Diseases Commons^™

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 …

Genetic Variants In Cyp2b6 And Hsd17b12 Associated With Risk Of Squamous Cell Carcinoma Of The Head And Neck, Hongliang Liu, Guojun Li, Erich M Sturgis, Sanjay Shete, Kristina R Dahlstrom, Mulong Du, Christopher I Amos, David C Christiani, Philip Lazarus, Qingyi Wei

Faculty, Staff and Students Publications

Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA with risk of squamous cell carcinoma of the head and neck (SCCHN) in European populations using two published genome-wide association study datasets. In the single-locus analysis, we identified two SNPs (rs145533669 and rs35246205) in CYP2B6 to be associated with risk of SCCHN (P = 1.57 × 10

Neither Tumor-Infiltrating Lymphocytes Nor Cytotoxic T Cells Predict Enhanced Benefit From Chemotherapy In The Dbcg77b Phase Iii Clinical Trial, Elahe Shenasa, Elisabeth Specht Stovgaard, Maj-Britt Jensen, Karama Asleh, Nazia Riaz, Dongxia Gao, Samuel Leung, Bent Ejlertsen, Anne-Vibeke Laenkholm, Torsten O. Nielsen

Section of General Surgery

Recent studies have shown that immune infiltrates in the tumor microenvironment play a role in response to therapy, with some suggesting that patients with immunogenic tumors may receive increased benefit from chemotherapies. We evaluated this hypothesis in early breast cancer by testing the interaction between immune biomarkers and chemotherapy using materials from DBCG77B, a phase III clinical trial where high-risk premenopausal women were randomized to receive chemotherapy or no chemotherapy. Tissue microarrays were evaluated for tumor-infiltrating lymphocytes (TILs) assessed morphologically on hematoxylin and eosin-stained slides, and by immunohistochemistry for CD8, FOXP3, LAG-3, PD-1 and PD-L1. Following REMARK reporting guidelines, data …

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

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 …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

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 …

Advances In Head And Neck Cancer Pain, Y Ye, D D Jensen, C T Viet, H L Pan, W M Campana, M Amit, M D Boada

Faculty, Staff and Student Publications

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune …

Tp53-Altered Chronic Lymphocytic Leukemia Treated With Firstline Bruton’S Tyrosine Kinase Inhibitor-Based Therapy: A Retrospective Analysis, Hua-Jay J Cherng, Raamis Khwaja, Rashmi Kanagal-Shamanna, Guilin Tang, Jan Burger, Philip Thompson, Alessandra Ferrajoli, Zeev Estrov, Koji Sasaki, Deepa Sampath, Xuemei Wang, Hagop Kantarjian, Michael Keating, William G Wierda, Nitin Jain

Faculty, Staff and Student Publications

Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL); however, it is unknown how variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] influences efficacy of firstline BTKi. We performed a retrospective analysis of 130 patients with CLL with baseline del(17p) and/or TP53-m treated with BTKi with or without the BCL2 inhibitor venetoclax (VEN) and with or without CD20 antibody in the firstline setting. A total of 104/130 (80%) patients …

Identifying Factors Associated With Detection Of Sessile Gastric Polyps In Patients With Familial Adenomatous Polyposis, Gautam N Mankaney, Michael Cruise, Shashank Sarvepalli, Amit Bhatt, David Liska, Carol A Burke

Faculty, Staff and Students Publications

Background and study aims  Gastric cancer (GC) is increasingly reported and a leading cause of death in patients with familial adenomatous polyposis (FAP). Identifying features in patients with FAP who harbor sessile gastric polyps, likely precursors to GC, may lead to alterations in endoscopic surveillance in those patients and allow endoscopic intervention to decrease the risk of GC. The aim of this study was to identify demographic and clinical factors in patients with FAP who harbor sessile gastric polyps.

Patients and methods  We retrospectively compared demographic, clinical, and endoscopic features in consecutive adult patients with FAP who presented for a …

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 …

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 …

A Large-Scale Genome-Wide Gene-Gene Interaction Study Of Lung Cancer Susceptibility In Europeans With A Trans-Ethnic Validation In Asians, Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D Mckay, John K Field, Sanjay S Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J Hung, Christopher I Amos, Hongbing Shen, Feng Chen, David C Christiani

Faculty, Staff and Students Publications

INTRODUCTION: Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

METHODS: Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms …

Cross-Ancestry Genome-Wide Meta-Analysis Of 61,047 Cases And 947,237 Controls Identifies New Susceptibility Loci Contributing To Lung Cancer, Jinyoung Byun, Younghun Han, Yafang Li, Jun Xia, Erping Long, Jiyeon Choi, Xiangjun Xiao, Meng Zhu, Wen Zhou, Ryan Sun, Yohan Bossé, Zhuoyi Song, Ann Schwartz, Christine Lusk, Thorunn Rafnar, Kari Stefansson, Tongwu Zhang, Wei Zhao, Rowland W Pettit, Yanhong Liu, Xihao Li, Hufeng Zhou, Kyle M Walsh, Ivan Gorlov, Olga Gorlova, Dakai Zhu, Susan M Rosenberg, Susan Pinney, Joan E Bailey-Wilson, Diptasri Mandal, Mariza De Andrade, Colette Gaba, James C Willey, Ming You, Marshall Anderson, John K Wiencke, Demetrius Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig Bojeson, Hermann Brenner, Maria Teresa Landi, Stephen J Chanock, Mattias Johansson, Thomas Muley, Angela Risch, H-Erich Wichmann, Heike Bickeböller, David C Christiani, Gad Rennert, Susanne Arnold, John K Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Hongbing Shen, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Alpa Patel, Qing Lan, Nathaniel Rothman, Fiona Taylor, Linda Kachuri, John S Witte, Lori C Sakoda, Margaret Spitz, Paul Brennan, Xihong Lin, James Mckay, Rayjean J Hung, Christopher I Amos

Faculty, Staff and Students Publications

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung …

Proteomes Of Extracellular Vesicles From Pancreatic Cancer Cells And Cancer-Associated Fibroblasts, Sharon Pan, Lisa A Lai, Diane M Simeone, David W Dawson, Yuanqing Yan, Tatjana Crnogorac-Jurcevic, Ru Chen, Teresa A Brentnall

Faculty, Staff and Students Publications

OBJECTIVES: Extracellular vesicles (EVs) are lipid bound vesicles secreted by cells into the extracellular environment. Studies have implicated EVs in cell proliferation, epithelial-mesenchymal transition, metastasis, angiogenesis, and mediating the interaction of tumor cells and microenvironment. A systematic characterization of EVs from pancreatic cancer cells and cancer-associated fibroblasts (CAFs) would be valuable for studying the roles of EV proteins in pancreatic tumorigenesis.

METHODS: Proteomic and functional analyses were applied to characterize the proteomes of EVs released from 5 pancreatic cancer lines, 2 CAF cell lines, and a normal pancreatic epithelial cell line (HPDE).

RESULTS: More than 1400 nonredundant proteins were identified …

Advances In Management And Therapeutics Of Cutaneous Basal Cell Carcinoma, Olivia M Chen, Keemberly Kim, Chelsea Steele, Kelly M Wilmas, Nader Aboul-Fettouh, Carrick Burns, Hung Quoc Doan, Sirunya Silapunt, Michael R Migden

Faculty, Staff and Student Publications

Basal cell carcinoma (BCC), the most common cancer in humans, is a malignant neoplasm of cells derived from the basal layer of the epidermis. Tumor characteristics such as histologic subtype, primary versus recurrent tumor, anatomic location, size, and patient attributes determine the risk level and acceptable treatment options. Surgical options offer histologic confirmation of tumor clearance. Standard excision provides post-treatment histologic assessment, while Mohs micrographic surgery (MMS) provides complete margin assessment intraoperatively. Additional treatment options may be employed in the correct clinical context. Small and low-risk BCCs, broad field cancerization, locally-advanced disease, metastatic disease, cosmetic concerns, or morbidity with surgical …

Reporting Of Mycetoma Cases From Skin And Soft Tissue Biopsies Over A Period Of Ten Years: A Single Center Report And Literature Review From Pakistan, Mohammad Zeeshan, Saira Fatima, Joveria Farooqi, Kauser Jabeen, Arsalan Ahmed, Afreen Haq, Muhammad Omer Arif, Afia Zafar

Department of Pathology and Laboratory Medicine

Background: Mycetoma is an important neglected tropical disease associated with debilitation, disfigurement and death if not diagnosed and treated adequately. In Pakistan, mycetoma cases have frequently been diagnosed in histopathology and microbiology laboratories. However, there is scarcity of published data from this country. Therefore, the objectives of this study were to evaluate the frequency and type of mycetoma reported in skin and soft tissue biopsies from a single center over 10 years and review of published literature from Pakistan.
Method: This descriptive observational retrospective study was conducted at the Aga Khan University Hospital laboratory, Karachi, Pakistan. Laboratory data from 2009-2018 …

Advances In Cutaneous Squamous Cell Carcinoma Management, Carrick Burns, Shelby Kubicki, Quoc-Bao Nguyen, Nader Aboul-Fettouh, Kelly M Wilmas, Olivia M Chen, Hung Quoc Doan, Sirunya Silapunt, Michael R Migden

Faculty, Staff and Student Publications

cSCC is increasing in prevalence due to increased lifespans and improvements in survival for conditions that increase the risk of cSCC. The absolute mortality of cSCC exceeds melanoma in the United States and approaches that of melanoma worldwide. This review presents significant changes in the management of cSCC, focusing on improvements in risk stratification, new treatment options, optimization of existing treatments, and prevention strategies. One major breakthrough in cSCC treatment is the advent of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1), which have ushered in a renaissance in the treatment of …

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 …

Real-World Third Covid-19 Vaccine Dosing And Antibody Response In Patients With Hematologic Malignancies, Michael A. Thompson, Sigrun Hallmeyer, Veronica E. Fitzpatrick, Yunqi Liao, Michael P. Mullane, Stephen C. Medlin, Kenneth Copeland, James L. Weese

Journal of Patient-Centered Research and Reviews

Purpose: This study sought to describe the changes in immune response to a third dose of either Pfizer’s or Moderna’s COVID-19 mRNA vaccine (3V) among patients with hematologic malignancies, as well as associated characteristics

Methods: This retrospective cohort study analyzed pre-3V and post-3V data on 493 patients diagnosed with hematologic malignancies across a large Midwestern health system between August 28, 2021, and November 1, 2021. For antibody testing, S1 spike antigen of the SARS-CoV-2 virus titer was used to determine serostatus.

Results: Among 493 participants, 274 (55.6%) were seropositive both pre- and post-3V (+/+) while 115 (23.3%) seroconverted to positive …

Pneumonitis After Immune Checkpoint Inhibitor Therapies In Patients With Acute Myeloid Leukemia: A Retrospective Cohort Study, Ajay Sheshadri, Alberto A Goizueta, Vickie R Shannon, David London, Guillermo Garcia-Manero, Hagop M Kantarjian, Farhad Ravandi-Kashani, Tapan M Kadia, Marina Y Konopleva, Courtney D Dinardo, Sherry Pierce, Abdulrazzak Zarifa, Aya A Albittar, Linda L Zhong, Fechukwu O Akhmedzhanov, Muhammad H Arain, Mansour Alfayez, Ahmad Alotaibi, Mehmet Altan, Aung Naing, Tito R Mendoza, Myrna C B Godoy, Girish Shroff, Sang T Kim, Saadia A Faiz, Dimitrios P Kontoyiannis, Fareed Khawaja, Kristofer Jennings, Naval G Daver

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality.

Methods: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were …

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 …

Prediction Of Survival With Intensive Chemotherapy In Acute Myeloid Leukemia, Koji Sasaki, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Nicholas Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Joseph Khoury, Sergej Konoplev, Sanam Loghavi, Keyur Patel, Guillermo Montalban-Bravo, Lucia Masarova, Marina Konopleva, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, …

Mice Lacking Wnt9a Or Wnt4 Are Prone To Develop Spontaneous Osteoarthritis With Age And Display Alteration In Either The Trabecular Or Cortical Bone Compartment, Stefan Teufel, Lena Wolff, Ulrich König, Akio Kobayashi, Richard Behringer, Christine Hartmann

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a common degenerative disease of the joint, with a complex multifactorial not yet fully understood etiology. Over the past years, the Wnt signaling pathway has been implicated in osteoarthritis. In a recent genomewide association study (GWAS), the chromosomal location on chromosome 1, linked to the Wnt3a-Wnt9a gene locus, was identified as the most significant locus associated with a thumb osteoarthritis endophenotype. Previously, it was shown that WNT9a is involved in maintaining synovial cell identity in the elbow joint during embryogenesis. Here, we report that the conditional loss of Wnt9a in the Prx1-Cre expressing limb mesenchyme or Prg4-CreER …

Lenalidomide Enhances Cd23car T Cell Therapy In Chronic Lymphocytic Leukemia, Sarah Tettamanti, Maria Caterina Rotiroti, Greta Maria Paola Giordano Attianese, Silvia Arcangeli, Ronghua Zhang, Priyanka Banerjee, Giovanni Galletti, Sheighlah Mcmanus, Massimiliano Mazza, Fabio Nicolini, Giovanni Martinelli, Cristina Ivan, Tania Veliz Rodriguez, Federica Barbaglio, Lydia Scarfò, Maurilio Ponzoni, William Wierda, Varsha Gandhi, Michael Keating, Andrea Biondi, Federico Caligaris-Cappio, Ettore Biagi, Paolo Ghia, Maria Teresa Sabrina Bertilaccio

Faculty, Staff and Student Publications

Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells. We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide maintained the in vitro effector functions of CD23.CAR+ T cells effector functions in terms of antigen-specific cytotoxicity, cytokine release …

The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Myeloid And Histiocytic/Dendritic Neoplasms, Joseph D Khoury, Eric Solary, Oussama Abla, Yassmine Akkari, Rita Alaggio, Jane F Apperley, Rafael Bejar, Emilio Berti, Lambert Busque, John K C Chan, Weina Chen, Xueyan Chen, Wee-Joo Chng, John K Choi, Isabel Colmenero, Sarah E Coupland, Nicholas C P Cross, Daphne De Jong, M Tarek Elghetany, Emiko Takahashi, Jean-Francois Emile, Judith Ferry, Linda Fogelstrand, Michaela Fontenay, Ulrich Germing, Sumeet Gujral, Torsten Haferlach, Claire Harrison, Jennelle C Hodge, Shimin Hu, Joop H Jansen, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Christian P Kratz, Xiao-Qiu Li, Megan S Lim, Keith Loeb, Sanam Loghavi, Andrea Marcogliese, Soheil Meshinchi, Phillip Michaels, Kikkeri N Naresh, Yasodha Natkunam, Reza Nejati, German Ott, Eric Padron, Keyur P Patel, Nikhil Patkar, Jennifer Picarsic, Uwe Platzbecker, Irene Roberts, Anna Schuh, William Sewell, Reiner Siebert, Prashant Tembhare, Jeffrey Tyner, Srdan Verstovsek, Wei Wang, Brent Wood, Wenbin Xiao, Cecilia Yeung, Andreas Hochhaus

Faculty, Staff and Students Publications

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought …

Changes In Measures Of Vestibular And Balance Function And Hippocampus Volume In Alzheimer's Disease And Mild Cognitive Impairment, Helen S Cohen, Christie M Lincoln, Valory N Pavlik, Haleh Sangi-Haghpeykar

Faculty, Staff and Students Publications

OBJECTIVE: To test the hypotheses that people with Alzheimer's disease and mild cognitive impairment have increased frequency of vestibular impairments and decreased hippocampal volume compared with healthy age-matched controls.

STUDY DESIGN: Retrospective, with some historical controls.

SETTING: Out-patient, tertiary care center.

SUBJECTS: People with mild to moderate dementia diagnosed with Alzheimer's disease and with mild cognitive impairment. Main Outcome Measures: A standard clinical battery of objective tests of the vestibular system, and screening for balance; available clinical diagnostic magnetic resonance imaging (MRIs) were reviewed and postprocessed to quantify the left and right hippocampal volumes utilizing both manual segmentation and computer …

Detection Accuracy Of The Cobas Hpv Assay For High-Risk Hpv In Head And Neck Fna Biopsy Specimens, Ming Guo, Abha Khanna, Agata A Tinnirello, Jessica Hwang, Ping Zhang, Li Xu, Guojun Li, Kristina R Dahlstrom, Erich M Sturgis, John Stewart

Faculty, Staff and Students Publications

BACKGROUND: This study evaluated the detection accuracy of the Cobas human papillomavirus (HPV) assay for high-risk human papillomavirus (hrHPV) and HPV-16 in head and neck fine-needle aspiration (FNA) specimens with squamous cell carcinoma.

METHODS: Head and neck FNA biopsy specimens from 2012 to 2020 were retrospectively collected. Cobas HPV testing was performed on 90 FNA specimens with valid Cervista HPV testing results. Results of Cobas HPV and Cervista HPV assays were compared. A Linear Array or SPF10-LiPA25 HPV genotyping assay resolved cases with discrepant results. The κ value and accuracy of Cobas HPV testing were calculated. The accuracy of the …