Neoplasms Commons^™

Differential Effects Of Pancreatic Cancer-Derived Extracellular Vesicles Driving A Suppressive Environment, Anurag Purushothaman, Jacqueline Oliva-Ramírez, Warapen Treekitkarnmongkol, Deivendran Sankaran, Mark W Hurd, Nagireddy Putluri, Anirban Maitra, Cara Haymaker, Subrata Sen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs …

A Blood-Based Metabolomic Signature Predictive Of Risk For Pancreatic Cancer, Ehsan Irajizad, Ana Kenney, Tiffany Tang, Jody Vykoukal, Ranran Wu, Eunice Murage, Jennifer B Dennison, Marta Sans, James P Long, Maureen Loftus, John A Chabot, Michael D Kluger, Fay Kastrinos, Lauren Brais, Ana Babic, Kunal Jajoo, Linda S Lee, Thomas E Clancy, Kimmie Ng, Andrea Bullock, Jeanine M Genkinger, Anirban Maitra, Kim-Anh Do, Bin Yu, Brian M Wolpin, Sam Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the …

Her3 Functions As An Effective Therapeutic Target In Triple Negative Breast Cancer To Potentiate The Antitumor Activity Of Gefitinib And Paclitaxel, Hui Lyu, Fei Shen, Sanbao Ruan, Congcong Tan, Jundong Zhou, Ann D. Thor, Bolin Liu

School of Medicine Faculty Publications

Background: Triple negative breast cancer (TNBC) represents a significant clinical challenge. Chemotherapy remains the mainstay for a large part of TNBC patients, whereas drug resistance and tumor recurrence frequently occur. It is in urgent need to identify novel molecular targets for TNBC and develop effective therapy against the aggressive disease. Methods: Immunohistochemistry was performed to examine the expression of HER3 in TNBC samples. Western blots were used to assess protein expression and activation. Cell proliferation and viability were determined by cell growth (MTS) assays. TCGA databases were analyzed to correlate HER3 mRNA expression with the clinical outcomes of TNBC patients. …

Ciliochoroidal Melanoma Masquerading As A Conjunctival Nevus, Samantha Pastore, Konica Singla, Carol L. Shields

Wills Eye Hospital Papers

No abstract provided.

Conditional Risks Of Biochemical Failure And Prostate Cancer-Specific Death In Patients Undergoing External Beam Radiotherapy: A Secondary Analysis Of 2 Randomized Clinical Trials, Gregory S. Alexander, Rebecca F Krc, James W Assif, Kai Sun, Jason K Molitoris, Phuoc Tran, Zaker Rana, Søren M Bentzen, Mark V Mishra

Department of Radiation Oncology Faculty Papers

IMPORTANCE: As patients achieve years of survival after treatment for prostate cancer, the risk of biochemical failure (BF) or prostate cancer-specific death (PCSD) may evolve over time, with clinical relevance to both patients and clinicians.

OBJECTIVE: To determine conditional BF-free survival, PSCD, and overall survival estimates for patients with low- or intermediate-risk prostate cancer enrolled in the Radiation Therapy Oncology Group (RTOG) 0126 and RTOG 0415 clinical trials. A secondary objective was to determine whether prognostic factors at diagnosis remain relevant at later points in follow-up.

DESIGN, SETTING, AND PARTICIPANTS: A pooled secondary analysis of patients treated with external-beam radiotherapy …

Genetic Susceptibility To Cognitive Decline Following Craniospinal Irradiation For Pediatric Central Nervous System Tumors, Austin L Brown, Pagna Sok, Kimberly P Raghubar, Philip J Lupo, Melissa A Richard, Alanna C Morrison, Jun J Yang, Clinton F Stewart, Mehmet Fatih Okcu, Murali M Chintagumpala, Amar Gajjar, Lisa S Kahalley, Heather Conklin, Michael E Scheurer

Faculty, Staff and Student Publications

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI.

METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups.

RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

Uveal Melanoma Causing Iridodialysis: Tip Of The Iceberg, Deepthi E. Kurian, Konica Singla, Carol L. Shields

Wills Eye Hospital Papers

No abstract provided.

Characteristics And Clinical Outcomes Of Patients With Acute Myeloid Leukemia With Inv(3)(Q21q262) Or T(3; 3)(Q21; Q262), Guillaume Richard-Carpentier, Caitlin R Rausch, Koji Sasaki, Danielle Hammond, Kiyomi Morita, Koichi Takahashi, Guilin Tang, Rashmi Kanagal-Shamanna, Kapil Bhalla, Courtney D Dinardo, Gautam Borthakur, Naveen Pemmaraju, Elizabeth J Shpall, Amin Alousi, Naval G Daver, Guillermo Garcia-Manero, Marina Y Konopleva, Farhad Ravandi, Hagop M Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission …

Carm1 Arginine Methyltransferase As A Therapeutic Target For Cancer, Margarida Santos, Jee Won Hwang, Mark T Bedford

Faculty, Staff and Student Publications

Coactivator-associated arginine methyltransferase 1 (CARM1) is an arginine methyltransferase that posttranslationally modifies proteins that regulate multiple levels of RNA production and processing. Its substrates include histones, transcription factors, coregulators of transcription, and splicing factors. CARM1 is overexpressed in many different cancer types, and often promotes transcription factor programs that are co-opted as drivers of the transformed cell state, a process known as transcription factor addiction. Targeting these oncogenic transcription factor pathways is difficult but could be addressed by removing the activity of the key coactivators on which they rely. CARM1 is ubiquitously expressed, and its KO is less detrimental in …

Detection Method Has Independent Prognostic Significance In The Plco Lung Screening Trial, James P Long, Yu Shen

Faculty, Staff and Student Publications

Prognostic models in cancer use patient demographic and tumor characteristics to predict survival and dynamic disease prognosis. Past work in breast cancer has shown that cancer detection method, screen-detected or symptom-detected, has prognostic significance. We investigate this phenomenon in the lung component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial. Patients were randomized to intervention, receiving four annual chest x-rays (CXRs), or to control, receiving usual care. Patients were followed for a total of approximately 13 years. In PLCO, lung cancer detection method has independent prognostic value exceeding that of variables commonly used in lung cancer prognostic models, …

Small Molecules Targeting Insm1 For The Treatment Of High-Risk Neuroblastoma, Michael S. Lan, Chiachen Chen

School of Medicine Faculty Publications

Human neuroblastoma (NB) is the most common childhood extracranial tumor arising from the sympathetic nervous system. It is also a clinically heterogeneous disease that ranges from spontaneous regression to high-risk stage 4 disease. The cause of this disease remains elusive. However, the amplification of NMYC oncogene occurred in roughly 30% of NB patients, which strongly correlated with the advanced stage of disease subtype and the worse prognosis status. We discovered that N-Myc oncoprotein binds and activates INSM1, a zinc-finger transcription factor of neuroendocrine tumors. We also found that INSM1 modulates N-Myc stability mediated through PI3K/AKT/GSK3β signaling pathway. Therefore, INSM1 emerges …

Unlocking The Potential Of Kinase Targets In Cancer: Insights From Canceromicsnet, An Ai-Driven Approach To Drug Response Prediction In Cancer, Manali Singha, Limeng Pu, Gopal Srivastava, Xialong Ni, Brent A. Stanfield, Ifeanyi K. Uche, Paul J.F. Rider, Konstantin G. Kousoulas, J. Ramanujam, Michal Brylinski

School of Medicine Faculty Publications

Deregulated protein kinases are crucial in promoting cancer cell proliferation and driving malignant cell signaling. Although these kinases are essential targets for cancer therapy due to their involvement in cell development and proliferation, only a small part of the human kinome has been targeted by drugs. A comprehensive scoring system is needed to evaluate and prioritize clinically relevant kinases. We recently developed CancerOmicsNet, an artificial intelligence model employing graph-based algorithms to predict the cancer cell response to treatment with kinase inhibitors. The performance of this approach has been evaluated in large-scale benchmarking calculations, followed by the experimental validation of selected …

Spatial Transcriptomics Of Intraductal Papillary Mucinous Neoplasms Of The Pancreas Identifies Nkx6-2 As A Driver Of Gastric Differentiation And Indolent Biological Potential, Marta Sans, Yuki Makino, Jimin Min, Kimal I Rajapakshe, Michele Yip-Schneider, C Max Schmidt, Mark W Hurd, Jared K Burks, Javier A Gomez, Fredrik I Thege, Johannes F Fahrmann, Robert A Wolff, Michael P Kim, Paola A Guerrero, Anirban Maitra

Faculty, Staff and Student Publications

Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric …

Her3 Targeting Augments The Efficacy Of Panobinostat In Claudin-Low Triple-Negative Breast Cancer Cells, Hui Lyu, Defu Hou, Hao Liu, Sanbao Ruan, Congcong Tan, Jiande Wu, Chindo Hicks, Bolin Liu

School of Medicine Faculty Publications

Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used …

Use Of Electronic Health Record Reminders To Improve Primary Care Providers’ Colorectal Cancer Screening Recommendations., Terra Renee Schrembs

Doctor of Nursing Practice Papers

Background: Colorectal cancer (CRC) is the third most common worldwide cause of cancer morbidity and mortality. CRC mortality is preventable through regular screening. Electronic health record (EHR) reminders for providers can increase providers’ CRC screening recommendations and lead to earlier CRC diagnosis. According to the National Cancer Institute’s Screening and Risk Factors Report for Kentucky by County 2008-2010, 62.7% of adults in a rural Kentucky county aged 50-75 had completed a home based FOBT in the past two years or have ever had a colorectal endoscopy.

Purpose: The purpose of this DNP project was to implement and evaluate an …

Use Of The Decipher Genomic Classifier Among Men With Prostate Cancer In The United States, Nicholas G. Zaorsky, James A. Proudfoot, Angela Y. Jia, Raed Zuhour, Randy Vince Jr., Yang Liu, Xin Zhao, Jim Hu, Nicola Schussler, Jennifer L. Stevens, Suzanne Bentler, Rosemary D. Cress, Jennifer A. Doherty, Eric B. Durbin, Susan Gershman, Iona Cheng, Lou Gonsalves, Brenda Y. Hernandez, Lihua Liu, Bozena M. Morawski, Maria Schymura, Stephen M. Schwartz, Kevin C. Ward, Charles Wiggins, Xiao-Cheng Wu, Jonathan Shoag, Lee Ponsky, Alan Dal Pra, Edward M. Schaeffer, Et Al

School of Medicine Faculty Publications

Background: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer. Methods: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic …

Definitive Liver Radiotherapy For Intrahepatic Cholangiocarcinoma With Extrahepatic Metastases, Brian De, Rituraj Upadhyay, Kaiping Liao, Tiffany Kumala, Christopher Shi, Grace Dodoo, Joseph Abi Jaoude, Kelsey L Corrigan, Gohar S Manzar, Kathryn E Marqueen, Vincent Bernard, Sunyoung S Lee, Kanwal P S Raghav, Jean-Nicolas Vauthey, Ching-Wei D Tzeng, Hop S Tran Cao, Grace Lee, Jennifer Y Wo, Theodore S Hong, Christopher H Crane, Bruce D Minsky, Grace L Smith, Emma B Holliday, Cullen M Taniguchi, Albert C Koong, Prajnan Das, Milind Javle, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

INTRODUCTION: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT.

METHODS: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by …

Nivolumab And Ipilimumab In Combination With Radiotherapy In Patients With High-Risk Locally Advanced Squamous Cell Carcinoma Of The Head And Neck., Jennifer Johnson, Ioannis A. Vathiotis, Larry Harshyne, Ayesha Ali, Voichita Bar-Ad, Rita S. Axelrod, Emily Lorber, Joseph Curry, David Cognetti, Adam J. Luginbuhl, Madalina Tuluc, Scott W Keith, M.G. Mahoney, Athanassios Argiris

Department of Medical Oncology Faculty Papers

BACKGROUND: The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN).

METHODS: Patients with newly diagnosed, stage IVA-IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary …

Clinical And Environmental Factors Affecting The Survival Outcomes Among Stage 1a Tn0m0 First Primary Non-Small Cell Lung Carcinoma Patients In The United States., Naiya Patel

Electronic Theses and Dissertations

Background: Lung cancer is the second leading cause of death in the United States (U.S.). The most prevalent histological type of lung cancer is Non-Small Cell Lung Cancer (NSCLC), which has an overall five years survival of 5% if left untreated. Therefore, early treatment of NSCLC is vital to improve overall survival (OS) outcomes. Several factors affect survival outcomes, which can be categorized as modifiable or non-modifiable. The difference in timely receipt of guideline-concordant treatment affects the survival outcomes of patients with stage 1A NSCLC. This dissertation explored factors that affect treatment and survival outcomes among stage 1A NSCLC patients …