary C Farach-Carson, William R Thompson

Faculty, Staff and Student Publications

Purpose of review: In this review, we discuss the mechanism of action of gabapentinoids and the potential consequences of long-term treatment with these drugs on the musculoskeletal system.

Recent findings: Gabapentinoids, such as gabapentin (GBP) and pregabalin (PGB) were designed as antiepileptic reagents and are now commonly used as first-line treatment for neuropathic pain and increasingly prescribed off-label for other pain disorders such as migraines and back pain. GBP and PGB exert their analgesic actions by selectively binding the α2δ1 auxiliary subunit of voltage-sensitive calcium channels, thereby inhibiting channel function. Numerous tissues express the α2δ1 subunit where GBP and PGB …

Autologous Humanized Mouse Models To Study Combination And Single-Agent Immunotherapy For Colorectal Cancer Patient-Derived Xenografts, Preeti Kanikarla Marie, Alexey V Sorokin, Lea A Bitner, Rebecca Aden, Michael Lam, Ganiraju Manyam, Melanie N Woods, Amanda Anderson, Anna Capasso, Natalie Fowlkes, Michael J Overman, David G Menter, Scott Kopetz

Faculty, Staff and Student Publications

Designing studies of immunotherapy is limited due to a lack of pre-clinical models that reliably predict effective immunotherapy responses. To address this gap, we developed humanized mouse models of colorectal cancer (CRC) incorporating patient-derived xenografts (PDX) with human peripheral blood mononuclear cells (PBMC). Humanized mice with CRC PDXs were generated via engraftment of autologous (isolated from the same patients as the PDXs) or allogeneic (isolated from healthy donors) PBMCs. Human T cells were detected in mouse blood, tissues, and infiltrated the implanted PDXs. The inclusion of anti-PD-1 therapy revealed that tumor responses in autologous but not allogeneic models were more …

Clinically Significant Metachronous Colorectal Pathology Detected Among Young-Onset Colorectal Cancer Survivors: Implications For Post-Resection Surveillance Guidelines, Oliver Peacock, Eduardo Vilar, Montserrat Guraieb-Trueba, Selvi Thirumurthi, George J Chang, Y Nancy You

Faculty, Staff and Student Publications

No abstract provided.

Mathematical Modeling Of Cancer Immunotherapy For Personalized Clinical Translation, Joseph D Butner, Prashant Dogra, Caroline Chung, Renata Pasqualini, Wadih Arap, John Lowengrub, Vittorio Cristini, Zhihui Wang

Faculty, Staff and Student Publications

Encouraging advances are being made in cancer immunotherapy modeling, especially in the key areas of developing personalized treatment strategies based on individual patient parameters, predicting treatment outcomes and optimizing immunotherapy synergy when used in combination with other treatment approaches. Here we present a focused review of the most recent mathematical modeling work on cancer immunotherapy with a focus on clinical translatability. It can be seen that this field is transitioning from pure basic science to applications that can make impactful differences in patients' lives. We discuss how researchers are integrating experimental and clinical data to fully inform models so that …

Utility Of Measurable Residual Disease For Predicting Treatment Outcomes With Bcr- And Bcl2-Targeted Therapies In Patients With Cll, William G Wierda, Thomas J Kipps, Othman Al-Sawaf, Brenda Chyla, Juliana M L Biondo, Yong Mun, Yanwen Jiang, John F Seymour

Faculty, Staff and Student Publications

Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve …

Heterogeneous Nuclear Ribonucleoprotein K Is Overexpressed In Acute Myeloid Leukemia And Causes Myeloproliferation In Mice Via Altered, Marisa J L Aitken, Prerna Malaney, Xiaorui Zhang, Shelley M Herbrich, Lauren Chan, Oscar Benitez, Ashley G Rodriguez, Huaxian Ma, Rodrigo Jacamo, Ruizhi Duan, Todd M Link, Steven M Kornblau, Rashmi Kanagal-Shamanna, Carlos E Bueso-Ramos, Sean M Post

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is driven by numerous molecular events that contribute to disease progression. Herein, we identify hnRNP K overexpression as a recurrent abnormality in AML that negatively correlates with patient survival. Overexpression of hnRNP K in murine fetal liver cells results in altered self-renewal and differentiation potential. Further, murine transplantation models reveal that hnRNP K overexpression results in myeloproliferation in vivo. Mechanistic studies expose a direct functional relationship between hnRNP K and RUNX1—a master transcriptional regulator of hematopoiesis often dysregulated in leukemia. Molecular analyses show that overexpression of hnRNP K results in an enrichment of an …

Implications Of Ras Mutational Status In Subsets Of Patients With Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes, Daniel Rivera, Kunhwa Kim, Rashmi Kanagal-Shamanna, Gautam Borthakur, Guillermo Montalban-Bravo, Naval Daver, Courtney Dinardo, Nicholas J Short, Musa Yilmaz, Naveen Pemmaraju, Koichi Takahashi, Elias J Jabbour, Sherry Pierce, Marina Konopleva, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with …