Diseases Commons^™

An International Working Group Consensus Report For The Prioritization Of Molecular Biomarkers For Ewing Sarcoma, David S Shulman, Sarah B Whittle, Didier Surdez, Kelly M Bailey, Enrique De Álava, Jason T Yustein, Adam Shlien, Masanori Hayashi, Alexander J R Bishop, Brian D Crompton, Steven G Dubois, Neerav Shukla, Patrick J Leavey, Stephen L Lessnick, Heinrich Kovar, Olivier Delattre, Thomas G P Grünewald, Cristina R Antonescu, Ryan D Roberts, Jeffrey A Toretsky, Franck Tirode, Richard Gorlick, Katherine A Janeway, Damon Reed, Elizabeth R Lawlor, Patrick J Grohar

Faculty, Staff and Students Publications

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled …

Stones, Bones, And Groans With Cancerous Overtones - A Rare Case Of Diffuse Large B Cell Lymphoma Presenting As Hypercalcemia, Evan Becker, Caitlyn Moss, Steve Chung

Advances in Clinical Medical Research and Healthcare Delivery

Diffuse large B cell lymphoma (DLBCL) is a type of non-Hodgkin lymphoma that can present in a variety of ways including fever, weight loss, weakness, and drenching night sweats. Uncommonly, hypercalcemia of malignancy can be associated with DLBCL through multiple mechanisms that include synthesis of parathyroid hormone related peptide (PTHrP) or elevated calcitriol levels. It is estimated that hypercalcemia in the setting of DLBCL is present in 18% of newly diagnosed cases. This report details a case of an 80-year-old man with history of chronic anemia and CKD stage 3b that presented with weakness, decreased oral intake, and self-reported weight …

Serpinb3 Drives Cancer Stem Cell Survival In Glioblastoma, Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen Mccortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia

Department of Medicine Faculty Papers

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced …

Retinoic Acid Receptor Activation Reduces Metastatic Prostate Cancer Bone Lesions By Blocking The Endothelial-To-Osteoblast Transition, Guoyu Yu, Paul G Corn, Pengfei Shen, Jian H Song, Yu-Chen Lee, Song-Chang Lin, Jing Pan, Sandeep K Agarwal, Theocharis Panaretakis, Maurizio Pacifici, Christopher J Logothetis, Li-Yuan Yu-Lee, Sue-Hwa Lin

Faculty, Staff and Students Publications

Metastatic prostate cancer (PCa) in the bone induces bone-forming lesions that contribute to progression and therapy resistance. PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition in response to tumor-secreted BMP4. Current strategies targeting PCa-induced bone formation are lacking. Here, we show that activation of retinoic acid receptor (RAR) inhibits EC-to-OSB transition and reduces PCa-induced bone formation. Treatment with palovarotene, an RARγ agonist being tested for heterotopic ossification in fibrodysplasia ossificans progressiva, inhibited EC-to-OSB transition and osteoblast mineralization in vitro and decreased tumor-induced bone formation and tumor growth in several osteogenic PCa models, and similar effects …

Effectiveness And Safety Of Immunosuppressants And Biological Therapy For Chronic Spontaneous Urticaria: A Network Meta-Analysis, Wen-Kuang Lin, Shwu-Jiuan Lin, Woan-Ruoh Lee, Chia-Chieh Lin, Weei-Chin Lin, Hua-Ching Chang, Chi-Tsun Cheng, Jason C Hsu

Faculty, Staff and Students Publications

Chronic spontaneous urticaria (CSU) is the most common phenotype of chronic urticaria. We compared treatment effects and safety profiles of the medications in patients with CSU. We searched PubMed, MEDLINE, and Web of Science for randomized control trials (RCTs), from 1 January 2000 to 31 July 2021, which evaluated omalizumab and immunosuppressants. Network meta-analyses (NMAs) were performed with a frequentist approach. Outcome assessments considered the efficacy (Dermatology Life Quality Index (DLQI) and weekly urticaria activity score (UAS7)) and tolerability profiles with evaluations of study quality, inconsistencies, and heterogeneity. We identified 14 studies which we included in our direct and indirect …

A Nanoengineered Topical Transmucosal Cisplatin Delivery System Induces Anti-Tumor Response In Animal Models And Patients With Oral Cancer, Manijeh Goldberg, Aaron Manzi, Amritpreet Birdi, Brandon Laporte, Peter Conway, Stefanie Cantin, Vasudha Mishra, Alka Singh, Alexander T Pearson, Eric R Goldberg, Sam Goldberger, Benjamin Flaum, Rifat Hasina, Nyall R London, Gary L Gallia, Chetan Bettegowda, Simon Young, Vlad Sandulache, James Melville, Jonathan Shum, Sonya E O'Neill, Erkin Aydin, Alex Zhavoronkov, Anxo Vidal, Atenea Soto, Maria Jose Alonso, Ari J Rosenberg, Mark W Lingen, Anil D'Cruz, Nishant Agrawal, Evgeny Izumchenko

Faculty, Staff and Students Publications

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor …

The Prostate Cancer Androgen Receptor Cistrome In African American Men Associates With Upregulation Of Lipid Metabolism And Immune Response, Jacob E Berchuck, Elio Adib, Sarah Abou Alaiwi, Amit K Dash, Jin Na Shin, Dallin Lowder, Collin Mccoll, Patricia Castro, Ryan Carelli, Elisa Benedetti, Jenny Deng, Matthew Robertson, Sylvan C Baca, Connor Bell, Heather M Mcclure, Talal El Zarif, Matthew P Davidsohn, Gitanjali Lakshminarayanan, Kinza Rizwan, Darlene G Skapura, Sandra L Grimm, Christel M Davis, Erik A Ehli, Kaitlin M Kelleher, Ji-Heui Seo, Nicholas Mitsiades, Cristian Coarfa, Mark M Pomerantz, Massimo Loda, Michael Ittmann, Matthew L Freedman, Salma Kaochar

Faculty, Staff and Students Publications

African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and …

Ribonucleotide Reductase Subunit Switching In Hepatoblastoma Drug Response And Relapse, Anthony Brown

Theses and Dissertations (ETD)

Hepatoblastoma is the most common primary liver cancer in infants and young children. Despite being a very rare cancer that accounts for only 0.5-2% if all childhood cancer cases, HB has the largest increase in incidence among childhood cancers in the United States and worldwide. The five-year survival rate of children with the aggressive forms of HB, including those that have developed metastatic or recurrent diseases, is less than 40% due to the lack of effective treatment. We aim to identify targetable mechanisms underlying the progression and drug resistance of high-risk HB. Our recent work on HB mouse and organoid …

Unraveling The Effects Of Aerobic Exercise And Erk5 Signaling In The Solid Tumor Microenvironment Using Murine Models, Hannah Savage

Dissertations and Theses (Open Access)

Solid tumors are comprised of multiple cell types which communicate and work together to promote tumor progression. Advances in the treatment of solid tumors have armed clinicians with more efficacious pharmacologic agents and combinations. However, a focus on drug adjuvants in the treatment of solid cancer has left gaps in knowledge regarding non-pharmacologic treatment adjuvants, like aerobic exercise. The current dissertation investigates pharmacologic and non-pharmacologic based approaches to remodel the solid tumor microenvironment landscape and alter therapeutic efficacy. We disassemble compartments of the tumor microenvironment, including tumor vasculature and immune infiltrate, using mouse models and single cell techniques, to elucidate …

Glutathione Peroxidase 2 Is A Metabolic Driver Of The Tumor Immune Microenvironment And Immune Checkpoint Inhibitor Response, Kazi Mokim Ahmed, Ratna Veeramachaneni, Defeng Deng, Nagireddy Putluri, Vasanta Putluri, Maria F Cardenas, David A Wheeler, William K Decker, Andy I Frederick, Sawad Kazi, Andrew G Sikora, Vlad C Sandulache, Mitchell J Frederick

Faculty, Staff and Students Publications

BACKGROUND: The existence of immunologically 'cold tumors' frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden.

METHODS: Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot …

Oropharyngeal Cancer Outcomes Correlate With P16 Status, Multinucleation And Immune Infiltration, David C Wilde, Patricia D Castro, Kaustav Bera, Syeling Lai, Anant Madabhushi, German Corredor, Can Koyuncu, James S Lewis, Cheng Lu, Mitchell J Frederick, Allan M Frederick, Avery E Haugen, Jose P Zevallos, Erich M Sturgis, Justin Shi, Andrew T Huang, David J Hernandez, Heath D Skinner, Jan O Kemnade, Wendong Yu, Andrew G Sikora, Vlad C Sandulache

Faculty, Staff and Students Publications

Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells …

Reconstructive Outcomes Of Multilayered Closure Of Large Skull Base Dural Defects Following Open Anterior Craniofacial Resection, Justin Shi, Tokunbo Ayeni, Kathleen Kelly Gallagher, Akash J Patel, Ali Jalali, David J Hernandez, Angela D Haskins, Vlad C Sandulache, Erich M Sturgis, Andrew T Huang

Faculty, Staff and Students Publications

Introduction  Standardized reconstruction protocols for large open anterior skull base defects with dural resection are not well described. Here we report the outcomes and technique of a multilayered reconstructive algorithm utilizing local tissue, dural graft matrix, and microvascular free tissue transfer (MVFTT) for reconstruction of these deformities.

Design  This study is a retrospective review.

Results  Eleven patients (82% males) met inclusion criteria, with five (45%) having concurrent orbital exenteration and eight (73%) requiring maxillectomy. All patients required dural resection with or without intracranial tumor resection, with the average dural defect being 36.0 ± 25.9 cm ² . Dural graft matrices …

Gis Automated Delineation And Analysis Of Cancer Service Areas In The United States, Changzhen Wang

LSU Doctoral Dissertations

Delineating a meaningful and reliable geographic unit pertaining to cancer care is essential in examining geographic variations in cancer care for better analysis, management, and planning. Public health researchers have devoted great efforts to defining various service areas, which; however, lack scientific rigor or are unrepresentative of the highly specialized cancer care markets, and their methods have become obsolete in the era of big data and high geo-computation. This study develops the “Spatially Constrained Leiden (ScLeiden)” method, a network community detection algorithm in Geographic Information Systems (GIS), and applies it to delineate a series of coherent cancer service …

Cardiac Metastasis After Curative Treatment Of Hepatocellular Carcinoma: Risk Factors, Treatment Options, And Prognosis, Gaurav Jain, Mathew Otto, Mubeen Khan Mohammed Abdul, Manpreet Chadha, Ajay Sahajpal

Journal of Patient-Centered Research and Reviews

Hepatocellular carcinoma (HCC) is primary hepatic malignancy with a high incidence of recurrence. The risk of recurrence directly correlates to patient’s overall prognosis. Management of advanced HCC involves a combination of surgical resection, locoregional therapy, and systemic treatment. Distant metastases are rare, and intraventricular cardiac metastases are even more infrequent. This brief review details an illustrative case of cardiac metastasis after curative treatment of primary HCC and then summarizes the literature on risk factors, treatment options, and patient prognosis in the setting of distant metastases from HCC. Prognosis of metastasis to the heart is generally poor, and available evidence emphasizes …

Long-Term Follow-Up For The Development Of Subsequent Malignancies In Patients Treated With Genetically Modified Iecs, David H M Steffin, Ibrahim N Muhsen, Laquisa C Hill, Carlos A Ramos, Nabil Ahmed, Meenakshi Hegde, Tao Wang, Mengfen Wu, Stephen Gottschalk, Sarah B Whittle, Premal D Lulla, Maksim Mamonkin, Bilal Omer, Rayne H Rouce, Andras Heczey, Leonid S Metelitsa, Bambi J Grilley, Catherine Robertson, Virginia Torrano, Natalia Lapteva, Adrian P Gee, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop

Faculty, Staff and Students Publications

Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, …

Synthetic Essentiality Of Tryptophan 2,3-Dioxygenase 2 In Apc-Mutated Colorectal Cancer, Rumi Lee, Jiexi Li, Jun Li, Chang-Jiun Wu, Shan Jiang, Wen-Hao Hsu, Deepavali Chakravarti, Peiwen Chen, Kyle A Labella, Jing Li, Denise J Spring, Di Zhao, Y Alan Wang, Ronald A Depinho

Faculty, Staff and Student Publications

Inactivation of adenomatous polyposis coli (APC) is common across many cancer types and serves as a critical initiating event in most sporadic colorectal cancers. APC deficiency activates WNT signaling, which remains an elusive target for cancer therapy, prompting us to apply the synthetic essentiality framework to identify druggable vulnerabilities for APC-deficient cancers. Tryptophan 2,3-dioxygenase 2 (TDO2) was identified as a synthetic essential effector of APC-deficient colorectal cancer. Mechanistically, APC deficiency results in the TCF4/β-catenin-mediated upregulation of TDO2 gene transcription. TDO2 in turn activates the Kyn-AhR pathway, which increases glycolysis to drive anabolic cancer cell growth and CXCL5 secretion to recruit …