Digital Commons Network^™

Direct Cd32 T-Cell Cytotoxicity: Implications For Breast Cancer Prognosis And Treatment, Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli, Gabriele Toietta, Silvia Baldari, Tommaso Sconocchia, Francesca De Paolis, Anna Aureli, Giandomenica Iezzi, Maria Irno Consalvo, Francesco Buccisano, Maria I Del Principe, Luca Maurillo, Adriano Venditti, Alessio Ottaviani, Giulio C Spagnoli

Faculty, Staff and Student Publications

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice …

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 …

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 …

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 …

India Field Epidemiology Training Program Response To Covid-19 Pandemic, 2020-2021, Sujeet Kumar Singh, Tanzin Dikid, Meera Dhuria, Arti Bahl, Ramesh Chandra, Vaisakh Thandayamparambil Pradeep, Surendra Mohan Prajapati, Nishant Nirwan, Lipsy Paul, Manoj Murhekar, Prabhdeep Kaur, Ganeshkumar Parasuraman, Prashant Bhat, Sheila Longkumer, Kevisetuo Anthony Dzeyie, Pankaj Bhatnagar, Nhu Nguyen Tran Minh, Sukarma Tanwar, Rajesh Yadav, Meghna Desai

Faculty, Staff and Student Publications

The India Field Epidemiology Training Program (FETP) has played a critical role in India's response to the ongoing COVID-19 pandemic. During March 2020-June 2021, a total of 123 FETP officers from across 3 training hubs were deployed in support of India's efforts to combat COVID-19. FETP officers have successfully mitigated the effect of COVID-19 on persons in India by conducting cluster outbreak investigations, performing surveillance system evaluations, and developing infection prevention and control tools and guidelines. This report discusses the successes of select COVID-19 pandemic response activities undertaken by current India FETP officers and proposes a pathway to augmenting India's …

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, …

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 …

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 …

Hpv-Associated Anal Cancer Knowledge, Attitudes, And Health Communication Behaviors Among Non-Clinical Providers At Hiv/Aids Service Organizations In Southern United States Region, Olufunto A Olusanya, Aditi Tomar, Jonathan Thomas, Praisy Johnson, Lisa T Wigfall

Faculty, Staff and Student Publications

Co-infection with HIV/HPV and bio-behavioral risk factors (e.g., immunodeficiency, un-protected sex) increase likelihood for developing anal and other HPV-associated cancers among people living with HIV/AIDS (PLWHA). We explored knowledge, attitudes, and health communication regarding HPV-associated anal cancers among HIV/AIDS service organization (ASO) employees/volunteers delivering non-clinical services to PLWHA. Participants (n=59) were recruited from six ASOs located in the South United States Census region and completed a 118-item self-administered survey. For current analyses, outcome measures were knowledge, attitudes, and health communication regarding anal cancer. Descriptive statistics assessed outcome measures which were subsequently dichotomized into binary variables (i.e., high/favorable or low/unfavorable). Fisher's …

Chronic Kidney Disease In Public Renal Practices In Queensland, Australia, 2011–2018, Wendy E Hoy, Zaimin Wang, Jianzhen Zhang, Vishal Diwan, Anne Cameron, Sree K Venuthurupalli, Robert G Fassett, Samuel Chan, Helen G Healy, Ken-Soon Tan, Richard Baer, Andrew J Mallett, Nicholas Gray, Murty Mantha, Roy Cherian, Clyson Mutatiri, Krishan Madhan, George Kan, Geoffrey Mitchell, Shahadat Hossain, Danielle Wu, Thin Han, Adrian Kark, Thomas Titus, Dwarakanatan Ranganathan, Ann Bonner, Sridevi Govindarajulu, Nhmrc Ckd.Cre And The Ckd.Qld Collaborative

Faculty, Staff and Student Publications

AIM: To describe adults with (non-dialysis) chronic kidney disease (CKD) in nine public renal practice sites in the Australian state of Queensland.

METHODS: 7,060 persons were recruited to a CKD Registry in May 2011 and until start of kidney replacement therapy (KRT), death without KRT or June 2018, for a median period of 3.4 years.

RESULTS: The cohort comprised 7,060 persons, 52% males, with a median age of 68 yr; 85% had CKD stages 3A to 5, 45.4% were diabetic, 24.6% had diabetic nephropathy, and 51.7% were obese. Younger persons mostly had glomerulonephritis or genetic renal disease, while older persons …

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.

Quantitative Apparent Diffusion Coefficients From Peritumoral Regions As Early Predictors Of Response To Neoadjuvant Systemic Therapy In Triple-Negative Breast Cancer, Benjamin C Musall, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Abeer H Abdelhafez, Jong Bum Son, Jia Sun, Lumarie Santiago, Gary J Whitman, Tanya W Moseley, Marion E Scoggins, Hagar S Mahmoud, Jason B White, Ken-Pin Hwang, Nabil A Elshafeey, Medine Boge, Shu Zhang, Jennifer K Litton, Vicente Valero, Debu Tripathy, Alastair M Thompson, Clinton Yam, Peng Wei, Stacy L Moulder, Mark D Pagel, Wei T Yang, Jingfei Ma, Gaiane M Rauch

Faculty, Staff and Student Publications

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC) is a strong predictor of patient survival. Edema in the peritumoral region (PTR) has been reported to be a negative prognostic factor in TNBC.

PURPOSE: To determine whether quantitative apparent diffusion coefficient (ADC) features from PTRs on reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) predict the response to NAST in TNBC.

STUDY TYPE: Prospective.

POPULATION/SUBJECTS: A total of 108 patients with biopsy-proven TNBC who underwent NAST and definitive surgery during 2015-2020.

FIELD STRENGTH/SEQUENCE: A 3.0 T/rFOV single-shot diffusion-weighted echo-planar imaging sequence (DWI).

ASSESSMENT: Three scans were …

Immunological Conversion Of Solid Tumours Using A Bispecific Nanobioconjugate For Cancer Immunotherapy, Yifei Lu, Kristin Huntoon, Daeyong Lee, Yifan Wang, Jonghoon Ha, Yaqing Qie, Xuefeng Li, Benjamin R Schrank, Shiyan Dong, Thomas D Gallup, Minjeong Kang, Hai Zhao, Yi An, Zhaogang Yang, Jing Li, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Solid tumours display a limited response to immunotherapies. By contrast, haematological malignancies exhibit significantly higher response rates to immunotherapies as compared with solid tumours. Among several microenvironmental and biological disparities, the differential expression of unique immune regulatory molecules contributes significantly to the interaction of blood cancer cells with immune cells. The self-ligand receptor of the signalling lymphocytic activation molecule family member 7 (SLAMF7), a molecule that is critical in promoting the body's innate immune cells to detect and engulf cancer cells, is expressed nearly exclusively on the cell surface of haematologic tumours, but not on solid ones. Here we show …

Engineered Exosomes Targeting Myc Reverse The Proneural-Mesenchymal Transition And Extend Survival Of Glioblastoma, Amanda R Haltom, Wafa E Hassen, Janine Hensel, Jiha Kim, Hikaru Sugimoto, Bingrui Li, Kathleen M Mcandrews, Meagan R Conner, Michelle L Kirtley, Xin Luo, Bingqing Xie, Olga V Volpert, Susan Olalekan, Natalia Maltsev, Anindita Basu, Valerie S Lebleu, Raghu Kalluri

Faculty, Staff and Student Publications

Dysregulated Myc signaling is a key oncogenic pathway in glioblastoma multiforme (GBM). Yet, effective therapeutic targeting of Myc continues to be challenging. Here, we demonstrate that exosomes generated from human bone marrow mesenchymal stem cells (MSCs) engineered to encapsulate siRNAs targeting Myc (iExo-Myc) localize to orthotopic GBM tumors in mice. Treatment of late stage GBM tumors with iExo-Myc inhibits proliferation and angiogenesis, suppresses tumor growth, and extends survival. Transcriptional profiling of tumors reveals that the mesenchymal transition and estrogen receptor signaling pathways are impacted by Myc inhibition. Single nuclei RNA sequencing (snRNA-seq) shows that iExo-Myc treatment induces transcriptional repression of …

Accuracy And Safety Of Scout Dose Resin Yttrium-90 Microspheres For Radioembolization Therapy Treatment Planning: A Prospective Single-Arm Clinical Trial, Nima Kokabi, Linzi A Webster, Mohammad Elsayed, Jeffrey M Switchenko, Bernard Chen, David Brandon, James Galt, Ila Sethi, Mircea Cristescu, S Cheenu Kappadath, David M Schuster

Faculty, Staff and Student Publications

PURPOSE: To compare the accuracy and safety of 0.56 GBq resin yttrium-90 (

MATERIALS AND METHODS: This prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout

RESULTS: Thirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx

CONCLUSIONS: Compared with MAA, scout

Hypofractionated, 3-Week, Preoperative Radiotherapy For Patients With Soft Tissue Sarcomas (Hyport-Sts): A Single-Centre, Open-Label, Single-Arm, Phase 2 Trial, B Ashleigh Guadagnolo, Roland L Bassett, Devarati Mitra, Ahsan Farooqi, Caroline Hempel, Courtney Dorber, Tiara Willis, Wei-Lien Wang, Ravin Ratan, Neeta Somaiah, Robert S Benjamin, Keila E Torres, Kelly K Hunt, Christopher P Scally, Emily Z Keung, Robert L Satcher, Justin E Bird, Patrick P Lin, Bryan S Moon, Valerae O Lewis, Christina L Roland, Andrew J Bishop

Faculty, Staff and Student Publications

BACKGROUND: The standard preoperative radiotherapy regimen of 50 Gy delivered in 25 fractions for 5 weeks for soft tissue sarcomas results in excellent local control, with major wound complications occurring in approximately 35% of patients. We aimed to investigate the safety of a moderately hypofractionated, shorter regimen of radiotherapy, which could be more convenient for patients.

METHODS: This single-centre, open-label, single-arm, phase 2 trial (HYPORT-STS) was done at a single tertiary cancer care centre (MD Anderson Cancer Center, Houston, TX, USA). We administered preoperative radiotherapy to a dose of 42·75 Gy in 15 fractions of 2·85 Gy/day for 3 weeks …

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 …

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 …

Quality-Of-Life Outcomes In Older Patients With Early-Stage Rectal Cancer Receiving Organ-Preserving Treatment With Hypofractionated Short-Course Radiotherapy Followed By Transanal Endoscopic Microsurgery (Trec): Non-Randomised Registry Of Patients Unsuitable For Total Mesorectal Excision, Alexandra Gilbert, Victoria Homer, Kristian Brock, Stephan Korsgen, Ian Geh, James Hill, Talvinder Gill, Paul Hainsworth, Matthew Tutton, Jim Khan, Jonathan Robinson, Mark Steward, Christopher Cunningham, Manjinder Kaur, Laura Magill, Ann Russell, Philip Quirke, Nicholas P West, David Sebag-Montefiore, Simon P Bach, Trec Collaborators

Faculty, Staff and Student Publications

BACKGROUND: Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal …

Mdm2 Antagonist Improves Therapeutic Activity Of Azacitidine In Myelodysplastic Syndromes And Chronic Myelomonocytic Leukemia, Yue Wei, Hong Zheng, Pamela Pennington Lockyer, Faezeh Darbaniyan, Ziyi Li, Rashmi Kanagal-Shamanna, Kelly A Soltysiak, Hui Yang, Irene Ganan-Gomez, Guillermo Montalban-Bravo, Kelly S Chien, Kim-Anh Do, Naval Daver, Guillermo Garcia-Manero

Faculty, Staff and Student Publications

Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone …

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 …

Neoadjuvant Chemo-Immunotherapy For Lung Cancer: How Much Is Too Much?, Nathaniel Deboever, Jianjun Zhang

Faculty, Staff and Student Publications

No abstract provided.

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 …