Genetic Phenomena Commons^™

The Clinicopathologic Features And Molecular Signatures Of Blastoid High-Grade B Cell Lymphoma, Not Otherwise Specified, Lianqun Qiu, Pei Lin, Mahsa Khanlari, Jie Xu, Evan N Cohen, Sofia Garces, Roberto N Miranda, Wei Wang, Hong Fang, Carlos E Bueso-Ramos, L Jeffrey Medeiros, Shaoying Li

Faculty, Staff and Student Publications

A small subset of high-grade B-cell lymphoma (HGBL) with blastoid morphology remains poorly understood. We assessed 55 cases of blastoid HGBL, not otherwise specified (NOS) and compared their clinicopathologic characteristics with those of 81 non-blastoid HGBL-NOS and 62 blastoid HGBL with MYC and BCL2, with or without BCL6 rearrangements (double/triple-hit lymphoma [D/THL]). Patients with blastoid HGBL-NOS showed similar clinicopathologic features to patients with blastoid D/THLs and non-blastoid HGBL-NOS, except more frequently with a history of low-grade B-cell lymphoma, bone marrow involvement, and BCL2 rearrangement (P < .05) compared to the latter. MYC rearrangement (MYC-R), detected in 40% of blastoid HGBL-NOS, was associated with aggressive clinicopathologic features and poorer overall survival, even worse than that of blastoid D/THL (P < .05). Transcriptome profiling revealed a distinct gene expression pattern with differentially expressed genes enriched in MYC and P53-targeted genes in MYC-R blastoid HGBL-NOS. Fifty-two percent of blastoid HGBL-NOS had a double hit-like signature, similar to non-blastoid HGBL-NOS (P = .73). The overall survival of the blastoid HGBL-NOS group was similar to that of the blastoid D/THL group but appeared poorer than that of its non-blastoid counterparts (P = .07). Taken together, blastoid HGBL-NOS is an aggressive B-cell lymphoma that shares overlapping clinicopathologic and genetic features with non-blastoid HGBL-NOS. MYC-R in patients with blastoid HGBL-NOS identifies a highly aggressive subgroup with distinct aggressive clinicopathologic features, unique molecular signatures, and a dismal clinical outcome.

Baseline Extracellular Vesicle Mirna-30c And Autophagic Ctcs Predict Chemoradiotherapy Resistance And Outcomes In Patients With Lung Cancer, Diego De Miguel-Perez, Francisco Gabriel Ortega, Rosario Guerrero Tejada, Antonio Martínez-Única, Christine B Peterson, Alessandro Russo, Muthukumar Gunasekaran, Andres F Cardona, Victor Amezcua, Jose Antonio Lorente, Jose Expósito Hernández, Christian Rolfo, Maria Jose Serrano

Faculty, Staff and Student Publications

Concurrent chemoradiotherapy (cCRT) is the mainstay of treatment for patients diagnosed with locally advanced non-small cell lung cancer (NSCLC). One significant challenge in the effectiveness of this therapy is the potential development of resistance mechanisms, where autophagy up-regulation has been proposed as a key contributing factor. However, there is a lack of reliable biomarkers to predict outcomes on these patients. Interestingly, for addressing this gap, extracellular vesicles (EVs) and circulating tumor cells (CTCs) have emerged as potential sources of such biomarkers. In this study, we investigated EV-associated miRNAs and presence of autophagic CTCs in prospectively collected serial samples from 38 …

The Landscape Of Alterations From 1407 Ultra-Rare Sarcomas From The Aacr Genie Database: Clinical Implications, Ryan A Denu, Justin T Moyers, Mohamed A Gouda, Anthony P Conley, Alexander J Lazar, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS.

Experimental design: Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data.

Results: Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most …

An Overview Of The Immune Modulatory Properties Of Long Non-Coding Rnas And Their Potential Use As Therapeutic Targets In Cancer, Moises Martinez-Castillo, Abdelrahman M Elsayed, Gabriel López-Berestein, Paola Amero, Cristian Rodríguez-Aguayo

Faculty, Staff and Student Publications

Long non-coding RNAs (lncRNAs) play pivotal roles in regulating immune responses, immune cell differentiation, activation, and inflammatory processes. In cancer, they are gaining prominence as potential therapeutic targets due to their ability to regulate immune checkpoint molecules and immune-related factors, suggesting avenues for bolstering anti-tumor immune responses. Here, we explore the mechanistic insights into lncRNA-mediated immune modulation, highlighting their impact on immunity. Additionally, we discuss their potential to enhance cancer immunotherapy, augmenting the effectiveness of immune checkpoint inhibitors and adoptive T cell therapies. LncRNAs as therapeutic targets hold the promise of revolutionizing cancer treatments, inspiring further research in this field …

Identification Of Blood Protein Biomarkers Associated With Prostate Cancer Risk Using Genetic Prediction Models: Analysis Of Over 140,000 Subjects, Hua Zhong, Jingjing Zhu, Shuai Liu, Dalia H Ghoneim, Praveen Surendran, Tao Liu, Sarah Fahle, Adam Butterworth, Md Ashad Alam, Hong-Wen Deng, Herbert Yu, Chong Wu, Lang Wu

Faculty, Staff and Student Publications

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant …

Dicarboxylic Acylcarnitine Biomarkers In Peroxisome Biogenesis Disorders, Michael F Wangler, Barbara Lesko, Rejwi Dahal, Sharayu Jangam, Pradnya Bhadane, Theodore E Wilson, Molly Mcpheron, Marcus J Miller

Duncan NRI Faculty and Staff Publications

The peroxisome is an essential eukaryotic organelle with diverse metabolic functions. Inherited peroxisomal disorders are associated with a wide spectrum of clinical outcomes and are broadly divided into two classes, those impacting peroxisome biogenesis (PBD) and those impacting specific peroxisomal factors. Prior studies have indicated a role for acylcarnitine testing in the diagnosis of some peroxisomal diseases through the detection of long chain dicarboxylic acylcarnitine abnormalities (C16-DC and C18-DC). However, there remains limited independent corroboration of these initial findings and acylcarnitine testing for peroxisomal diseases has not been widely adopted in clinical laboratories. To explore the utility of acylcarnitine testing …

Blood-Based Migration Signature Biomarker Panel Discriminates Early Stage New Onset Diabetes Related Pancreatic Ductal Adenocarcinoma From Type 2 Diabetes, Seetharaman Balasenthil, Suyu Liu, Jianliang Dai, William R Bamlet, Gloria Petersen, Suresh T Chari, Anirban Maitra, Nanyue Chen, Subrata Sen, Ann Mcneill Killary

Faculty, Staff and Student Publications

Background and aims: While type 2 diabetes is a well-known risk factor for pancreatic ductal adenocarcinoma (PDAC), PDAC-induced new-onset diabetes (PDAC-NOD) is a manifestation of underlying PDAC. In this study, we sought to identify potential blood-based biomarkers for distinguishing PDAC-NOD from type 2 diabetes (T2DM) without PDAC.

Materials and methods: By ELISA analysis, a migration signature biomarker panel comprising tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FNIII-C) and CA 19-9 was analyzed in plasma samples from 50 PDAC-NOD and 50 T2DM controls.

Results: Both TFPI (area under the curve (AUC) 0.71) and TNC-FNIII-C (AUC 0.69) outperformed CA 19-9 (AUC 0.60) …

Circulating Micrornas And Cytokines As Prognostic Biomarkers For Doxorubicin-Induced Cardiac Injury And For Evaluating The Effectiveness Of An Exercise Intervention, Prince Jeyabal, Anchit Bhagat, Fei Wang, Michael Roth, J Andrew Livingston, Susan C Gilchrist, Jose Banchs, Michelle A T Hildebrandt, Joya Chandra, Anita Deswal, Efstratios Koutroumpakis, Jian Wang, Najat C Daw, Theresa A Honey, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Purpose: To define a set of biomarkers that can be used to identify patients at high risk of developing late doxorubicin (DOX)-induced cardiac morbidity with the goal of focused monitoring and early interventions.

Experimental design: Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 hours), cytokines (24 hours), and troponin (24 hours, 4 and 6 weeks). Cardiac function was evaluated using echocardiography before and 24 hours after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples …

Priorities And Progress In Gram-Positive Bacterial Infection Research By The Antibacterial Resistance Leadership Group: A Narrative Review, Sarah B Doernberg, Cesar A Arias, Deena R Altman, Ahmed Babiker, Helen W Boucher, C Buddy Creech, Sara E Cosgrove, Scott R Evans, Vance G Fowler, Stephanie A Fritz, Toshimitsu Hamasaki, Brendan J Kelly, Sixto M Leal, Catherine Liu, Thomas P Lodise, Loren G Miller, Jose M Munita, Barbara E Murray, Melinda M Pettigrew, Felicia Ruffin, Marc H Scheetz, Bo Shopsin, Truc T Tran, Nicholas A Turner, Derek J Williams, Smitha Zaharoff, Thomas L Holland

Faculty, Staff and Student Publications

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, …

Clinical And Biological Significance Of Circulating Mirnas In Chronic Pancreatitis Patients Undergoing Total Pancreatectomy With Islet Autotransplantation, Srividya Vasu, Giovanna Saracino, Carly M Darden, Kenjiro Kumano, Yang Liu, Michael C Lawrence, Bashoo Naziruddin

Faculty, Staff and Student Publications

Background: Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA-mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes.

Methods: Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real-time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool.

Results: …

Mortality Benefit Of A Blood-Based Biomarker Panel For Lung Cancer On The Basis Of The Prostate, Lung, Colorectal, And Ovarian Cohort, Ehsan Irajizad, Johannes F Fahrmann, Tracey Marsh, Jody Vykoukal, Jennifer B Dennison, James P Long, Kim-Anh Do, Ziding Feng, Samir Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

Purpose: To investigate the utility of integrating a panel of circulating protein biomarkers in combination with a risk model on the basis of subject characteristics to identify individuals at high risk of harboring a lethal lung cancer.

Methods: Data from an established logistic regression model that combines four-marker protein panel (4MP) together with the Prostate, Lung, Colorectal, and Ovarian (PLCO) risk model (PLCOm2012) assayed in prediagnostic sera from 552 lung cancer cases and 2,193 noncases from the PLCO cohort were used in this study. Of the 552 lung cancer cases, 387 (70%) died of lung cancer. Cumulative incidence of lung …

Prognostic Significance Of Trophoblastic Cell Surface Antigen 2 Expression And Pathologic Parameters In Patients With Ampullary Adenocarcinoma, Yujie Zhang, Hua Wang, Michael Overman, Matthew Hg Katz, Huamin Wang

Faculty, Staff and Student Publications

Trophoblastic cell surface antigen 2 (TROP2) has been reported to be up-regulated in several types of carcinomas and is associated with aggressive behavior and poor survival. However, TROP2 expression and its clinical significance in ampullary adenocarcinoma (AA) have not been investigated. We examined TROP2 expression by immunohistochemistry in 112 patients with AAs. The associations of TROP2 expression with clinicopathologic characteristics were evaluated by χ2 analyses or Fisher's exact tests. The associations of TROP2 expression and pathologic parameters with survival were evaluated by the Kaplan-Meier method and univariate and multivariate Cox regression analyses. Eighty-six AAs (76.8%) were positive for TROP2, which …

Pathologist-Initiated Reflex Testing For Biomarkers In Non-Small-Cell Lung Cancer: Expert Consensus On The Rationale And Considerations For Implementation, J R Gosney, L Paz-Ares, P Jänne, K M Kerr, N B Leighl, M D Lozano, U Malapelle, T Mok, B S Sheffield, A Tufman, I I Wistuba, S Peters

Faculty, Staff and Student Publications

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

Pitfalls In Machine Learning-Based Assessment Of Tumor-Infiltrating Lymphocytes In Breast Cancer: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, Jeppe Thagaard, Glenn Broeckx, David B Page, Chowdhury Arif Jahangir, Sara Verbandt, Zuzana Kos, Rajarsi Gupta, Reena Khiroya, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Mohamed Amgad, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Eva Balslev, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Alexandros Chardas, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Anders B Dahl, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Johan Doré Hansen, Sarah N Dudgeon, Thomas Ebstrup, Mahmoud Elghazawy, Claudio Fernandez-Martín, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Steven N Hart, Johan Hartman, Søren Hauberg, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Roslind, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Ely Scott, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Susan Fineberg, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Reena Md Zin, Sylvia Adams, John Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. …

Spatial Analyses Of Immune Cell Infiltration In Cancer: Current Methods And Future Directions: A Report Of The International Immuno-Oncology Biomarker Working Group On Breast Cancer, David B Page, Glenn Broeckx, Chowdhury Arif Jahangir, Sara Verbandt, Rajarsi R Gupta, Jeppe Thagaard, Reena Khiroya, Zuzana Kos, Khalid Abduljabbar, Gabriela Acosta Haab, Balazs Acs, Guray Akturk, Jonas S Almeida, Isabel Alvarado-Cabrero, Farid Azmoudeh-Ardalan, Sunil Badve, Nurkhairul Bariyah Baharun, Enrique R Bellolio, Vydehi Bheemaraju, Kim Rm Blenman, Luciana Botinelly Mendonça Fujimoto, Najat Bouchmaa, Octavio Burgues, Maggie Chon U Cheang, Francesco Ciompi, Lee Ad Cooper, An Coosemans, Germán Corredor, Flavio Luis Dantas Portela, Frederik Deman, Sandra Demaria, Sarah N Dudgeon, Mahmoud Elghazawy, Scott Ely, Claudio Fernandez-Martín, Susan Fineberg, Stephen B Fox, William M Gallagher, Jennifer M Giltnane, Sacha Gnjatic, Paula I Gonzalez-Ericsson, Anita Grigoriadis, Niels Halama, Matthew G Hanna, Aparna Harbhajanka, Alexandros Hardas, Steven N Hart, Johan Hartman, Stephen Hewitt, Akira I Hida, Hugo M Horlings, Zaheed Husain, Evangelos Hytopoulos, Sheeba Irshad, Emiel Am Janssen, Mohamed Kahila, Tatsuki R Kataoka, Kosuke Kawaguchi, Durga Kharidehal, Andrey I Khramtsov, Umay Kiraz, Pawan Kirtani, Liudmila L Kodach, Konstanty Korski, Anikó Kovács, Anne-Vibeke Laenkholm, Corinna Lang-Schwarz, Denis Larsimont, Jochen K Lennerz, Marvin Lerousseau, Xiaoxian Li, Amy Ly, Anant Madabhushi, Sai K Maley, Vidya Manur Narasimhamurthy, Douglas K Marks, Elizabeth S Mcdonald, Ravi Mehrotra, Stefan Michiels, Fayyaz Ul Amir Afsar Minhas, Shachi Mittal, David A Moore, Shamim Mushtaq, Hussain Nighat, Thomas Papathomas, Frederique Penault-Llorca, Rashindrie D Perera, Christopher J Pinard, Juan Carlos Pinto-Cardenas, Giancarlo Pruneri, Lajos Pusztai, Arman Rahman, Nasir Mahmood Rajpoot, Bernardo Leon Rapoport, Tilman T Rau, Jorge S Reis-Filho, Joana M Ribeiro, David Rimm, Anne Vincent-Salomon, Manuel Salto-Tellez, Joel Saltz, Shahin Sayed, Kalliopi P Siziopikou, Christos Sotiriou, Albrecht Stenzinger, Maher A Sughayer, Daniel Sur, Fraser Symmans, Sunao Tanaka, Timothy Taxter, Sabine Tejpar, Jonas Teuwen, E Aubrey Thompson, Trine Tramm, William T Tran, Jeroen Van Der Laak, Paul J Van Diest, Gregory E Verghese, Giuseppe Viale, Michael Vieth, Noorul Wahab, Thomas Walter, Yannick Waumans, Hannah Y Wen, Wentao Yang, Yinyin Yuan, Sylvia Adams, John Mark Seaverns Bartlett, Sibylle Loibl, Carsten Denkert, Peter Savas, Sherene Loi, Roberto Salgado, Elisabeth Specht Stovgaard

Faculty, Staff and Student Publications

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical …

Sox11 Is An Effective Discriminatory Marker, When Used In Conjunction With Ck20 And Ttf1, For Merkel Cell Carcinoma: Comparative Analysis Of Sox11, Ck20, Pax5, And Ttf1 Expression In Merkel Cell Carcinoma And Pulmonary Small Cell Carcinoma, Woo Cheal Cho, Kaitlin Vanderbeck, Priyadharsini Nagarajan, Denái R Milton, Pavandeep Gill, Wei-Lien Wang, Jonathan L Curry, Carlos A Torres-Cabala, Doina Ivan, Victor G Prieto, Phyu P Aung

Faculty, Staff and Student Publications

Context.—: Distinction between Merkel cell carcinoma (MCC) and pulmonary small cell carcinoma (PSmCC) can be challenging, even with the aid of immunohistochemistry (IHC) analysis of CK20 and TTF1, as these tumors occasionally lack classic immunophenotypes (CK20+/TTF1- in MCC and CK20-/TTF1+ in PSmCC).

Objective.—: To evaluate the diagnostic utility of SOX11 and PAX5 IHC for distinguishing MCCs from PSmCCs and compare it with that of CK20 and TTF1 IHC.

Design.—: SOX11, PAX5, CK20, and TTF1 expression (pattern, intensity, and proportion of tumor cells expressing protein) was assessed in 31 primary and 16 metastatic MCCs and 20 primary and 9 metastatic PSmCCs. …

Adaptive Immunity In Genitourinary Cancers, Madhuri Koti, Trinity Bivalacqua, Peter C Black, Toni Cathomen, Matthew D Galsky, James L Gulley, Molly A Ingersoll, Ashish M Kamat, Wassim Kassouf, D Robert Siemens, Jianjun Gao

Faculty, Staff and Student Publications

Context: While urothelial and renal cell cancers have exhibited modest responses to novel immune checkpoint inhibitors targeting the programmed death ligand 1 and its receptor, response rates in patients with prostate cancer have remained poor. The factors underlying suboptimal outcomes observed in patients treated with novel immunotherapies are still to be resolved.

Objective: To review the literature and describe the key adaptive immune physiological events associated with cancer progression and therapeutic response in genitourinary (GU) cancers.

Evidence acquisition: We performed a nonsystematic, collaborative narrative review to highlight recent advancements leading to the current state of knowledge on the critical mediators …

Polymorphisms Within Autophagy-Related Genes As Susceptibility Biomarkers For Multiple Myeloma: A Meta-Analysis Of Three Large Cohorts And Functional Characterization, Esther Clavero, José Manuel Sanchez-Maldonado, Angelica Macauda, Rob Ter Horst, Belém Sampaio-Marques, Artur Jurczyszyn, Alyssa Clay-Gilmour, Angelika Stein, Michelle A T Hildebrandt, Niels Weinhold, Gabriele Buda, Ramón García-Sanz, Waldemar Tomczak, Ulla Vogel, Andrés Jerez, Daria Zawirska, Marzena Wątek, Jonathan N Hofmann, Stefano Landi, John J Spinelli, Aleksandra Butrym, Abhishek Kumar, Joaquín Martínez-López, Sara Galimberti, María Eugenia Sarasquete, Edyta Subocz, Elzbieta Iskierka-Jażdżewska, Graham G Giles, Malwina Rybicka-Ramos, Marcin Kruszewski, Niels Abildgaard, Francisco García Verdejo, Pedro Sánchez Rovira, Miguel Inacio Da Silva Filho, Katalin Kadar, Małgorzata Razny, Wendy Cozen, Matteo Pelosini, Manuel Jurado, Parveen Bhatti, Marek Dudzinski, Agnieszka Druzd-Sitek, Enrico Orciuolo, Yang Li, Aaron D Norman, Jan Maciej Zaucha, Rui Manuel Reis, Miroslaw Markiewicz, Juan José Rodríguez Sevilla, Vibeke Andersen, Krzysztof Jamroziak, Kari Hemminki, Sonja I Berndt, Vicent Rajkumar, Grzegorz Mazur, Shaji K Kumar, Paula Ludovico, Arnon Nagler, Stephen J Chanock, Charles Dumontet, Mitchell J Machiela, Judit Varkonyi, Nicola J Camp, Elad Ziv, Annette Juul Vangsted, Elizabeth E Brown, Daniele Campa, Celine M Vachon, Mihai G Netea, Federico Canzian, Asta Försti, Juan Sainz

Faculty, Staff and Student Publications

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of …

Impact Of Biomarker-Matched Therapies On Outcomes In Patients With Sarcoma Enrolled In Early-Phase Clinical Trials (Samba 101), Roberto Carmagnani Pestana, Justin T Moyers, Jason Roszik, Shiraj Sen, David S Hong, Aung Naing, Cynthia E Herzog, Siqing Fu, Sarina A Piha-Paul, Jordi Rodon, Timothy A Yap, Daniel D Karp, Apostolia M Tsimberidou, Shubham Pant, Maria A Zarzour, Ravin Ratan, Vinod Ravi, Robert S Benjamin, Alexander J Lazar, Wei-Lien Wang, Najat Daw, Jonathan B Gill, Douglas J Harrison, Valerae O Lewis, Christina L Roland, Shreyaskumar R Patel, J Andrew Livingston, Neeta Somaiah, Joseph A Ludwig, Anthony P Conley, Nelson Hamerschlak, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.

Experimental design: In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021.

Results: Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, …

Multi-Institutional Study Of Pathologist Reading Of The Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay For Gastric Or Gastroesophageal Junction Cancer, Aileen I Fernandez, Charles J Robbins, Patricia Gaule, Diana Agostini-Vulaj, Robert A Anders, Andrew M Bellizzi, Wei Chen, Zongming Eric Chen, Purva Gopal, Lei Zhao, Mikhail Lisovsky, Xiuli Liu, Jinru Shia, Huamin Wang, Zhaohai Yang, Leena Mccann, Yvonne G Chan, Jodi Weidler, Michael Bates, Xuchen Zhang, David L Rimm

Faculty, Staff and Student Publications

The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 …

Machine Learning Models For The Identification Of Prognostic And Predictive Cancer Biomarkers: A Systematic Review, Qasem Al-Tashi, Maliazurina B Saad, Amgad Muneer, Rizwan Qureshi, Seyedali Mirjalili, Ajay Sheshadri, Xiuning Le, Natalie I Vokes, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

The identification of biomarkers plays a crucial role in personalized medicine, both in the clinical and research settings. However, the contrast between predictive and prognostic biomarkers can be challenging due to the overlap between the two. A prognostic biomarker predicts the future outcome of cancer, regardless of treatment, and a predictive biomarker predicts the effectiveness of a therapeutic intervention. Misclassifying a prognostic biomarker as predictive (or vice versa) can have serious financial and personal consequences for patients. To address this issue, various statistical and machine learning approaches have been developed. The aim of this study is to present an in-depth …

Assessment And Prediction Of Glioblastoma Therapy Response: Challenges And Opportunities, Dan Qi, Jing Li, C Chad Quarles, Ekokobe Fonkem, Erxi Wu

Faculty, Staff and Student Publications

Glioblastoma is the most aggressive type of primary adult brain tumour. The median survival of patients with glioblastoma remains approximately 15 months, and the 5-year survival rate is < 10%. Current treatment options are limited, and the standard of care has remained relatively constant since 2011. Over the last decade, a range of different treatment regimens have been investigated with very limited success. Tumour recurrence is almost inevitable with the current treatment strategies, as glioblastoma tumours are highly heterogeneous and invasive. Additionally, another challenging issue facing patients with glioblastoma is how to distinguish between tumour progression and treatment effects, especially when relying on routine diagnostic imaging techniques in the clinic. The specificity of routine imaging for identifying tumour progression early or in a timely manner is poor due to the appearance similarity of post-treatment effects. Here, we concisely describe the current status and challenges in the assessment and early prediction of therapy response and the early detection of tumour progression or recurrence. We also summarize and discuss studies of advanced approaches such as quantitative imaging, liquid biomarker discovery and machine intelligence that hold exceptional potential to aid in the therapy monitoring of this malignancy and early prediction of therapy response, which may decisively transform the conventional detection methods in the era of precision medicine.

A Distinct Pattern Of Growth And Rac1 Signaling In Melanoma Brain Metastasis Cells, Ioana Stejerean-Todoran, Phyllis A Gimotty, Andrea Watters, Patricia Brafford, Clemens Krepler, Tetiana Godok, Haiyin Li, Zuriñe Bonilla Del Rio, Anke Zieseniss, Dörthe M Katschinski, Sinem M Sertel, Silvio O Rizzoli, Bradley Garman, Katherine L Nathanson, Xiaowei Xu, Qing Chen, Jack H Oswald, Michal Lotem, Gordon B Mills, Michael A Davies, Michael P Schön, Ivan Bogeski, Meenhard Herlyn, Adina Vultur

Faculty, Staff and Student Publications

Background: Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.

Methods: We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.

Results: Brain-specific genetic alterations were not detected; however, MBM cells in vitro …

Mutation-Agnostic Detection Of Colorectal Cancer Using Liquid Biopsy-Based Methylation-Specific Signatures, Mohamed A Gouda, Dzifa Y Duose, Morten Lapin, Stephanie Zalles, Helen J Huang, Yuanxin Xi, Xiaofeng Zheng, Amira I Aldesoky, Alshimaa M Alhanafy, Mohamed A Shehata, Jing Wang, Scott Kopetz, Funda Meric-Bernstam, Ignacio I Wistuba, Rajyalakshmi Luthra, Filip Janku

Faculty, Staff and Student Publications

Detection of methylation patterns in circulating tumor DNA (ctDNA) can offer a novel approach for cancer diagnostics given the unique signature for each tumor type. We developed a next-generation sequencing (NGS)-based assay targeting 32 CpG sites to detect colorectal cancer-specific ctDNA. NGS was performed on bisulfite-converted libraries and status dichotomization was done using median methylation ratios at all targets. We included plasma samples from patients with metastatic colorectal (n = 20) and non-colorectal cancers (n = 8); and healthy volunteers (n = 4). Median methylation ratio was higher in colorectal cancer compared with non-colorectal cancers (P = .001) and normal …

Phenotypic Plasticity In Circulating Tumor Cells Is Associated With Poor Response To Therapy In Metastatic Breast Cancer Patients, Evan N Cohen, Gitanjali Jayachandran, Hui Gao, Phillip Peabody, Heather B Mcbride, Franklin D Alvarez, Megumi Kai, Juhee Song, Yu Shen, Jie S Willey, Bora Lim, Vicente Valero, Naoto T Ueno, James M Reuben

Faculty, Staff and Student Publications

Circulating tumor cells (CTCs) are indicators of metastatic spread and progression. In a longitudinal, single-center trial of patients with metastatic breast cancer starting a new line of treatment, a microcavity array was used to enrich CTCs from 184 patients at up to 9 timepoints at 3-month intervals. CTCs were analyzed in parallel samples from the same blood draw by imaging and by gene expression profiling to capture CTC phenotypic plasticity. Enumeration of CTCs by image analysis relying primarily on epithelial markers from samples obtained before therapy or at 3-month follow-up identified the patients at the highest risk of progression. CTC …

Baseline Extracellular Vesicle Tgf-Β Is A Predictive Biomarker For Response To Immune Checkpoint Inhibitors And Survival In Non-Small Cell Lung Cancer, Diego De Miguel-Perez, Alessandro Russo, Muthukumar Gunasekaran, Francesco Buemi, Lisa Hester, Xiaoxuan Fan, Brandon A Carter-Cooper, Rena G Lapidus, Ariel Peleg, Marisol Arroyo-Hernández, Andres F Cardona, Aung Naing, Fred R Hirsch, Philip C Mack, Sunjay Kaushal, Maria Jose Serrano, Vincenzo Adamo, Oscar Arrieta, Christian Rolfo

Faculty, Staff and Student Publications

Background: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in …

Gene Expression Profiling Of Circulating Tumor Cells Captured By Microcavity Array Is Superior To Enumeration In Demonstrating Therapy Response In Patients With Newly Diagnosed Advanced And Locally Advanced Non-Small Cell Lung Cancer, Evan N Cohen, Gitanjali Jayachandran, Hui Gao, Phillip Peabody, Heather B Mcbride, Franklin D Alvarez, Pablo Lopez Bravo, Wei Qiao, Suyu Liu, Luyang Yao, Steven H Lin, James M Reuben

Faculty, Staff and Student Publications

Background: Circulating tumor cells (CTCs) are a promising non-invasive tool for monitoring therapy response. The only Food and Drug Administration (FDA)-approved test is limited to enumeration of epithelial CTC without further characterization and is not approved for the management of non-small cell lung cancer (NSCLC). Here we use a MicroCavity Array (MCA) system to capture CTC agnostic of epithelial markers for further molecular testing in NSCLC.

Methods: CTCs were enumerated by fluorescent microscopy as longitudinal sampling throughout disease management from 213 NSCLC patients. CTC-enriched samples from a subset of 127 patients were interrogated for gene expression by reverse transcription polymerase …

Mass Spectrometry Based Biomarkers For Early Detection Of Hcc Using A Glycoproteomic Approach, Yehia Mechref, Wenjing Peng, Sakshi Gautam, Parisa Ahmadi, Yu Lin, Jianhui Zhu, Jie Zhang, Suyu Liu, Amit G Singal, Neehar D Parikh, David M Lubman

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform …

A Th2-Score In The Tumor Microenvironment As A Predictive Biomarker Of Response To Bacillus Calmette Guérin In Patients With Non-Muscle Invasive Bladder Carcinoma: A Retrospective Study, Gustavo Martín Villoldo, María Teresa Pombo, Mariana Aris, Joaquín Chemi, Pablo Mandó, Supriya Nagaraju, Juan Camean, Adrián Burioni, Deborah Egea, Mora Amat, José León Mellado, José Mordoh, Alberto Villaronga, María Marcela Barrio

Faculty, Staff and Student Publications

Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk non-muscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ …

Propranolol Modulates Cerebellar Circuit Activity And Reduces Tremor., Joy Zhou, Meike E Van Der Heijden, Luis E Salazar Leon, Tao Lin, Lauren N Miterko, Dominic J Kizek, Ross M Perez, Matea Pavešković, Amanda M Brown, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8^wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8^wdl/wdl mice to control levels. …