Medical Specialties Commons^™

Primary Central Nervous System Lymphoma: Predictors Of Response To Induction Therapy And Patterns Of Progression, Louis Cappelli, Allison Kayne, Jennifer Newman, Ahmed Elguindy, Narendranath Epperla, Joshua D. Palmer, Ubaldo E. Martinez-Outshoorn, Pierluigi Porcu, Wenyin Shi, Iyad Alnahhas

Department of Radiation Oncology Faculty Papers

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive variant of non-Hodgkin lymphoma. While PCNSL is often sensitive to induction high-dose methotrexate (HDMTX) based chemotherapy, recurrence rates remain high, approaching 50% within 5 years. The most common molecular alterations in PCNSL include mutations in MYD88 and CD79 and CDKN2A homozygous deletion. There are no predictive or prognostic molecular markers in PCNSL.

METHODS: We conducted a retrospective review of 40 patients with PCNSL treated at Thomas Jefferson University and Ohio State University between 2011 and 2023. We created a clinically annotated database of patient characteristics and outcomes. For …

Idh Status Dictates Ohsv Mediated Metabolic Reprogramming Affecting Anti-Tumor Immunity, Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur

Faculty, Staff and Student Publications

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an …

High-Grade Astrocytoma With Piloid Features: A Single-Institution Case Series And Literature Review, Eric A Goethe, Subhiksha Srinivasan, Swaminathan Kumar, Sujit S Prabhu, Maria A Gubbiotti, Sherise D Ferguson

Faculty, Staff and Student Publications

High-grade astrocytoma with piloid features (HGAP) is a recently described primary brain tumor and the first requiring a specific methylation pattern for diagnosis, as its histologic features are often compatible with other tumors such as glioblastoma (GBM). Characterized by molecular alterations in CDKN2A/B, NF1, BRAF, FGFR1, and ATRX, they may be located anywhere in the CNS but show a predilection for the posterior fossa. Reports are limited to retrospective case series, and the standard of care is not yet established. We performed a retrospective review of electronic medical records of all patients with HGAP at our institution. Records were queried …

Dual Targeting Of Ezh2 And Ezh1 Drives Exit Of Leukemia Stem Cells From Quiescence And Potentiates Chemotherapy In Acute Myeloid Leukemia, Hiroki Akiyama, Yuki Nishida, Kyung Hee Chang, Andrea D Bedoy, Muharrem Muftuoglu, Wencai Ma, Mahesh Basyal, Zoe Hirschi, Daisuke Honma, Shinji Tsutsumi, Jing Wang, Weiguo Zhang, Xuelin Huang, Raajit K Rampal, Olalekan O Oluwole, Dale Lee Bixby, Naval G Daver, Michael Andreeff

Faculty, Staff and Student Publications

No abstract provided.

Retrospective Analysis Of Cement Extravasation Rates In Vertebroplasty, Kyphoplasty, And Bone Tumor Radiofrequency Ablation, Soun Sheen, Prit Hasan, Xiaowen Sun, Jian Wang, Claudio Tatsui, Kent Nouri, Saba Javed

Faculty, Staff and Student Publications

Background: Percutaneous vertebral augmentation techniques, including vertebroplasty, kyphoplasty, and bone tumor radiofrequency ablation (BT-RFA), are commonly used to treat painful vertebral compression fractures (VCFs). While generally safe and effective, they carry risks, including cement extravasation, which can lead to pulmonary embolism or spinal cord compression. This study aims to compare the rate of cement extravasation across different vertebral augmentation techniques and identify potential risk factors.

Methods: A retrospective cohort study was conducted at a comprehensive cancer center on 1002 procedure encounters in 888 patients who underwent vertebral augmentation for painful VCFs. Data were collected on patient demographics, fracture pathology, procedure …

Impact Of Age On Biology, Presentation And Outcomes In Marginal Zone Lymphoma: Results From A Multicenter Cohort Study, Pallawi Torka, Natalie S. Grover, Timothy J. Voorhees, Reem Karmali, Kaitlin Annunzio, Marcus P. Watkins, Andrea Anampa-Guzmán, Heather Reves, Montreh Tavakkoli, Beth Christian, Colin Thomas, Stefan K. Barta, Praveen Ramakrishnan Geethakumari, Nancy L. Bartlett, Geoffrey Shouse, Adam J. Olszewski, Narendranath Epperla

Department of Medicine Faculty Papers

Given the paucity of age-specific data about biology, presentation, and treatment outcomes in adults with MZL, we sought to evaluate differences between younger (≤ 70 years) and older (> 70 years) patients with MZL in a large retrospective cohort treated in the contemporary era (2010 onwards). The primary objective was progression-free survival (PFS), while secondary objectives included the evaluation of overall survival (OS) and the cumulative incidence of transformation between the 2 groups. A total of 598 patients were included in the analysis and among these 32% were > 70 years of age. There were no age-based differences in the prevalence …

Unveiling The Potential Of Urolithin A In Cancer Therapy: Mechanistic Insights To Future Perspectives Of Nanomedicine, Vinita Karumuru, Anupam Dhasmana, Narsimha Mamidi, Subhash Chauhan, Murali Yallapu

School of Medicine Publications

Cancer remains a leading global health challenge, with high mortality rates persisting despite significant advancements in therapeutic interventions. Major obstacles, including systemic toxicity, therapy resistance, metastasis, and relapses, emphasize the urgent need for safer, more effective, and readily accessible treatment strategies. Among emerging alternatives, natural bioactive compounds have gained considerable attention because of their diverse therapeutic potential and lower toxicity profiles. Urolithin A (UA), a metabolite derived from ellagic acid through gut microbiota metabolism, has emerged as a compelling anticancer agent. UA has multiple mechanisms of action, including the regulation of autophagy, enhancement of mitochondrial function, and inhibition of tumor …

Can The Discovery Of High-Impact Diagnostics Be Improved By Matching The Sampling Rate Of Clinical Diagnostics To The Frequency Domain Of Diagnostic Information?, Steven W Millward, Peng Wei, David Piwnica-Worms, Seth T Gammon

Faculty, Staff and Student Publications

Over the past 30 years, academic and industrial research investigators have developed molecular reporters to visualize cell death in complex biological systems. In parallel, clinical researchers, chemists, biochemists, and molecular biologists have endeavored to translate these molecular tools into clinical imaging agents. Despite these efforts, there are no clinically approved imaging methodologies with which to image cell death consistently and quantitatively. One reason may reside in the intrinsic mismatch between the sampling frequency of translational molecular imaging and the biochemical kinetics that define cell death. Beyond cell death imaging, many active research programs are now attempting to create translational diagnostic …

Swi/Snf Complex-Mediated Znf410 Cooperative Binding Maintains Chromatin Accessibility And Enhancer Activity, Siyuan Xu, Chuxuan Peng, Ren Ren, Haowen Lu, Han Zhao, Sijian Xia, Yijie Shen, Bin Xu, Haoyue Zhang, Xiaodong Cheng, Gerd A Blobel, Xianjiang Lan

Faculty, Staff and Student Publications

The clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in the eukaryotic genome. However, the contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. In particular, three ZNF410 motifs …

Desmoplastic Small Round Cell Tumor: An Update Of Current Management Practices, Ahmed Gawash, Alexa Simonetti, Brandon J Goodwin, Alissa Brotman O'Neill

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) poses a diagnostic challenge, initiating with imaging techniques like ultrasound, CT, MRI, and PET scans, with CT being the primary choice for abdominal tumor visualization. Despite advances, the absence of a standardized staging system complicates the diagnostic process.

METHODS: A comprehensive literature review and search strategy, encompassing databases like PubMed and Cochrane was performed.

RESULTS: Systemic chemotherapy, notably the P6 regimen, is the cornerstone of DSRCT treatment, while other options, including CDK4/6 inhibitors, antibody-drug conjugates, and anlotinib present varying efficacy. A novel chemotherapeutic agent, ONC-201, exhibits promise, inhibiting tumor growth in preclinical models. …

Unmet Supportive Care Needs In Patients With Advanced Cancer And Its Impact On Distress, Kayla W Miranda, Benjamin L Musher, Hoda J Badr

Faculty, Staff and Students Publications

Purpose: Patients with advanced cancer endure considerable physical and emotional distress without sufficient supportive care. This cross-sectional study examined the relationship between cancer-related symptoms, supportive care needs, and distress levels in patients with advanced lung, head and neck, or gastrointestinal cancers.

Methods: 158 patients were assessed for symptom burden and distress levels using the M.D. Anderson Symptom Inventory (MDASI) and unmet needs using the Supportive Care Needs Survey (SCNS-34) within one month of treatment initiation. Pearson correlations and multiple regression analyses were used to explore associations between supportive care needs and distress.

Results: Distress levels were moderate across the study …

Partnering With Social Media Influencers To Promote Hpv Vaccination In Diverse Communities, Amy Leader, Amelia Burke-Garcia, Dasha Afanaseva, Erin Cutroneo, Preethi Selvan, Kayla Madden, Joshua Banks, Angela Sustaita-Ruiz

Department of Medical Oncology Faculty Papers

BACKGROUND: While human papillomavirus (HPV) vaccination is one of the most effective ways to prevent HPV-related cancers, many children and adolescents remain unvaccinated. Resistance often stems from parental vaccine hesitancy and mistrust of the health care system, both of which may be higher in communities of color. Partnering with social media influencers may be an effective method for disseminating health messages. We tested the impact of HPV social media posts developed by influencers on outcomes of knowledge, attitudes, and intentions to vaccinate.

METHODS: Ten social media influencers who identified as African American or Hispanic created posts about the HPV vaccine. …

Short Report: The Variants In Chek2 In Metastatic Uveal Melanoma, Mizue Terai, Rino S. Seedor, Usman Ashraf, Gretchen Hubbard, Sergei A. Koshkin, Marlana Orloff, Takami Sato

Department of Medical Oncology Faculty Papers

No abstract provided.

Rnase1-Driven Alk-Activation Is An Oncogenic Driver And Therapeutic Target In Non-Small Cell Lung Cancer, Zhengyu Zha, Chunxiao Liu, Meisi Yan, Cong Chen, Cheng Yu, Yaohui Chen, Chenhao Zhou, Lu Li, Yi-Chuan Li, Hiro Yamaguchi, Leiguang Ye, Tong Liu, Ying-Nai Wang, Heng-Huan Lee, Wen-Hao Yang, Li-Chuan Chan, Baozhen Ke, Jennifer L Hsu, Lieming Ding, Dong Ji, Peng Pan, Yiran Meng, Yue Pu, Lunxu Liu, Mien-Chie Hung

Faculty, Staff and Student Publications

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, …

Association Between B-Cell Marker Expression And Runx1 Lesions In Acute Myeloid Leukemia, Beyond Runx1::Runx1t1 Fusion: Diagnostic Pitfalls With Mixed-Phenotype Acute Leukemia—B/Myeloid, Giby V George, Malgorzata Kajstura, Audrey N Jajosky, Hong Fang, Fatima Zahra Jelloul, Andrew G Evans, W Richard Burack, John M Bennett, L Jeffrey Medeiros, Wei Wang, Siba El Hussein

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with RUNX1::RUNX1T1 fusion is well known to often demonstrate aberrant upregulation of CD19 expression. We studied the clinicopathologic and genetic features of 16 cases of AML with various RUNX1 lesions, including mutations, copy number gains, and translocations other than fusions with RUNX1T1. Most of these cases were classified as AML-myelodysplasia-related or AML-post-cytotoxic therapy based on the cytogenetic and molecular work-up. These neoplasms showed partial expression of one or more B-cell antigens by flow cytometry and/or immunohistochemistry, fulfilling the criteria for mixed-phenotype acute leukemia (MPAL)-B/myeloid (i.e., ≥20% blasts expressing B and myeloid lineage antigens) …

Enriched Pathways In Gut Microbiome Predict Response To Immune Checkpoint Inhibitor Treatment Across Demographic Regions And Various Cancer Types, Xunhui Cai, Jennifer Y Cho, Lijun Chen, Yufeng Liu, Fenghu Ji, Katia Salgado, Siyi Ge, Dehua Yang, Hui Yu, Jianbo Shao, P Andrew Futreal, Boris Sepesi, Don Gibbons, Yaobing Chen, Guoping Wang, Chao Cheng, Meng Wu, Jianjun Zhang, Ansel Hsiao, Tian Xia

Faculty, Staff and Student Publications

Understanding the effect of gut microbiota function on immune checkpoint inhibitor (ICI) responses is urgently needed. Here, we integrated 821 fecal metagenomes from 12 datasets to identify differentially abundant genes and construct random forest models to predict ICI response. Gene markers demonstrated excellent predictive performance, with an average area under the curve (AUC) of 0.810. Pathway analyses revealed that quorum sensing (QS), ABC transporters, flagellar assembly, and amino acid biosynthesis pathways were enriched between responders (R) and non-responders (NRs) across 12 datasets. Furthermore,

Kras Mutation Detection By Liquid Biopsy For Pancreatic Ductal Adenocarcinoma, Mahmoud Yousef, Abdelrahman Yousef, Mark W Hurd, Ashwathy Pillai, Saikat Chowdhury, Rebecca Snyder, Mark Knafl, Ryan L Lewis, Paul M Roy, Mohammad Fanaeian, Sali Albarouki, Luca F Castelnovo, Jennifer Peterson, Brandon G Smaglo, Robert A Wolff, Shubham Pant, Jason Willis, Ryan Huey, Michael Overman, Ching-Wei Tzeng, Michael P Kim, Naruhiko Ikoma, Jess E Maxwell, Matthew H G Katz, Huamin Wang, Anirban Maitra, Eugene Koay, Ethan B Ludmir, Anthony Chen, Camila Lopez, Haoqiang Ying, John Paul Shen, Dan Zhao

Faculty, Staff and Student Publications

The clinical utility of liquid biopsy (LB) for pancreatic ductal adenocarcinoma (PDAC) remain understudied. Our single-institution cohort of 311 PDAC patients with non-tumor tissues informed LB found 81.2% positivity (N = 186) in metastatic cases and in 52.4% (N = 43) of localized disease. KRAS mutations were detected in 64.6% (N = 148) of metastatic cases and 16% (N = 13) for localized disease. Positive LB, especially KRAS mutation detection, is associated with worse overall survival (OS) in metastatic PDAC (median 14.5 vs. 31.3 months, HR = 2.7, 95%CI = 1.7-4.3, P <  0.0001). The positive concordance rates of KRAS and TP53 mutations were 63% and 68% in metastatic disease but only 7% (KRAS) and 33% (TP53) in localized disease, respectively. Among the 41 patients who underwent serial liquid biopsy testing, 25% tested positive after an initial negative result. LB detects therapeutically targetable mutations in 58.5% of PDAC patients and is associated with OS.

Multimeric Transcription Factor Bcl11a Utilizes Two Zinc-Finger Tandem Arrays To Bind Clustered Short Sequence Motifs, John R Horton, Meigen Yu, Jujun Zhou, Melody Tran, Rithvi R Anakal, Yue Lu, Robert M Blumenthal, Xiaotian Zhang, Yun Huang, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

BCL11A, a transcription factor, is vital for hematopoiesis, including B and T cell maturation and the fetal-to-adult hemoglobin switch. Mutations in BCL11A are linked to neurodevelopmental disorders. BCL11A contains two DNA-binding zinc-finger arrays, low-affinity ZF2-3 and high-affinity ZF4-6, separated by a 300-amino-acid linker. ZF2-3 and ZF4-5 share 73% identity, including five out of six DNA base-interacting residues. These arrays bind similar short sequence motifs in clusters, with the linker enabling a broader binding span. Crystallographic structures of ZF4-6, in complex with oligonucleotides from the β-globin locus region, reveal DNA sequence recognition by residues Asn756 (ZF4), Lys784 and Arg787 (ZF5). A …

Reduced Venetoclax Exposure To 7 Days Vs Standard Exposure With Hypomethylating Agents In Newly Diagnosed Aml Patients, Christophe Willekens, Alexandre Bazinet, Samy Chraibi, Alex Bataller, Justine Decroocq, Naszrin Arani, Benjamin Carpentier, Caitlin Rausch, Delphine Lebon, Abhishek Maiti, Nicolas Gauthier, Nicholas Short, Sarah Bonnet, Koji Sasaki, Sabine Khalife-Hachem, Mahesh Swaminathan, Jean-Baptiste Micol, Florence Pasquier, Christophe Marzac, Damien Roos-Weil, Laurent Pascal, Naval Daver, Tapan Kadia, Didier Bouscary, Farhad Ravandi, Arnaud Pages, Hagop Kantarjian, Stéphane De Botton, Courtney Dinardo

Faculty, Staff and Student Publications

Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. While the VEN label recommends continuous 28-day cycles, shortened VEN durations may induce similar response rates and improve tolerability. It is unknown how a VEN exposure reduced to 7 days during cycles compares to standard HMA + VEN. We retrospectively compared newly diagnosed AML patients treated with azacitidine (AZA) x 7 days plus VEN x 7 days ("7 + 7" regimen) from the first cycle (n = 82) vs patients treated with standard dose HMA + VEN (std-HMA/VEN) …

Humanized Saccharomyces Cerevisiae Provides A Facile And Effective Tool To Identify Damaging Human Variants That Cause Exosomopathies, Khondakar Sayef Ahammed, Milo B Fasken, Anita H Corbett, Ambro Van Hoof

Faculty, Staff and Student Publications

The RNA exosome is an evolutionarily conserved, multiprotein complex that is the major RNase in 3' processing and degradation of a wide range of RNAs in eukaryotes. Single amino acid changes in RNA exosome subunits cause rare genetic diseases collectively called exosomopathies. However, distinguishing disease-causing variants from nonpathogenic ones remains challenging, and the mechanism by which these variants cause disease is largely unknown. Previous studies have employed a budding yeast model of RNA exosome-linked diseases that relies on mutating the orthologous yeast genes. Here, we develop a humanized yeast model of exosomopathies that allows us to unambiguously assess damaging effects …

Developing An Online Community Advisory Board (Cab) Of Parents From Social Media To Co-Design An Human Papillomavirus Vaccine Intervention: Participatory Research Study, Regan M. Murray, Shawn C. Chiang, Ann C. Klassen, Jennifer A. Manganello, Amy E. Leader, Wen-Juo Lo, Philip M. Massey

Department of Medical Oncology Faculty Papers

BACKGROUND: Social media health interventions have grown significantly in recent years. However, researchers are still developing innovative methods to meaningfully engage online communities to inform research activities. Little has been documented describing this approach of using online community advisory boards (CABs) to co-create health communication interventions on social media.

OBJECTIVE: This study describes the formation, engagement, and maintenance of an online CAB focused on co-creating a health education intervention for parents regarding the human papillomavirus (HPV) vaccine. The study provides guiding principles for public health researchers implementing such CABs in future digital health interventions.

METHODS: In May 2020, Twitter was …

Deep Learning-Based Automatic Segmentation Of Cerebral Infarcts On Diffusion Mri, Wi-Sun Ryu, Dawid Schellingerhout, Jonghyeok Park, Jinyong Chung, Sang-Wuk Jeong, Dong-Seok Gwak, Beom Joon Kim, Joon-Tae Kim, Keun-Sik Hong, Kyung Bok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Yong-Jin Cho, Hong-Kyun Park, Byung-Chul Lee, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Man Seok Park, Dongmin Kim, Oh Young Bang, Eung Yeop Kim, Chul-Ho Sohn, Hosung Kim, Hee-Joon Bae, Dong-Eog Kim

Faculty, Staff and Student Publications

We explored effects of (1) training with various sample sizes of multi-site vs. single-site training data, (2) cross-site domain adaptation, and (3) data sources and features on the performance of algorithms segmenting cerebral infarcts on Magnetic Resonance Imaging (MRI). We used 10,820 annotated diffusion-weighted images (DWIs) from 10 university hospitals. Algorithms based on 3D U-net were trained using progressively larger subsamples (ranging from 217 to 8661), while internal testing employed a distinct set of 2159 DWIs. External validation was conducted using three unrelated datasets (n = 2777, 50, and 250). For domain adaptation, we utilized 50 to 1000 subsamples from …

Evolution Of The Tumor Immune Landscape During Treatment With Tebentafusp, A T Cell Receptor-Cd3 Bispecific, Joseph Sacco, Peter Kirk, Emma Leach, Alexander Shoushtari, Richard Carvajal, Camille Britton-Rivet, Sophie Khakoo, Laura Collins, Luis De La Cruz-Merino, Zeynep Eroglu, Alexandra Ikeguchi, Paul Nathan, Omid Hamid, Marcus Butler, Sarah Stanhope, Koustubh Ranade, Takami Sato

Department of Medical Oncology Faculty Papers

Metastatic uveal melanoma is an aggressive disease with poor outcome, which is refractory to immune checkpoint inhibitors. A T cell receptor (TCR)-based CD3 bispecific, tebentafusp, delivers clinical benefit in patients with metastatic uveal melanoma. Understanding the molecular basis for the anti-tumor activity of tebentafusp in an indication where checkpoint inhibitors are ineffective could aid in identification of other solid tumor indications where CD3 bispecifics may serve an unmet need. By analyzing tumor biopsies taken prior to treatment, early on-treatment, and at progression (NCT02570308), using RNA sequencing (RNA-seq) and immunohistochemistry (IHC), we show that expression of interferon-related genes in the tumor …

Comprehensive Assessment Of Initial Adaptation Of Extended-Spectrum Β-Lactamase-Positive St131 Escherichia Coli To Carbapenem Exposure, William C Shropshire, Xinhao Song, Jordan Bremer, Seokju Seo, Susana Rodriguez, Selvalakshmi Selvaraj Anand, An Q Dinh, Micah M Bhatti, Anna Konovalova, Cesar A Arias, Awdhesh Kalia, Yousif Shamoo, Samuel A Shelburne

Faculty, Staff and Student Publications

Background: It remains unclear how high-risk Escherichia coli lineages, like sequence type (ST) 131, initially adapt to carbapenem exposure in their progression to carbapenem resistance.

Methods: Carbapenem mutation frequency was measured in multiple subclades of extended-spectrum β-lactamase (ESBL)-positive ST131 clinical isolates using a fluctuation assay followed by whole genome sequencing (WGS) characterization. Genomic, transcriptomic, and porin analyses of the ST131 C2/H30Rx isolate MB1860, under prolonged, increasing carbapenem exposure was performed using 2 experimental evolutionary platforms to measure fast versus slow adaptation.

Results: All 13 ESBL-positive ST131 strains selected from a diverse (n = 184) ST131 bacteremia cohort had detectable ertapenem …

Integrated Analysis Of Molecular And Clinical Features Associated With Overall Survival In Melanoma Patients With Brain Metastasis, Swaminathan Kumar, Meredith S Pelster, Merve Hasanov, Renato A Guerrieri, Courtney W Hudgens, Debora A Ledesma, Fuchenchu Wang, Grant M Fischer, Julie M Simon, Lauren E Haydu, Kalman V Katlowitz, Y N Vashisht Gopal, Jennifer L Mcquade, Lawrence N Kwong, Jason T Huse, Alexander J Lazar, Michael T Tetzlaff, Jeffrey E Gershenwald, Aron Y Joon, Ken Chen, Ziyi Li, Prahlad T Ram, Sherise D Ferguson, Michael A Davies

Faculty, Staff and Student Publications

Melanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with RNA-seq data generated from their MBMs. The median post-operative OS was 8.6 months …

Single-Cell Analyses Reveal A Functionally Heterogeneous Exhausted Cd8+ T-Cell Subpopulation That Is Correlated With Response To Checkpoint Therapy In Melanoma, Kelly M Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M Haugh, Laura A Huppert, Lauren S Levine, Margaret M Lowe, Michael Alvarado, Markee Micu, Katy K Tsai, Melissa Chow, Meromit Singer, Jason M Schenkel, Arlene H Sharpe, Michael D Rosenblum, Kristen E Pauken, Adil I Daud

Faculty, Staff and Student Publications

PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or nonresponders. Although CD8+ tumor-infiltrating lymphocytes (TIL) have been associated with immune checkpoint therapy response, there is no consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX) because TPEX proliferate more in response to PD-1 inhibitors than other exhausted T-cell (TEX) subpopulations. However, immune checkpoint inhibitor treatment drives TPEX differentiation into other TEX populations that can mediate antitumor immunity. These data complicate the …

Germline Pathogenic Drosha Variants Are Linked To Pineoblastoma And Wilms Tumor Predisposition, Peter N Fiorica, Lisa Golmard, Jung Kim, Riyue Bao, Frank Y Lin, Angshumoy Roy, Allison Pribnow, Melissa R Perrino, Julien Masliah-Planchon, Sophie Michalak-Provost, Jennifer Wong, Mathilde Filser, Dominique Stoppa-Lyonnet, Franck Bourdeaut, Afane Brahimi, Olivier Ingster, Giselle Saulnier Sholler, Sarah A Jackson, Mark M Sasaki, Trent Fowler, Anita Ng, Ryan J Corbett, Rebecca S Kaufman, Jeremy S Haley, David J Carey, Kuan-Lin Huang, Sharon J Diskin, Jo Lynne Rokita, Hussam Al-Kateb, Rose B Mcgee, Joshua D Schiffman, Kenneth S Chen, Douglas R Stewart, D Williams Parsons, Sharon E Plon, Kris Ann P Schultz, Kenan Onel

Center for Medical Ethics and Health Policy Staff Publications

Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported.

Experimental design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts.

Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a …

Long-Read Single-Cell Rna Sequencing Enables The Study Of Cancer Subclone-Specific Genotypes And Phenotypes In Chronic Lymphocytic Leukemia, Gage S Black, Xiaomeng Huang, Yi Qiao, Philip Moos, Deepa Sampath, Deborah M Stephens, Jennifer A Woyach, Gabor T Marth

Faculty, Staff and Student Publications

Bruton tyrosine kinase (BTK) inhibitors are effective for the treatment of chronic lymphocytic leukemia (CLL) due to BTK's role in B cell survival and proliferation. Treatment resistance is most commonly caused by the emergence of the hallmark BTKC481S mutation that inhibits drug binding. In this study, we aimed to investigate cancer subclones harboring a BTKC481S mutation and identify cells with co-occurring CLL driver mutations. In addition, we sought to determine whether BTK-mutated subclones exhibit distinct transcriptomic behavior when compared to other cancer subclones. To achieve these goals, we use scBayes, which integrates bulk DNA sequencing and single-cell …

Results Of The Phase I/Ii Study And Preliminary B-Cell Gene Signature Of Combined Inhibition Of Glutamine Metabolism And Egfr In Colorectal Cancer, Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning

Faculty, Staff and Student Publications

Purpose: EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Patients and methods: We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET …

Update On Cancer And Central Nervous System Tumor Surveillance In Pediatric Nf2-, Smarcb1-, And Lztr1-Related Schwannomatosis, Melissa R Perrino, Marjolijn C J Jongmans, Gail E Tomlinson, Mary-Louise C Greer, Sarah R Scollon, Sarah G Mitchell, Jordan R Hansford, Kris Ann P Schultz, Wendy K Kohlmann, Jennifer M Kalish, Suzanne P Macfarland, Anirban Das, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Uri Tabori, Gina M Ney, Philip J Lupo, Jack J Brzezinski, Douglas R Stewart, Emma R Woodward, Christian P Kratz

Faculty, Staff and Students Publications

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence …