Genetic Phenomena Commons^™

Prevalence, Diagnostic Features, And Medical Outcomes Of Females With Turner Syndrome With A Trisomy X Cell Line (45, X/47, Xxx): Results From The Insights Registry, Natalia Klamut, Samantha Bothwell, Alexandra E Carl, Vaneeta Bamba, Jennifer R Law, Karen O Klein, Catherina T Pinnaro, Patricia Y Fechner, Siddharth K Prakash, Iris Gutmark-Little, Susan Howell, Nicole Tartaglia, Marybel Good, Kelly C Ranallo, Shanlee M Davis

Faculty, Staff and Student Publications

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly …

Artificial Intelligence And Machine Learning In Cancer Pain: A Systematic Review, Vivian Salama, Brandon Godinich, Yimin Geng, Laia Humbert-Vidan, Laura Maule, Mohamed A Naser, Abdallah S R Mohamed, Clifton D Fuller, Amy C Moreno

Faculty, Staff and Student Publications

Background/objectives: Pain is a challenging multifaceted symptom reported by most cancer patients. This systematic review aims to explore applications of artificial intelligence/machine learning (AI/ML) in predicting pain-related outcomes and pain management in cancer.

Methods: A comprehensive search of Ovid MEDLINE, EMBASE and Web of Science databases was conducted using terms: "Cancer," "Pain," "Pain Management," "Analgesics," "Artificial Intelligence," "Machine Learning," and "Neural Networks" published up to September 7, 2023. AI/ML models, their validation and performance were summarized. Quality assessment was conducted using PROBAST risk-of-bias andadherence to TRIPOD guidelines.

Results: Forty four studies from 2006 to 2023 were included. Nineteen studies used …

Imipridones Inhibit Tumor Growth And Improve Survival In An Orthotopic Liver Metastasis Mouse Model Of Human Uveal Melanoma, Chandrani Chattopadhyay, Janos Roszik, Rajat Bhattacharya, Md Alauddin, Iqbal Mahmud, Mir Mustafa Ali, Varun Vijay Prabhu, Philip L Lorenzi, Bo Wei, Elizabeth Burton, Rohini R Morey, Rossana Lazcano, Michael A Davies, Sapna P Patel, Elizabeth A Grimm

Faculty, Staff and Student Publications

Background: Uveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.

Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.

Results: CLPP expression was detected in primary …

Excess Risk Of Chronic Health Conditions In Black Adolescent And Young Adult Cancer Survivors, Amy M Berkman, Eunju Choi, Christabel K Cheung, John M Salsman, Susan K Peterson, Qian Lu, Aryce Battle, Michelle A T Hildebrandt, Susan K Parsons, Michael E Roth

Faculty, Staff and Student Publications

Background: The US population of adolescent and young adult (age 15-39 years at diagnosis) cancer survivors is growing. Previous studies have identified racial and ethnic disparities in survival and health outcomes in racially minoritized survivors, including Black survivors, compared with White survivors. However, comparisons should be made between those of the same race or ethnicity with and without a history of AYA cancer to fully understand the association of a cancer diagnosis with socioeconomic status (SES) and health outcomes within a minoritized population.

Methods: Non-Hispanic Black AYA cancer survivors and non-Hispanic Black age- and sex-matched controls were identified from self-reported …

Adjuvant Rituximab And Elevated Intratumoural Cd8 Expression Are Associated With Sustained Disease Control After Radiotherapy In A Randomised Trial Of Systemic Therapy In Early-Stage Follicular Lymphoma, Michael P Macmanus, John F Seymour, Hennes Tsang, Richard Fisher, Colm Keane, Soi C Law, Karthik Nath, Stephen H Kazakoff, Mario L Marques-Piubelli, Daniela E Duenas, Michael R Green, Daniel Roos, Peter O'Brien, Andrew Mccann, Richard Tsang, Sidney Davis, David Christie, Chan Cheah, Benhur Amanuel, Tara Cochrane, Jason Butler, Anna Johnston, Mohamed Shanavas, Li Li, Claire Vajdic, Robert Kridel, Victoria Shelton, Samantha Hershenfield, Tara Baetz, David Lebrun, Nathalie Johnson, Marianne Brodtkorb, Maja Ludvigsen, Francesco D'Amore, Ella R Thompson, Piers Blombery, Maher K Gandhi, Joshua W D Tobin

Faculty, Staff and Student Publications

Background: We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies.

Methods: Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT + CVP). From 2006 rituximab was added to IFRT + CVP (IFRT + R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively).

Findings: Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at …

3d Gamma Analysis Between Treatment Plans For Nominally Beam-Matched Medical Linear Accelerators Using Pymedphys, Fada Guan, William Donahue, Simon Biggs, Matthew Jennings, Emily Draeger, Yuenan Wang, David J Carlson, Zhe Chen, Dae Yup Han

Faculty, Staff and Student Publications

Beam-matched linear accelerators (linacs) enable flexible patient scheduling and efficient treatment delivery in the event of unexpected machine downtime. The purpose of this study was to test the feasibility of 3D gamma index as an additional metric beyond standard measurement-based comparisons for more efficient evaluation of treatment plans between linacs with nominally matched beam models to ensure safe patient transfer. Seventeen 3D conformal radiotherapy (3DCRT) plans and thirty-six volumetric-modulated radiation therapy (VMAT) plans for different disease sites were selected from the original linac. An in-house script was used to automatically create new plans for the target linac and calculate dose …

Anti-Programmed Death Ligand 1 Plus Targeted Therapy In Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial, Maria E Cabanillas, Ramona Dadu, Renata Ferrarotto, Maria Gule-Monroe, Suyu Liu, Michelle D Williams, Jennifer R Wang, Charles Lu, Matthew Ning, Brian A Mckinley, Scott E Woodman, Dzifa Duose, Gary B Gunn, Naifa L Busaidy, Rare Tumor Initiative Team

Faculty, Staff and Student Publications

Importance: Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors.

Objective: To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS).

Design, setting, and participants: A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus …

Emergence Of Igh::Ccnd1 Rearrangement And Mutations In Tp53, Btk, And Bcl2 Associated With Therapy Resistance In Chronic Lymphocytic Leukemia, Qing Wei, Hong Fang, James M Jing, Roman Segura-Rivera, L Jeffrey Medeiros

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is an indolent low-grade B-cell neoplasm that generally responds well to treatment. Rarely, CLL cases exhibit an IGH::CCND1 rearrangement, presenting a diagnostic challenge in distinguishing between clonal evolution within CLL and an independent mantle cell lymphoma. We report a case of CLL with the emergence of an IGH::CCND1 rearrangement and mutations associated with treatment resistance, including TP53, BTK, and BCL2, during disease progression. Immunophenotypic, cytogenetic, and molecular analyses support that these alterations are secondary events within the CLL clone. This case demonstrates dynamic clonal selection and expansion in response to treatments, which, in turn, contributes to …

Early Detection Of Pancreatic Cancer: Study Design And Analytical Considerations In Biomarker Discovery And Early Phase Validation Studies, Lynette M Smith, Douglas W Mahoney, William R Bamlet, Fang Yu, Suyu Liu, Sourat Darabi, Qiao-Li Wang, Gregory A Coté, Michael J Demeure, Zhen Zhang, Sudhir Srivastava, Akhil Chawla, Grant Izmirlian, Janet E Olson, Brian M Wolpin, Jeanine M Genkinger, Kenneth S Zaret, Randall Brand, Eugene J Koay, Ann L Oberg

Faculty, Staff and Student Publications

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that is challenging to detect at an early stage. Biomarkers are needed that can detect PDAC early in the course of disease when interventions lead to the best outcomes. We highlight study design and statistical considerations that inform pancreatic cancer early detection biomarker evaluation.

Methods: We describe experimental design strategies in this setting useful for streamlining biomarker evaluation at each Early Detection Research Network (EDRN) phase of biomarker development. We break the early EDRN phases into sub-phases, proposing objectives, study design strategies, and biomarker performance benchmarks.

Results: The goal of …

Wirelessly Actuated Microfluidic Pump And Valve For Controlled Liquid Delivery In Dental Implants, Yilan Xu, Honglu Lin, Boyang Xiao, Hutomo Tanoto, Joel Berinstein, Simon Young, Xiaoguang Dong

Faculty, Staff and Student Publications

Enabling minimally invasive and precise control of liquid release in dental implants is crucial for therapeutic functions such as delivering antibiotics to prevent biofilm formation, infusing stem cells to promote osseointegration, and administering other biomedicines. However, achieving controllable liquid cargo release in dental implants remains challenging due to the lack of wireless and miniaturized fluidic control mechanisms. Here wireless miniature pumps and valves that allow remote activation of liquid cargo delivery in dental implants, actuated and controlled by external magnetic fields (< 65 mT), are reported. A magnet-screw mechanism in a fluidic channel to function as a piston pump, alongside a flexible magnetic valve designed to open and close the fluidic channel, is proposed. The mechanisms are showcased by storing and releasing of liquid up to 52 µL in a dental implant. The liquid cargos are delivered directly to the implant-bone interface, a region traditionally difficult to access. On-demand liquid delivery is further showed by a metal implant inside both dental phantoms and porcine jawbones. The mechanisms are promising for controllable liquid release after implant placement with minimal invasion, paving the way for implantable devices that enable long-term and targeted delivery of therapeutic agents in various bioengineering applications.

Vitamin D In Patients With Low Tumor-Burden Indolent Non-Hodgkin Lymphoma Treated With Rituximab Therapy (Ilyad): A Randomized, Phase 3 Clinical Trial, Jonathan W Friedberg, Michael T Brady, Myla Strawderman, Brad S Kahl, Izidore S Lossos, Patrick M Reagan, Barbara L Averill, Andrea Baran, Grerk Sutamtewagul, Paul M Barr, John P Leonard, John M Ashton, John G Strang, Francisco Vega, Derick R Peterson, Loretta J Nastoupil

Faculty, Staff and Student Publications

Background: There is a significant association between low vitamin D levels at diagnosis of indolent B-cell lymphomas and inferior overall survival (OS). To determine whether supplemental vitamin D improves event-free survival (EFS) in these patients, we conducted a comparative double-blind study of vitamin D3 vs. placebo.

Methods: In this phase 3, randomized, double-blind, placebo-controlled trial, patients with low tumor burden follicular, marginal zone or small lymphocytic lymphoma, age 18 or older, with stage two or greater disease and no prior systemic treatment were enrolled at 7 academic cancer centers. Patients were stratified by histology and FLIPI (Follicular Lymphoma International Prognostic …

Prediction Of Pathological Complete Response To Chemotherapy For Breast Cancer Using Deep Neural Network With Uncertainty Quantification, Bowen Jing, Kai Wang, Erich Schmitz, Shanshan Tang, Yunxiang Li, Jing Wang

Faculty, Staff and Student Publications

Background: The I-SPY 2 trial is a national-wide, multi-institutional clinical trial designed to evaluate multiple new therapeutic drugs for high-risk breast cancer. Previous studies suggest that pathological complete response (pCR) is a viable indicator of long-term outcomes of neoadjuvant chemotherapy for high-risk breast cancer. While pCR can be assessed during surgery after the chemotherapy, early prediction of pCR before the completion of the chemotherapy may facilitate personalized treatment management to achieve an improved outcome. Notably, the acquisition of dynamic contrast-enhanced magnetic resonance (DCEMR) images at multiple time points during the I-SPY 2 trial opens up the possibility of achieving early …

Mimicking Large Spot-Scanning Radiation Fields For Proton Flash Preclinical Studies With A Robotic Motion Platform, Fada Guan, Dadi Jiang, Xiaochun Wang, Ming Yang, Kiminori Iga, Lawrence Bronk, Liang Wang, Youming Guo, Narayan Sahoo, David R Grosshans, Albert C Koong, Xiaorong R Zhu, Radhe Mohan

Faculty, Staff and Student Publications

Previously, a synchrotron-based horizontal proton beamline (87.2 MeV) was successfully commissioned to deliver radiation doses in FLASH and conventional dose rate modes to small fields and volumes. In this study, we developed a strategy to increase the effective radiation field size using a custom robotic motion platform to automatically shift the positions of biological samples. The beam was first broadened with a thin tungsten scatterer and shaped by customized brass collimators for irradiating cell/organoid cultures in 96-well plates (a 7-mm-diameter circle) or for irradiating mice (1-cm

Surfactant Protein-C Regulates Alveolar Type 2 Epithelial Cell Lineages Via The Cd74 Receptor, Krishan G Jain, Yang Liu, Runzhen Zhao, Preeti J Muire, Nan-Miles Xi

Faculty, Staff and Student Publications

Background: Deficiency of surfactant protein-C (SPC) increases susceptibility to lung infections and injury, and suppressed expression of SPC has been associated with the severity of acute respiratory distress syndrome (ARDS). Alveolar type 2 epithelial cells (AT2) are critical for maintenance and repair of the lung. However, the role of the SPC in the regulation of AT2 cell lineage and the underlying mechanisms are not completely understood.

Methods: This study aimed to investigate the mechanisms by which SPC regulates AT2 lineages. Sftpc-/- mice were used to model the SPC deficiency in ARDS patients. We utilized three-dimensional (3D) organoids to compare AT2 …

Off-Protocol Radiation Therapy In Phase 3 Metastatic Solid Tumor Trials, Alexander D Sherry, Timothy A Lin, Zachary R Mccaw, Esther J Beck, Ramez Kouzy, Adina H Passy, Gabrielle S Kupferman, Clifton David Fuller, Charles R Thomas, Eugene J Koay, Chad Tang, Pavlos Msaouel, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes.

Methods and materials: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from …

Dna Mismatch Repair Deficiency As A Biomarker In Sarcoma, Ryan A Denu, Christopher D Quintana-Perez, Sintawat Wangsiricharoen, Davis R Ingram, Khalida M Wani, Ravin Ratan, Y Nancy You

Faculty, Staff and Student Publications

Purpose: Lynch syndrome (LS) is a cancer predisposition syndrome caused by a germline loss-of-function mutation in a mismatch repair (MMR) gene. While sarcomas are not classically considered LS cancers, we investigated the MMR status and clinical features of sarcomas in LS patients to help inform optimal treatment strategies.

Methods: A prospectively maintained institutional clinical cancer genetics database was queried for LS patients (defined by pathogenic germline mutation in a MMR gene) with a documented diagnosis of sarcoma between 1998-2022. Tumor MMR status was determined by immunohistochemistry (IHC) for MMR proteins and secondarily by PCR assay if IHC was normal or …

Sleep Disturbances Based On Patient Reported Outcomes In Patients With Breast Cancer, Saadia A Faiz, Ashley S Knox, Bryan Fellman, Bibi Aneesah Jaumally, G Nancy Pacheco, Reeba Mathew, Jennifer K Litton, Diwakar D Balachandran, Lara Bashoura

Faculty, Staff and Student Publications

Purpose: Sleep disturbances are common in patients with breast cancer, but comprehensive evaluations with patient-reported outcomes (PRO) and sleep evaluation with polysomnography (PSG) are lacking. This study describes sleep disruption using PROs and PSG to identify underlying sleep disorders.

Methods: A retrospective review of patients with breast cancer undergoing formal sleep evaluation from 4/1/2009 to 7/31/2014 was performed. Clinical characteristics, PROs using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), and PSG data were reviewed.

Results: 404 patients were identified with 43% early, 30% locally advanced and 17% metastatic disease. PSQI revealed poor sleep in 75%, and ESS …

Gravity- Vs Wall Suction-Driven Large-Volume Thoracentesis: A Randomized Controlled Study, Samira Shojaee, Jasleen Pannu, Lonny Yarmus, Alberto Fantin, Christina Macrosty, Labib Debiane, Saadia A Faiz, Carlos A Jimenez, Sameer K Avasarala, Erik Vakil, Andrew Demaio, Lara Bashoura, Keerthana Keshava, Travis Ferguson, Roberto Adachi, George A Eapen, David E Ost, Sami Bashour, Asad Khan, Vickie Shannon, Ajay Sheshadri, Roberto F Casal, Scott E Evans, Krystle Pew, Nadia Castaldo, Diwakar D Balachandran, Vincenzo Patruno, Robert Lentz, Cheryl Pai, Fabien Maldonado, Lance Roller, Junsheng Ma, Jhankruti Zaveri, Jenna Los, Luis Vaquero, Eva Ordonez, Gulmira Yermakhanova, Jason Akulian, Cole Burks, Roel-Rolando Almario, Marie Sauve, Jackson Pettee, Laila Z Noor, Muhammad H Arain, Horiana B Grosu

Faculty, Staff and Student Publications

Background: Prior studies have found no differences in procedural chest discomfort for patients undergoing manual syringe aspiration or drainage with gravity after thoracentesis. However, whether gravity drainage could protect against chest pain due to the larger negative-pressure gradient generated by wall suction has not been investigated.

Research question: Does wall suction drainage result in more chest discomfort compared with gravity drainage in patients undergoing large-volume thoracentesis?

Study design and methods: In this multicenter, single-blinded, randomized controlled trial, patients with large free-flowing effusions of ≥ 500 mL were assigned at a 1:1 ratio to wall suction or gravity drainage. Wall suction …

Sitravatinib In Patients With Solid Tumors Selected By Molecular Alterations: Results From A Phase Ib Study, Lyudmila Bazhenova, Dong-Wan Kim, Byoung Chul Cho, Sanjay Goel, Rebecca Heist, Keith D Eaton, Shubham Pant, Douglas R Adkins, Collin M Blakely, Xiaohong Yan, Saskia Neuteboom, James G Christensen, Richard Chao, Todd Bauer

Faculty, Staff and Student Publications

No abstract provided.

Hunting For Heroes: Brain Neurons Mediating Glp-1r Agonists In Obesity Treatment, Yuhan Cao, Qingchun Tong

Faculty, Staff and Student Publications

Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) have proven to be highly effective in reducing obesity across species and ages, gaining unmet popularity in clinical treatments against obesity. Although extensive research efforts have been made to explore how the brain regulates body weight homeostasis including the effect brought up by GLP-1 and its synthetic analogs GLP-1RAs, the identity of neurons and neural pathways that are responsible for the observed anti-obesity effect of GLP-1RAs remain largely elusive. Excitingly, three recent high-profile studies presented compelling evidence that each argues for the importance of GLP-1Rs in the dorsomedial hypothalamus, hindbrain, or lateral septum, …