Medical Sciences Commons^™

Complex I Inhibitor Of Oxidative Phosphorylation In Advanced Solid Tumors And Acute Myeloid Leukemia: Phase I Trials, Timothy A Yap, Naval Daver, Mikhila Mahendra, Jixiang Zhang, Carlos Kamiya-Matsuoka, Funda Meric-Bernstam, Hagop M Kantarjian, Farhad Ravandi, Meghan E Collins, Maria Emilia Di Francesco, Ecaterina E Dumbrava, Siqing Fu, Sisi Gao, Jason P Gay, Sonal Gera, Jing Han, David S Hong, Elias J Jabbour, Zhenlin Ju, Daniel D Karp, Alessia Lodi, Jennifer R Molina, Natalia Baran, Aung Naing, Maro Ohanian, Shubham Pant, Naveen Pemmaraju, Prithviraj Bose, Sarina A Piha-Paul, Jordi Rodon, Carolina Salguero, Koji Sasaki, Anand K Singh, Vivek Subbiah, Apostolia M Tsimberidou, Quanyun A Xu, Musa Yilmaz, Qi Zhang, Yuan Li, Christopher A Bristow, Meenakshi B Bhattacharjee, Stefano Tiziani, Timothy P Heffernan, Christopher P Vellano, Philip Jones, Cobi J Heijnen, Annemieke Kavelaars, Joseph R Marszalek, Marina Konopleva

Faculty, Staff and Student Publications

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow …

A Unified Mediation Analysis Framework For Integrative Cancer Proteogenomics With Clinical Outcomes, Licai Huang, James P Long, Ehsan Irajizad, James D Doecke, Kim-Anh Do, Min Jin Ha

Faculty, Staff and Student Publications

MOTIVATION: Multilevel molecular profiling of tumors and the integrative analysis with clinical outcomes have enabled a deeper characterization of cancer treatment. Mediation analysis has emerged as a promising statistical tool to identify and quantify the intermediate mechanisms by which a gene affects an outcome. However, existing methods lack a unified approach to handle various types of outcome variables, making them unsuitable for high-throughput molecular profiling data with highly interconnected variables.

RESULTS: We develop a general mediation analysis framework for proteogenomic data that include multiple exposures, multivariate mediators on various scales of effects as appropriate for continuous, binary and survival outcomes. …

Spatial Modelling Of The Tumor Microenvironment From Multiplex Immunofluorescence Images: Methods And Applications, Gayatri Kumar, Renganayaki Krishna Pandurengan, Edwin Roger Parra, Kasthuri Kannan, Cara Haymaker

Faculty, Staff and Student Publications

Spatial modelling methods have gained prominence with developments in high throughput imaging platforms. Multiplex immunofluorescence (mIF) provides the scope to examine interactions between tumor and immune compartment at single cell resolution using a panel of antibodies that can be chosen based on the cancer type or the clinical interest of the study. The markers can be used to identify the phenotypes and to examine cellular interactions at global and local scales. Several translational studies rely on key understanding of the tumor microenvironment (TME) to identify drivers of immune response in immunotherapy based clinical trials. To improve the success of ongoing …

Fostering A High-Functioning Team In Cancer Care Using The 4r Oncology Model: Assessment In A Large Health System And A Blueprint For Other Institutions, Raymond Liu, Christine B Weldon, Elizabeth Linehan, Nancy Gordon, Thea Abbe, Marti Hennings, Henie James, Jed Katzel, Chun Ng, Megumi Tomita, Jeffrey B Velotta, Stephanie Ossowski, Lori C Sakoda, Sharon Likely Sprague, Anna Dowling, Kimberly Beringer, Arliene Ravelo, Elaine Yu, Julia R Trosman

Faculty, Staff and Student Publications

PURPOSE: Delivering cancer care by high-functioning multidisciplinary teams promises to address care fragmentation, which threatens care quality, affects patient outcomes, and strains the oncology workforce. We assessed whether the 4R Oncology model for team-based interdependent care delivery and patient self-management affected team functioning in a large community-based health system.

METHODS: 4R was deployed at four locations in breast and lung cancers and assessed along four characteristics of high-functioning teams: recognition as a team internally and externally; commitment to an explicit shared goal; enablement of interdependent work to achieve the goal; and engagement in regular reflection to adapt objectives and processes. …

Radiotherapy Reimagined: Integrating Nanomedicines Into Radiotherapy Clinical Trials, Allison N Duross, Jack Phan, Alexander J Lazar, Joshua M Walker, Alexander R Guimaraes, Carole Baas, Sunil Krishnan, Charles R Thomas, Conroy Sun, Alexander F Bagley

Faculty, Staff and Student Publications

Radioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials. …

Associative Learning Contributes To The Persistence Of Fatigue-Like Behavior In Male Mice In A Model Of Cancer Survivorship, Elisabeth G Vichaya, Josephine K Darpolor, Phillip S Gross, Jessica M Molkentine, Daniel W Vermeer, Paola D Vermeer, John H Lee, Cullen M Taniguchi, Robert Dantzer

Faculty, Staff and Student Publications

Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative learning in the persistence of fatigue using a preclinical model of cancer survivorship. For this purpose, we used a murine model of human papilloma virus-related head and neck cancer paired with a curative regimen of cisplatin-based chemoradiation in male C57BL/6J mice. Fatigue-like behavior was assessed by measuring variations in voluntary …

Stem Cell Theory Of Cancer: Origin Of Metastasis And Sub-Clonality, Shi-Ming Tu, Cesar Moran, William Norton, Niki M Zacharias

Faculty, Staff and Student Publications

Metastasis may be the secret weapon cancer uses to dominate and subjugate, to persist and prevail. However, it is no longer a secret when we realize that a stem cell has the same ways and means to fulfill its own omnipotence and accomplish its own omnipresence… and when we realize that a cancer cell has its own version of stem-ness origin and stem-like nature. In this perspective, we discuss whether stem-ness enables metastasis or mutations drive metastasis. We ponder about low-grade versus high-grade tumors and about primary versus metastatic tumors. We wonder about stochasticity and hierarchy in the genesis and …

Regional Disparities In Major Cancer Incidence In Korea, 1999–2018, Eun Hye Park, Mee Joo Kang, Kyu-Won Jung, Eun Hye Park, E Hwa Yun, Hye-Jin Kim, Hyun-Joo Kong, Chang Kyun Choi, Jeong-Soo Im, Hong Gwan Seo

Faculty, Staff and Student Publications

OBJECTIVES: This study investigated regional disparities in the incidence of 8 major cancers at the municipal level in Korea during 1999-2018 and evaluated the presence or absence of hot spots of cancer clusters during 2014-2018.

METHODS: The Korea National Cancer Incidence Database was used. Age-standardized incidence rates were calculated by gender and region at the municipal level for 4 periods of 5 years and 8 cancer types. Regional disparities were calculated as both absolute and relative measures. The possibility of clusters was examined using global Moran's I with a spatial weight matrix based on adjacency or distance.

RESULTS: Regional disparities …

Selinexor In Combination With Weekly Paclitaxel In Patients With Metastatic Solid Tumors: Results Of An Open Label, Single-Center, Multi-Arm Phase 1b Study With Expansion Phase In Ovarian Cancer, Shannon N Westin, Siqing Fu, Apostolia Tsimberidou, Sarina Piha-Paul, Fechukwu Akhmedzhanov, Bulent Yilmaz, Lacey Mcquinn, Amanda L Brink, Jing Gong, Cheuk Hong Leung, Heather Lin, David S Hong, Shubham Pant, Brett Carter, Amir Jazaeri, David Gershenson, Anil K Sood, Robert L Coleman, Jatin Shah, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

OBJECTIVE: Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound which blocks Exportin-1 (XPO1). Our objective was to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel.

METHODS: This was an open label, single-center, multi-arm phase 1b study utilizing a "3 + 3" design and a "basket-type" expansion in recurrent solid tumors. Selinexor (60 mg or 80 mg twice weekly orally) and weekly paclitaxel (80 mg IV 2 week on, 1 week off) were one of 13 parallel arms. Efficacy was evaluated using RECIST version 1.1.

RESULTS: All 35 patients …

Next-Generation Ctla-4 Targeting Molecules And Combination Therapy: Promising Strategies For Improving Cancer Immunotherapy, Nils-Petter Rudqvist, Manushak Avagyan, Dhan Chand

Faculty, Staff and Student Publications

Radiation therapy and anti-CTLA-4 combination therapy can induce meaningful responses in some patients. Adding CD40 may provide additional benefit. Next-generation anti-CTLA-4 antibodies, such as botensilimab, are showing promise in clinical trials. Combining botensilimab with RT and/or CD40 agonist may offer additional benefits for challenging tumor types.

Translating Energy Balance Research From The Bench To The Clinic To The Community: Parallel Animal-Human Studies In Cancer, Miriam B Garcia, Keri L Schadler, Joya Chandra, Steven K Clinton, Kerry S Courneya, Zobeida Cruz-Monserrate, Carrie R Daniel, Andrew J Dannenberg, Wendy Demark-Wahnefried, Mark W Dewhirst, Carol J Fabian, Stephen D Hursting, Melinda L Irwin, Neil M Iyengar, Jennifer L Mcquade, Kathryn H Schmitz, Karen Basen-Engquist

Faculty, Staff and Student Publications

Advances in energy balance and cancer research to date have largely occurred in siloed work in rodents or patients. However, substantial benefit can be derived from parallel studies in which animal models inform the design of clinical and population studies or in which clinical observations become the basis for animal studies. The conference Translating Energy Balance from Bench to Communities: Application of Parallel Animal-Human Studies in Cancer, held in July 2021, convened investigators from basic, translational/clinical, and population science research to share knowledge, examples of successful parallel studies, and strong research to move the field of energy balance and cancer …

Contemporaneous Symptom Networks Of Multidimensional Symptom Experiences In Cancer Survivors: A Network Analysis, Zheng Zhu, Yanling Sun, Yi Kuang, Xiaoyi Yuan, Haiyan Gu, Jing Zhu, Weijie Xing

Faculty, Staff and Student Publications

Background: Symptom networks can provide empirical evidence for the development of personalized and precise symptom management strategies. However, few studies have explored the symptom networks of multidimensional symptom experiences in cancer survivors. The objectives of this study were to generate symptom networks of multidimensional symptom experiences in cancer survivors and explore the centrality indices and density in these symptom networks METHODS: Data from 1065 cancer survivors were obtained from the Shanghai CANcer Survivor (SCANS) Report. The MD Anderson Symptom Inventory was used to assess the prevalence and severity of 13 cancer-related symptoms. We constructed contemporaneous networks with all 13 symptoms …

Fanconi Anemia Caused By Biallelic Inactivation Of Brca2 Can Present With An Atypical Cancer Phenotype In Adulthood, Kara N Maxwell, Vishal Patel, Kevin T Nead, Shana Merrill, Dana Clark, Qinqin Jiang, Bradley Wubbenhorst, Kurt D'Andrea, Roger B Cohen, Susan M Domchek, Jennifer J D Morrissette, Roger A Greenberg, Daria V Babushok, Katherine L Nathanson

Faculty, Staff and Student Publications

Inherited biallelic pathogenic variants (PVs) in BRCA2 cause Fanconi Anemia complementation group D1 (FA-D1), a severe pediatric bone marrow failure and high-risk cancer syndrome. We identified biallelic BRCA2 PVs in a young adult with multiple basal cell carcinomas, adult-onset colorectal cancer and small cell neuroendocrine carcinoma, without bone marrow failure. No PVs were identified in any other known cancer susceptibility gene, and there was no evidence of reversion mosaicism. The proband's deceased sister had a classic FA-D1 presentation and was shown to carry the same biallelic BRCA2 PVs. A lymphoblastoid cell line derived from the proband demonstrated hypersensitivity to DNA …

Phase 1/2 Study Of Epacadostat In Combination With Durvalumab In Patients With Metastatic Solid Tumors, Aung Naing, Alain P Algazi, Gerald S Falchook, Benjamin C Creelan, John Powderly, Seth Rosen, Minal Barve, Niharika B Mettu, Pierre L Triozzi, John Hamm, Gongfu Zhou, Chris Walker, Zhiwan Dong, Manish R Patel

Faculty, Staff and Student Publications

Background: Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment.

Methods: The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors.

Results: The most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) …

Bayesian Single-To-Double Arm Transition Design Using Both Short-Term And Long-Term Endpoints, Tianlin Xu, Haolun Shi, Ruitao Lin

Faculty, Staff and Student Publications

The choice between single-arm designs versus randomized double-arm designs has been contentiously debated in the literature of phase II oncology trials. Recently, as a compromise, the single-to-double arm transition design was proposed, combining the two designs into one trial over two stages. Successful implementation of the two-stage transition design requires a suspension period at the end of the first stage to collect the response data of the already enrolled patients. When the evaluation of the primary efficacy endpoint is overly long, the between-stage suspension period may unfavorably prolong the trial duration and cause a delay in treating future eligible patients. …

Cancer-Associated Pyroptosis: A New License To Kill Tumor, Qing Kong, Zhibin Zhang

Faculty, Staff and Student Publications

Pyroptosis is a programmed necrotic cell death mediated by pore-forming Gasdermin (GSDM) proteins. After being unleashed from the C-terminal auto-inhibitory domains by proteolytic cleavage, the N-terminal domains of GSDMs oligomerize and perforate on the plasma membrane to induce cytolytic pyroptosis, releasing immune mediators and alarming the immune system. Upon infection or danger signal perception, GSDMD that functions downstream of the inflammasome, a supramolecular complex for inflammatory caspase activation, is cleaved and activated by inflammasome-activated caspase-1/4/5/11 in immune cells and epithelial cells to trigger pyroptosis and exert anti-infection protection. Unlike this inflammasome-activated pyroptosis (IAP), recent studies also suggest an emerging role …

Feasibility And Effectiveness Of A Worksite-Weight-Loss Program For Cancer Prevention Among School-District Employees With Overweight And Obesity, Che Young Lee, Michael C Robertson, Hannah Johnston, Thuan Le, Margaret Raber, Ruth Rechis, Katherine Oestman, Alise Neff, Amber Macneish, Karen M Basen-Engquist

Faculty, Staff and Students Publications

The effects of Vibrant Lives, a 6-month worksite-weight-loss program, were examined in a cohort of school-district employees with overweight or obesity. The VL Basic (VLB) participants received materials and tailored text messages, the VL Plus (VLP) participants additionally received WIFI-enabled activity monitors and scales and participated in health challenges throughout the school year, and the VL Plus with Support (VLP + S) participants additionally received coaching support. The levels of program satisfaction and retention and changes in weight, physical activity (PA), and diet were compared across groups using Pearson chi-square tests, repeated-measure mixed models, and logistic regression. After the program, …

A Path To Translation: How 3d Patient Tumor Avatars Enable Next Generation Precision Oncology, Shree Bose, Margarida Barroso, Milan G Chheda, Hans Clevers, Elena Elez, Salma Kaochar, Scott E Kopetz, Xiao-Nan Li, Funda Meric-Bernstam, Clifford A Meyer, Haiwei Mou, Kristen M Naegle, Martin F Pera, Zinaida Perova, Katerina A Politi, Benjamin J Raphael, Paul Robson, Rosalie C Sears, Josep Tabernero, David A Tuveson, Alana L Welm, Bryan E Welm, Christopher D Willey, Konstantin Salnikow, Jeffrey H Chuang, Xiling Shen

Faculty, Staff and Students Publications

3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here, we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to realize their potential for clinical decision making. 3D-PTAs require standardization criteria and prospective trials to establish clinical benefits. Innovative trial designs that combine omics and 3D-PTA readouts may lead to more accurate clinical predictors, and an integrated platform that combines diagnostic and therapeutic development will accelerate new treatments for patients with refractory disease.

Mechanisms Of Cancer Metastasis, Maria Castaneda, Petra Den Hollander, Nick A Kuburich, Jeffrey M Rosen, Sendurai A Mani

Faculty, Staff and Students Publications

Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease. Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression. This review describes the current state of knowledge of the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body. Open questions, avenues for future research, and therapeutic approaches with the potential to prevent or inhibit metastasis through personalization to each patient's mutation and/or immune profile are also highlighted.

Cancer Evaluations During The Covid-19 Pandemic: An Observational Study Using National Veterans Affairs Data, Ashley N D Meyer, Hardeep Singh, Andrew J Zimolzak, Li Wei, Debra T Choi, Abigail D Marinez, Daniel R Murphy

Faculty, Staff and Students Publications

INTRODUCTION: Fewer cancer diagnoses have been made during the COVID-19 pandemic. Pandemic-related delays in cancer diagnosis could occur from limited access to care or patient evaluation delays (e.g., delayed testing after abnormal results). Follow-up of abnormal test results warranting evaluation for cancer was examined before and during the pandemic.

METHODS: Electronic trigger algorithms were applied to the Department of Veterans Affairs electronic health record data to assess follow-up of abnormal test results before (March 10, 2019-March 7, 2020) and during (March 8, 2020-March 6, 2021) the pandemic.

RESULTS: Electronic triggers were applied to 8,021,406 veterans' electronic health records to identify …

Germline Genetic And Treatment-Related Risk Factors For Diabetes Mellitus In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study And St Jude Lifetime Cohorts, Melissa A Richard, Sogol Mostoufi-Moab, Nisha Rathore, Jessica Baedke, Austin L Brown, Stephen J Chanock, Danielle N Friedman, M Monica Gramatges, Rebecca M Howell, Kala Y Kamdar, Wendy M Leisenring, Lillian R Meacham, Lindsay M Morton, Kevin Oeffinger, Leslie L Robison, Yadav Sapkota, Charles A Sklar, Gregory T Armstrong, Smita Bhatia, Philip J Lupo

Center for Medical Ethics and Health Policy Staff Publications

Purpose: To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer.

Methods: Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer …

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 …

Structural Variants Drive Context-Dependent Oncogene Activation In Cancer, Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C Akdemir, Selene Tyndale, P Andrew Futreal, Graham Mcvicker, Geoffrey M Wahl, Jesse R Dixon

Faculty, Staff and Student Publications

Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific …

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 …

Lymphocyte Sparing Normal Tissue Effects In The Clinic (Lymphotec): A Systematic Review Of Dose Constraint Considerations To Mitigate Radiation-Related Lymphopenia In The Era Of Immunotherapy, Bhanuprasad Venkatesulu, Prashanth Giridhar, Lincoln Pujari, Brian Chou, Jae Han Lee, Alec M Block, Rituraj Upadhyay, James S Welsh, Matthew M Harkenrider, Sunil Krishnan, Vivek Verma, Cheng En Hsieh, Satyajit Pradhan, William Small, Abhishek A Solanki

Faculty, Staff and Student Publications

Background: Radiation-related lymphopenia has been associated with suboptimal tumor control rates leading to inferior survival outcomes. To date, no standardized dose constraints are available to limit radiation dose to resident and circulating lymphocyte populations. We undertook this systemic review of the literature to provide a synopsis of the dosimetric predictors of radiation-related lymphopenia in solid malignancies.

Methodology: A systematic literature review of PubMed (National Institutes of Health), Cochrane Central (Cochrane collaboration), and Google Scholar was conducted with the following keywords: "radiation", "lymphopenia", "cancer", "dosimetric predictors" with an inclusion deadline of May 31, 2022. Studies that met prespecified inclusion criteria were …

Radiomics In Abdominopelvic Solid-Organ Oncologic Imaging: Current Status, Xiaoyang Liu, Mohamed G Elbanan, Antonio Luna, Masoom A Haider, Andrew D Smith, Carl F Sabottke, Bradley M Spieler, Baris Turkbey, David Fuentes, Ahmed Moawad, Serageldin Kamel, Natally Horvat, Khaled M Elsayes

Faculty, Staff and Student Publications

Radiomics is the process of extraction of high-throughput quantitative imaging features from medical images. These features represent noninvasive quantitative biomarkers that go beyond the traditional imaging features visible to the human eye. This article first reviews the steps of the radiomics pipeline, including image acquisition, ROI selection and image segmentation, image preprocessing, feature extraction, feature selection, and model development and application. Current evidence for the application of radiomics in abdominopelvic solid-organ cancers is then reviewed. Applications including diagnosis, subtype determination, treatment response assessment, and outcome prediction are explored within the context of hepatobiliary and pancreatic cancer, renal cell carcinoma, prostate …

Genome Protection By Dna Polymerase Θ, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

DNA polymerase θ (Pol θ) is a DNA repair enzyme widely conserved in animals and plants. Pol θ uses short DNA sequence homologies to initiate repair of double-strand breaks by theta-mediated end joining. The DNA polymerase domain of Pol θ is at the C terminus and is connected to an N-terminal DNA helicase-like domain by a central linker. Pol θ is crucial for maintenance of damaged genomes during development, protects DNA against extensive deletions, and limits loss of heterozygosity. The cost of using Pol θ for genome protection is that a few nucleotides are usually deleted or added at the …

Genomic Profiling For Clinical Decision Making In Myeloid Neoplasms And Acute Leukemia, Eric J Duncavage, Adam Bagg, Robert P Hasserjian, Courtney D Dinardo, Lucy A Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M Vannucchi, Keyur P Patel, Daniel A Arber, Maria E Arcila, Rafael Bejar, Nancy Berliner, Michael J Borowitz, Susan Branford, Anna L Brown, Catherine A Cargo, Hartmut Döhner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellström-Lindberg, Annette S Kim, Jeffery M Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M Ross, Michael Savona, Akiko Shimamura, Radek C Skoda, Francesc Solé, Richard M Stone, Ayalew Tefferi, Matthew J Walter, David Wu, Benjamin L Ebert, Mario Cazzola

Faculty, Staff and Student Publications

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome …

Diet-Derived Metabolites And Mucus Link The Gut Microbiome To Fever After Cytotoxic Cancer Treatment, Zaker I Schwabkey, Diana H Wiesnoski, Chia-Chi Chang, Wen-Bin Tsai, Dung Pham, Saira S Ahmed, Tomo Hayase, Miriam R Ortega Turrubiates, Rawan K El-Himri, Christopher A Sanchez, Eiko Hayase, Annette C Frenk Oquendo, Takahiko Miyama, Taylor M Halsey, Brooke E Heckel, Alexandria N Brown, Yimei Jin, Mathilde Raybaud, Rishika Prasad, Ivonne Flores, Lauren Mcdaniel, Valerie Chapa, Philip L Lorenzi, Marc O Warmoes, Lin Tan, Alton G Swennes, Stephanie Fowler, Margaret Conner, Kevin Mchugh, Tyler Graf, Vanessa B Jensen, Christine B Peterson, Kim-Anh Do, Liangliang Zhang, Yushu Shi, Yinghong Wang, Jessica R Galloway-Pena, Pablo C Okhuysen, Carrie R Daniel-Macdougall, Yusuke Shono, Marina Burgos Da Silva, Jonathan U Peled, Marcel R M Van Den Brink, Nadim Ajami, Jennifer A Wargo, Pavan Reddy, Raphael H Valdivia, Lauren Davey, Gabriela Rondon, Samer A Srour, Rohtesh S Mehta, Amin M Alousi, Elizabeth J Shpall, Richard E Champlin, Samuel A Shelburne, Jeffrey J Molldrem, Mohamed A Jamal, Jennifer L Karmouch, Robert R Jenq

Faculty, Staff and Student Publications

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction …

Medicc2: Whole-Genome Doubling Aware Copy-Number Phylogenies For Cancer Evolution, Tom L Kaufmann, Marina Petkovic, Thomas B K Watkins, Emma C Colliver, Sofya Laskina, Nisha Thapa, Darlan C Minussi, Nicholas Navin, Charles Swanton, Peter Van Loo, Kerstin Haase, Maxime Tarabichi, Roland F Schwarz

Faculty, Staff and Student Publications

Aneuploidy, chromosomal instability, somatic copy-number alterations, and whole-genome doubling (WGD) play key roles in cancer evolution and provide information for the complex task of phylogenetic inference. We present MEDICC2, a method for inferring evolutionary trees and WGD using haplotype-specific somatic copy-number alterations from single-cell or bulk data. MEDICC2 eschews simplifications such as the infinite sites assumption, allowing multiple mutations and parallel evolution, and does not treat adjacent loci as independent, allowing overlapping copy-number events. Using simulations and multiple data types from 2780 tumors, we use MEDICC2 to demonstrate accurate inference of phylogenies, clonal and subclonal WGD, and ancestral copy-number states.