Genetic Phenomena Commons^™

Histopathological Tumour Response Scoring In Resected Pancreatic Cancer Following Neoadjuvant Therapy: International Interobserver Study (Isgpp-1), Boris V Janssen, Stijn Van Roessel, Susan Van Dieren, Onno De Boer, Volkan Adsay, Olca Basturk, Lodewijk Brosens, Fiona Campbell, Deyali Chatterjee, Angela Chou, Claudio Doglioni, Irene Esposito, Roger Feakins, Talia L Fuchs, Noriyoshi Fukushima, Anthony J Gill, Seung-Mo Hong, Ralph H Hruban, Jeffrey Kaplan, Alyssa Krasinkas, Claudio Luchini, Chanjuan Shi, Aatur Singhi, Elizabeth Thompson, Marie-Louise F Velthuysen, Marc G Besselink, Joanne Verheij, Huamin Wang, Caroline Verbeke, Arantza Fariña

Faculty, Staff and Student Publications

Background: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems.

Methods: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The …

Efficacy Of Cabozantinib In Metastatic Mit Family Translocation Renal Cell Carcinomas, Jonathan Thouvenin, Omar Alhalabi, Maria Carlo, Lucia Carril-Ajuria, Laure Hirsch, Nieves Martinez-Chanza, Sylvie Négrier, Luca Campedel, Dylan Martini, Delphine Borchiellini, Jad Chahoud, Massimo Lodi, Philippe Barthélémy, Elshad Hasanov, Andrew W Hahn, Thierry Gil, Srinivas R Viswanathan, Ziad Bakouny, Pavlos Msaouel, Mehmet Asim Bilen, Toni K Choueiri, Laurence Albiges, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear.

Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS).

Results: Fifty-two patients with metastatic TRCC treated in …

Prognostic Significance Of P16 And Its Relationship With Human Papillomavirus Status In Patients With Penile Squamous Cell Carcinoma: Results Of 5 Years Follow-Up, Jad Chahoud, Niki M Zacharias, Rachel Pham, Wei Qiao, Ming Guo, Xin Lu, Angelita Alaniz, Luis Segarra, Magaly Martinez-Ferrer, Frederico Omar Gleber-Netto, Curtis R Pickering, Priya Rao, Curtis A Pettaway

Faculty, Staff and Student Publications

Penile Squamous Cell Carcinoma (PSCC) is associated with high-risk human papillomavirus (HR-HPV). The immunohistochemical (IHC) test for p16INK4a (p16) is highly correlated with HR-HPV expression in other SCCs. To investigate whether the expression of p16 IHC or HR-HPV is associated with survival in PSCC, we conducted a single institution analysis of 143 patients with a diagnosis of PSCC and, available tissue were tested for p16 IHC staining patterns, histological subtype, tumor grade, and lymphovascular invasion (LVI) by an experienced pathologist. HR-HPV status using the Cobas PCR Assay or the RNAScope high-risk HPV in situ hybridization kit were also assessed. Patient …

Author Correction: Disrupted Ca2+ Homeostasis And Immunodeficiency In Patients With Functional Ip3 Receptor Subtype 3 Defects, Julika Neumann, Erika Van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele, François Vermeulen, Susan Schlenner, Isabelle Meyts, David I Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston

Faculty, Staff and Student Publications

This corrects the article "Disrupted Ca²⁺ homeostasis and immunodeficiency in patients with functional IP₃ receptor subtype 3 defects" on page 11.

Executive Summary Of The American Radium Society Appropriate Use Criteria For Management Of Uterine Clear Cell And Serous Carcinomas, Tracy Sherertz, Anuja Jhingran, Matthew Biagioli, David Gaffney, Mohamed Elshaikh, Robert L Coleman, Matthew Harkenrider, Elizabeth A Kidd, Shruti Jolly, Catheryn Yashar, Lorraine Portelance, Andrew Wahl, Aradhana Venkatesan, Linna Li, William Small, American Radium Society

Faculty, Staff and Student Publications

Background: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies.

Objective: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas.

Methods: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of …

Federated Learning Enables Big Data For Rare Cancer Boundary Detection, Sarthak Pati, Ujjwal Baid, Brandon Edwards, Micah Sheller, Shih-Han Wang, G Anthony Reina, Patrick Foley, Alexey Gruzdev, Deepthi Karkada, Christos Davatzikos, Chiharu Sako, Satyam Ghodasara, Michel Bilello, Suyash Mohan, Philipp Vollmuth, Gianluca Brugnara, Chandrakanth J Preetha, Felix Sahm, Klaus Maier-Hein, Maximilian Zenk, Martin Bendszus, Wolfgang Wick, Evan Calabrese, Jeffrey Rudie, Javier Villanueva-Meyer, Soonmee Cha, Madhura Ingalhalikar, Manali Jadhav, Umang Pandey, Jitender Saini, John Garrett, Matthew Larson, Robert Jeraj, Stuart Currie, Russell Frood, Kavi Fatania, Raymond Y Huang, Ken Chang, Carmen Balaña, Jaume Capellades, Josep Puig, Johannes Trenkler, Josef Pichler, Georg Necker, Andreas Haunschmidt, Stephan Meckel, Gaurav Shukla, Spencer Liem, Gregory S Alexander, Joseph Lombardo, Joshua D Palmer, Adam E Flanders, Adam P Dicker, Haris I Sair, Craig K Jones, Archana Venkataraman, Meirui Jiang, Tiffany Y So, Cheng Chen, Pheng Ann Heng, Qi Dou, Michal Kozubek, Filip Lux, Jan Michálek, Petr Matula, Miloš Keřkovský, Tereza Kopřivová, Marek Dostál, Václav Vybíhal, Michael A Vogelbaum, J Ross Mitchell, Joaquim Farinhas, Joseph A Maldjian, Chandan Ganesh Bangalore Yogananda, Marco C Pinho, Divya Reddy, James Holcomb, Benjamin C Wagner, Benjamin M Ellingson, Timothy F Cloughesy, Catalina Raymond, Talia Oughourlian, Akifumi Hagiwara, Chencai Wang, Minh-Son To, Sargam Bhardwaj, Chee Chong, Marc Agzarian, Alexandre Xavier Falcão, Samuel B Martins, Bernardo C A Teixeira, Flávia Sprenger, David Menotti, Diego R Lucio, Pamela Lamontagne, Daniel Marcus, Benedikt Wiestler, Florian Kofler, Ivan Ezhov, Marie Metz, Rajan Jain, Matthew Lee, Yvonne W Lui, Richard Mckinley, Johannes Slotboom, Piotr Radojewski, Raphael Meier, Roland Wiest, Derrick Murcia, Eric Fu, Rourke Haas, John Thompson, David Ryan Ormond, Chaitra Badve, Andrew E Sloan, Vachan Vadmal, Kristin Waite, Rivka R Colen, Linmin Pei, Murat Ak, Ashok Srinivasan, J Rajiv Bapuraj, Arvind Rao, Nicholas Wang, Ota Yoshiaki, Toshio Moritani, Sevcan Turk, Joonsang Lee, Snehal Prabhudesai, Fanny Morón, Jacob Mandel, Konstantinos Kamnitsas, Ben Glocker, Luke V M Dixon, Matthew Williams, Peter Zampakis, Vasileios Panagiotopoulos, Panagiotis Tsiganos, Sotiris Alexiou, Ilias Haliassos, Evangelia I Zacharaki, Konstantinos Moustakas, Christina Kalogeropoulou, Dimitrios M Kardamakis, Yoon Seong Choi, Seung-Koo Lee, Jong Hee Chang, Sung Soo Ahn, Bing Luo, Laila Poisson, Ning Wen, Pallavi Tiwari, Ruchika Verma, Rohan Bareja, Ipsa Yadav, Jonathan Chen, Neeraj Kumar, Marion Smits, Sebastian R Van Der Voort, Ahmed Alafandi, Fatih Incekara, Maarten M J Wijnenga, Georgios Kapsas, Renske Gahrmann, Joost W Schouten, Hendrikus J Dubbink, Arnaud J P E Vincent, Martin J Van Den Bent, Pim J French, Stefan Klein, Yading Yuan, Sonam Sharma, Tzu-Chi Tseng, Saba Adabi, Simone P Niclou, Olivier Keunen, Ann-Christin Hau, Martin Vallières, David Fortin, Martin Lepage, Bennett Landman, Karthik Ramadass, Kaiwen Xu, Silky Chotai, Lola B Chambless, Akshitkumar Mistry, Reid C Thompson, Yuriy Gusev, Krithika Bhuvaneshwar, Anousheh Sayah, Camelia Bencheqroun, Anas Belouali, Subha Madhavan, Thomas C Booth, Alysha Chelliah, Marc Modat, Haris Shuaib, Carmen Dragos, Aly Abayazeed, Kenneth Kolodziej, Michael Hill, Ahmed Abbassy, Shady Gamal, Mahmoud Mekhaimar, Mohamed Qayati, Mauricio Reyes, Ji Eun Park, Jihye Yun, Ho Sung Kim, Abhishek Mahajan, Mark Muzi, Sean Benson, Regina G H Beets-Tan, Jonas Teuwen, Alejandro Herrera-Trujillo, Maria Trujillo, William Escobar, Ana Abello, Jose Bernal, Jhon Gómez, Joseph Choi, Stephen Baek, Yusung Kim, Heba Ismael, Bryan Allen, John M Buatti, Aikaterini Kotrotsou, Hongwei Li, Tobias Weiss, Michael Weller, Andrea Bink, Bertrand Pouymayou, Hassan F Shaykh, Joel Saltz, Prateek Prasanna, Sampurna Shrestha, Kartik M Mani, David Payne, Tahsin Kurc, Enrique Pelaez, Heydy Franco-Maldonado, Francis Loayza, Sebastian Quevedo, Pamela Guevara, Esteban Torche, Cristobal Mendoza, Franco Vera, Elvis Ríos, Eduardo López, Sergio A Velastin, Godwin Ogbole, Mayowa Soneye, Dotun Oyekunle, Olubunmi Odafe-Oyibotha, Babatunde Osobu, Mustapha Shu'aibu, Adeleye Dorcas, Farouk Dako, Amber L Simpson, Mohammad Hamghalam, Jacob J Peoples, Ricky Hu, Anh Tran, Danielle Cutler, Fabio Y Moraes, Michael A Boss, James Gimpel, Deepak Kattil Veettil, Kendall Schmidt, Brian Bialecki, Sailaja Marella, Cynthia Price, Lisa Cimino, Charles Apgar, Prashant Shah, Bjoern Menze, Jill S Barnholtz-Sloan, Jason Martin, Spyridon Bakas

Faculty, Staff and Student Publications

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically …

Treatment Of Epilepsy Using A Targeted P38Γ Kinase Gene Therapy, Nicolle Morey, Magdalena Przybyla, Julia Van Der Hoven, Yazi D Ke, Fabien Delerue, Janet Van Eersel, Lars M Ittner

Faculty, Staff and Student Publications

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates …

Structural Variants Drive Context-Dependent Oncogene Activation In Cancer, Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C Akdemir, Selene Tyndale, P Andrew Futreal, Graham Mcvicker, Geoffrey M Wahl, Jesse R Dixon

Faculty, Staff and Student Publications

Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific …

Distinct Germline Genetic Susceptibility Profiles Identified For Common Non-Hodgkin Lymphoma Subtypes, Sonja I Berndt, Joseph Vijai, Yolanda Benavente, Nicola J Camp, Alexandra Nieters, Zhaoming Wang, Karin E Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F Skibola, Lindsay M Morton, Angela R Brooks-Wilson, Lauren R Teras, Charles Breeze, Joshua Arias, Hans-Olov Adami, Demetrius Albanes, Kenneth C Anderson, Stephen M Ansell, Bryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M Birmann, Paolo Boffetta, Paige M Bracci, Paul Brennan, Elizabeth E Brown, Laurie Burdett, Lisa A Cannon-Albright, Ellen T Chang, Brian C H Chiu, Charles C Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V Conti, David G Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, Arjan Diepstra, W Ryan Diver, Ahmet Dogan, Christopher K Edlund, Lenka Foretova, Joseph F Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M Habermann, Christopher A Haiman, Corinne Haioun, Jonathan N Hofmann, Theodore R Holford, Elizabeth A Holly, Amy Hutchinson, Aalin Izhar, Rebecca D Jackson, Ruth F Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K Link, Corrado Magnani, Marc Maynadie, James Mckay, Mads Melbye, Lucia Miligi, Roger L Milne, Thierry J Molina, Alain Monnereau, Rebecca Montalvan, Kari E North, Anne J Novak, Kenan Onel, Mark P Purdue, Kristin A Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W Sborov, Richard K Severson, Tait D Shanafelt, Martyn T Smith, Alexandra Smith, Kevin W Song, Lei Song, Melissa C Southey, John J Spinelli, Anthony Staines, Deborah Stephens, Heather J Sutherland, Kaitlyn Tkachuk, Carrie A Thompson, Hervé Tilly, Lesley F Tinker, Ruth C Travis, Jenny Turner, Celine M Vachon, Claire M Vajdic, Anke Van Den Berg, David J Van Den Berg, Roel C H Vermeulen, Paolo Vineis, Sophia S Wang, Elisabete Weiderpass, George J Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R Cerhan, Stephen J Chanock, Susan L Slager, Nathaniel Rothman

Faculty, Staff and Student Publications

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9,505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P<5 >× 10−8) for subsets of NHL subtypes, …

Clinically Significant Metachronous Colorectal Pathology Detected Among Young-Onset Colorectal Cancer Survivors: Implications For Post-Resection Surveillance Guidelines, Oliver Peacock, Eduardo Vilar, Montserrat Guraieb-Trueba, Selvi Thirumurthi, George J Chang, Y Nancy You

Faculty, Staff and Student Publications

No abstract provided.

Utility Of Measurable Residual Disease For Predicting Treatment Outcomes With Bcr- And Bcl2-Targeted Therapies In Patients With Cll, William G Wierda, Thomas J Kipps, Othman Al-Sawaf, Brenda Chyla, Juliana M L Biondo, Yong Mun, Yanwen Jiang, John F Seymour

Faculty, Staff and Student Publications

Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve …

Implications Of Ras Mutational Status In Subsets Of Patients With Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes, Daniel Rivera, Kunhwa Kim, Rashmi Kanagal-Shamanna, Gautam Borthakur, Guillermo Montalban-Bravo, Naval Daver, Courtney Dinardo, Nicholas J Short, Musa Yilmaz, Naveen Pemmaraju, Koichi Takahashi, Elias J Jabbour, Sherry Pierce, Marina Konopleva, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with …

Pet/Mr Imaging Of A Lung Metastasis Model Of Clear Cell Renal Cell Carcinoma With (2s,4r)-4-[18f]Fluoroglutamine, Alyssa C Pollard, Vincenzo Paolillo, Bhasker Radaram, Sarah Qureshy, Li Li, Tapati Maity, Lei Wang, Md Nasir Uddin, Christopher G Wood, Jose A Karam, Mark D Pagel, David Piwnica-Worms, Steven W Millward, Natalie Wall Fowlkes, William Norton, Brian J Engel, Federica Pisaneschi, Niki M Zacharias

Faculty, Staff and Student Publications

Purpose: Metabolic reprogramming plays an important role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Currently, positron emission tomography (PET) reporters are not used clinically to visualize altered glutamine metabolism in ccRCC, which greatly hinders detection, staging, and real-time therapeutic assessment. We sought to determine if (2S,4R)-4-[18F]fluoroglutamine ([18F]FGln) could be used to interrogate altered glutamine metabolism in ccRCC lesions in the lung.

Procedures: We generated a novel ccRCC lung lesion model using the ccRCC cell line UMRC3 stably transfected with GFP and luciferase constructs. This cell line was used for characterization of [18F]FGln uptake and retention by transport …

Genetic Landscape Of Indolent And Aggressive Kaposi Sarcomas, G G Malouf, X Lu, R Mouawad, J-P Spano, P Grange, F Yan, S Aractingi, X Su, N Dupin

Faculty, Staff and Student Publications

Background: Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown.

Objectives: To explore the tumour mutational burden in indolent and aggressive KS.

Methods: We performed whole-exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS.

Results: Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive …

A Phase Ii Randomized Double Blinded Trial Evaluating The Efficacy Of Curcumin With Pre-Operative Chemoradiation For Rectal Cancer, Jillian R Gunther, Awalpreet S Chadha, Sushovan Guha, Gottumukkala S Raju, Dipen M Maru, Mark F Munsell, Yan Jiang, Peiying Yang, Edd Felix, Marilyn Clemons, Geena George Mathew, Pankaj K Singh, John M Skibber, Miguel A Rodriguez-Bigas, George J Chang, Cathy Eng, Marc E Delclos, Christopher H Crane, Prajnan Das, Sunil Krishnan

Faculty, Staff and Student Publications

Background: In vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome.

Methods: From 2008-2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m2 twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood …

Lymphocyte Sparing Normal Tissue Effects In The Clinic (Lymphotec): A Systematic Review Of Dose Constraint Considerations To Mitigate Radiation-Related Lymphopenia In The Era Of Immunotherapy, Bhanuprasad Venkatesulu, Prashanth Giridhar, Lincoln Pujari, Brian Chou, Jae Han Lee, Alec M Block, Rituraj Upadhyay, James S Welsh, Matthew M Harkenrider, Sunil Krishnan, Vivek Verma, Cheng En Hsieh, Satyajit Pradhan, William Small, Abhishek A Solanki

Faculty, Staff and Student Publications

Background: Radiation-related lymphopenia has been associated with suboptimal tumor control rates leading to inferior survival outcomes. To date, no standardized dose constraints are available to limit radiation dose to resident and circulating lymphocyte populations. We undertook this systemic review of the literature to provide a synopsis of the dosimetric predictors of radiation-related lymphopenia in solid malignancies.

Methodology: A systematic literature review of PubMed (National Institutes of Health), Cochrane Central (Cochrane collaboration), and Google Scholar was conducted with the following keywords: "radiation", "lymphopenia", "cancer", "dosimetric predictors" with an inclusion deadline of May 31, 2022. Studies that met prespecified inclusion criteria were …

Bcl11b And Atoh8 Coordinate Cellular Plasticity For Reprogramming And Transformation, Mo-Fan Huang, Rachel Shoemaker, Dung-Fang Lee

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By dissecting and comparing the transcriptional trajectories and epigenomic traits of reprogramming and transforming cells at the single-cell resolution, Huyghe et al discovered Bcl11b and Atoh8, two key transcription factors controlling cell plasticity during pluripotent reprogramming and oncogenic transformation.

Monitoring Pd-L1 Expression On Circulating Tumor-Associated Cells In Recurrent Metastatic Non-Small-Cell Lung Carcinoma Predicts Response To Immunotherapy With Radiation Therapy, Jillian A Moran, Daniel L Adams, Martin J Edelman, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Zhongxing Liao, Kirby P Gardner, Cha-Mei Tang, Steven H Lin

Faculty, Staff and Student Publications

Purpose: Current diagnostic methods to determine programmed death 1 (PD-1) receptor and its ligand (PD-L1)/PD-1 immunotherapy (immune checkpoint inhibitor [ICI]) efficacy in recurrent or metastatic non-small-cell lung carcinoma (rmNSCLC) are imprecise. Although previously shown that patients with high tumor PD-L1 (≥ 50%) demonstrate clinical benefit in the form of disease reduction and improved survival, patients with low PD-L1 (< 50%) sometimes benefit from treatment. Since the PD-L1/PD-1 pathway is dynamic, monitoring PD-L1 levels during treatment may be more accurate than a static baseline tumor biopsy; however, rebiopsying the primary or metastatic disease is rarely feasible. Liquid biopsies that measure the upregulation of PD-L1 on tumor-associated cells (TACs), ie, cancer-associated macrophage-like cells and circulating tumor cells, have been performed, but their predictive value for ICI therapy efficacy is unknown.

Materials and methods: We initiated a single-blind prospective study to evaluate TAC PD-L1 expression changes in rmNSCLC from blood samples before (T0) and after (T1) treatment with ICI (ICI, n = 41) or without ICI (no ICI, n = 41). Anonymized …

Factors Modulating 99mtc-Maa Planar Lung Dosimetry For 90y Radioembolization, Benjamin P Lopez, Armeen Mahvash, James P Long, Marnix G E H Lam, S Cheenu Kappadath

Faculty, Staff and Student Publications

Purpose: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99m Tc-macro-aggregated albumin (99m Tc-MAA) planar imaging for treatment planning of 90 Y-microsphere radioembolization.

Methods and materials: LSFs in 52 planning and LDs in 44 treatment procedures were retrospectively calculated, in consecutive radioembolization patients over a 2 year interval, using 99m Tc-MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99m Tc-MAA shine-through compensations, and (4) lung mass estimations. The accuracy of each planar-based LSF and LD …

Tertiary Lymphoid Structure Signatures Are Associated With Immune Checkpoint Inhibitor Related Acute Interstitial Nephritis, Shailbala Singh, James P Long, Amanda Tchakarov, Yanlan Dong, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF …

Cerebrovascular Reactivity Mapping Using Resting-State Functional Mri In Patients With Gliomas, Mei-Yu Yeh, Henry S Chen, Ping Hou, Vinodh A Kumar, Jason M Johnson, Kyle R Noll, Sujit S Prabhu, Sherise D Ferguson, Donald F Schomer, Hsu-Hsia Peng, Ho-Ling Liu

Faculty, Staff and Student Publications

Background: Recently, a data-driven regression analysis method was developed to utilize the resting-state (rs) blood oxygenation level-dependent signal for cerebrovascular reactivity (CVR) mapping (rs-CVR), which was previously optimized by comparing with the CO2 inhalation-based method in health subjects and patients with neurovascular diseases.

Purpose: To investigate the agreement of rs-CVR and the CVR mapping with breath-hold MRI (bh-CVR) in patients with gliomas.

Study type: Retrospective.

Population: Twenty-five patients (12 males, 13 females; mean age ± SD, 48 ± 13 years) with gliomas.

Field strength/sequence: Dynamic T2*-weighted gradient-echo echo-planar imaging during a breath-hold paradigm and during the rs on a 3-T …

Identity-Related Experiences Of Asian American Trainees In Gynecologic Oncology, Jhalak Dholakia, Yeon Woo Lee, Karen H Lu, Warner K Huh, S Diane Yamada, Katherine C Fuh, Amanika S Kumar, Margaret I Liang, Navya Nair, Kenneth H Kim

Faculty, Staff and Student Publications

Background: Anti-Asian violence increased during the COVID-19 pandemic. Asian American/Pacific Islanders (AAPI) represent a diverse population experiencing a long history of stereotyping and exclusionism; however, this group is often left out of diversity/inclusion conversations. In academic medicine, AAPI are under-represented in leadership. We characterized the personal/professional experiences of AAPI gynecologic oncology trainees and assessed the impact of a virtual panel discussion with leaders in the field.

Methods: An anonymous survey was disseminated online to trainees in/interested in gynecologic oncology fellowship who identified as AAPI, using modified snowball sampling. A virtual session with AAPI leaders in gynecologic oncology discussed themes emerging …

Allergic Fungal Rhinosinusitis: The Role And Expectations Of Biologics, Amber U Luong, Andy Chua, Bader M Alim, Petter Olsson, Amin Javer

Faculty, Staff and Student Publications

Allergic fungal rhinosinusitis (AFRS) is a noninvasive subtype of chronic rhinosinusitis with nasal polyps (CRSwNP) that usually develops in immunocompetent atopic individuals and is more common in geographic regions characterized by warm temperatures and high humidity, conducive to higher environmental fungal presence. Allergic fungal rhinosinusitis usually presents with unique computed tomography findings and significant polyp burden, yet patients often report minimal sinus symptoms. Patients with AFRS often have extremely elevated serum total and fungal-specific IgE levels. Treatment almost always requires surgery, in which adjuvant medical therapy is critical to success. However, until recently the choice of adjuvant therapy has consisted …

Airway Mucus Dysfunction In Covid-19, Burton F Dickey, Jichao Chen, R Stokes Peebles

Faculty, Staff and Student Publications

No abstract provided.

Bayesian Hierarchical Random-Effects Meta-Analysis And Design Of Phase I Clinical Trials, Ruitao Lin, Haolun Shi, Guosheng Yin, Peter F Thall, Ying Yuan, Christopher R Flowers

Faculty, Staff and Student Publications

We propose a curve-free random-effects meta-analysis approach to combining data from multiple phase I clinical trials to identify an optimal dose. Our method accounts for between-study heterogeneity that may stem from different study designs, patient populations, or tumor types. We also develop a meta-analytic-predictive (MAP) method based on a power prior that incorporates data from multiple historical studies into the design and conduct of a new phase I trial. Performances of the proposed methods for data analysis and trial design are evaluated by extensive simulation studies. The proposed random-effects meta-analysis method provides more reliable dose selection than comparators that rely …

Development Of A Distributed International Patient Data Registry For Hairy Cell Leukemia, Leslie A Andritsos, Mirela Anghelina, Jasmine Neal, James S Blachly, Puneet Mathur, Omkar Lele, Claire Dearden, Sunil Iyengar, Matthew Cross, Clive S Zent, Kerry A Rogers, Narendranath Epperla, Gerard Lozanski, Christopher C Oakes, Eric Kraut, Amy S Ruppert, Qiuhong Zhao, Seema A Bhat, Francesco Forconi, Versha Banerji, Sasanka Handunnetti, Constantine S Tam, John F Seymour, Monica Else, Robert J Kreitman, Alan Saven, Timothy Call, Sameer A Parikh, Farhad Ravandi, James B Johnston, Enrico Tiacci, Xavier Troussard, Martin S Tallman, Sascha Dietrich, Tamar Tadmor, Alessandro Gozzetti, Pier Luigi Zinzani, Tadeusz Robak, Graeme Quest, Judit Demeter, Kanti Rai, Soledad A Fernandez, Michael Grever

Faculty, Staff and Student Publications

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand …

Prognostic Impact Of Breslow Thickness In Acral Melanoma: A Retrospective Analysis, Xiaoting Wei, Yu Chen, Hong Yao, Di Wu, Hang Li, Rui Zhang, Zhihong Chi, Chuanliang Cui, Xue Bai, Lili Mao, Zhonghui Qi, Ke Li, Shijie Lan, Lizhu Chen, Rui Guo, Xinyu Yao, Bin Lian, Yan Kong, Jie Dai, Bixia Tang, Xuan Wang, Jeffrey E Gershenwald, Charles M Balch, Jun Guo, Lu Si

Faculty, Staff and Student Publications

Background: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited.

Objective: The objective of the study was to determine the prognostic impact of Breslow thickness in AM.

Methods: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression.

Results: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The …

Neoadjuvant Chemo-Immunotherapy For Lung Cancer: How Much Is Too Much?, Nathaniel Deboever, Jianjun Zhang

Faculty, Staff and Student Publications

No abstract provided.

Direct Cd32 T-Cell Cytotoxicity: Implications For Breast Cancer Prognosis And Treatment, Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli, Gabriele Toietta, Silvia Baldari, Tommaso Sconocchia, Francesca De Paolis, Anna Aureli, Giandomenica Iezzi, Maria Irno Consalvo, Francesco Buccisano, Maria I Del Principe, Luca Maurillo, Adriano Venditti, Alessio Ottaviani, Giulio C Spagnoli

Faculty, Staff and Student Publications

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice …

Statistical Process Control To Monitor Use Of A Web-Based Autoplanning Tool, Hunter Mehrens, Raphael Douglas, Mary Gronberg, Kelly Nealon, Joy Zhang, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To investigate the use of statistical process control (SPC) for quality assurance of an integrated web-based autoplanning tool, Radiation Planning Assistant (RPA).

METHODS: Automatically generated plans were downloaded and imported into two treatment planning systems (TPSs), RayStation and Eclipse, in which they were recalculated using fixed monitor units. The recalculated plans were then uploaded back to the RPA, and the mean dose differences for each contour between the original RPA and the TPSs plans were calculated. SPC was used to characterize the RPA plans in terms of two comparisons: RayStation TPS versus RPA and Eclipse TPS versus RPA for …