Genetic Phenomena Commons^™

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, …

Clinicopathologic Features Of Therapy-Related Myeloid Neoplasms In Patients With Myeloma In The Era Of Novel Therapies, Fatima Zahra Jelloul, Andres E Quesada, Richard K Yang, Shaoying Li, Wei Wang, Jie Xu, Guilin Tang, C Cameron Yin, Hong Fang, Siba El Hussein, Joseph Khoury, Roland L Bassett, Guillermo Garcia-Manero, Elizabet E Manasanch, Robert Z Orlowski, Muzaffar H Qazilbash, Keyur P Patel, L Jeffrey Medeiros, Pei Lin

Faculty, Staff and Student Publications

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed …

Secondary Validation Of An Ovarian Cancer-Specific Comorbidity Index In A Us Population, Chelsey Vranes, Hui Zhao, Mette Calundann Noer, Shuangshuang Fu, Charlotte C Sun, Ross Harrison, Pedro T Ramirez, Claus Kim Høgdall, Sharon H Giordano, Larissa A Meyer

Faculty, Staff and Student Publications

Objectives: The Ovarian Cancer Comorbidity Index (OCCI) is an age-specific index developed and previously found to be more predictive of overall and cancer-specific survival than the Charlson Comorbidity Index (CCI). The objective was to perform secondary validation of the OCCI in a US population.

Methods: A cohort of ovarian cancer patients undergoing primary or interval cytoreductive surgery from January 2005 to January 2012 was identified in SEER-Medicare. OCCI scores were calculated with the regression coefficients determined from the original developmental cohort for five comorbidities. Cox regression analyses were used to calculate associations between the OCCI risk groups and 5-year overall …

Examining Stripes On A Herd Of Zebras: Impact Of Genomic Matching For Ultrarare Sarcomas In Phase 1 Clinical Trials (Samba 102), Justin T Moyers, Roberto Carmagnani Pestana, Jason Roszik, David S Hong, Aung Naing, Siqing Fu, Sarina Piha-Paul, Timothy A Yap, Daniel Karp, Jordi Rodon, Andy Livingston, Maria Alejandra Zarzour, Vinod Ravi, Shreyaskumar Patel, Robert S Benjamin, Joseph Ludwig, Cynthia Herzog, Ravin Ratan, Neeta Somaiah, Anthony Conley, Richard Gorlick, Funda Meric-Bernstam, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Recently, the Connective Tissue Oncology Society published consensus guidelines for recognizing ultrarare sarcomas (URS), defined as sarcomas with an incidence ≤1 per 1,000,000. We assessed the outcomes of 56 patients with soft tissue, and 21 with bone sarcomas, enrolled in Phase 1 trials.

Experimental design: In this Sarcoma-Matched Biomarker Analysis (SAMBA-102 study), we reviewed records from patients on Phase 1 trials at the University of Texas MD Anderson Cancer Center between January 2013 and June 2021.

Results: Among 587 sarcomas, 106 (18.1%) were classified as URS. Fifty (47%) were male, and the median age was 44.3 years (range, 19-82). …

Radiation Therapy Can Be Safely Incorporated Into Pretransplantation Treatment Regimens For Patients With Multiple Myeloma, Ethan P Damron, Muzaffar H Qazilbash, Penny Q Fang, Susan Y Wu, Bouthaina S Dabaja, Gabriela Rondon, Chitra Hosing, Richard E Champlin, Qaiser Bashir, Elizabeth J Shpall, Mark K Knafl, Hans C Lee, Elisabet E Manasanch, Krina Patel, Sheeba K Thomas, Robert Z Orlowski, Donna M Weber, Chelsea C Pinnix, Jillian R Gunther

Faculty, Staff and Student Publications

Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplantation (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. In this study, we retrospectively examined the possible effect of RT on PBPC collection. We reviewed the charts of 732 patients with MM treated with RT at our institution from 1999 to 2017, including patients who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM …

Repeatability And Reproducibility Assessment Of The Apparent Diffusion Coefficient In The Prostate: A Trial Of The Ecog-Acrin Research Group (Acrin 6701), Michael A Boss, Bradley S Snyder, Eunhee Kim, Dena Flamini, Sarah Englander, Karthik M Sundaram, Naveen Gumpeni, Suzanne L Palmer, Haesun Choi, Adam T Froemming, Thorsten Persigehl, Matthew S Davenport, Dariya Malyarenko, Thomas L Chenevert, Mark A Rosen

Faculty, Staff and Student Publications

Background: Uncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion-weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within-subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.

Purpose: Evaluation of the repeatability (same-day) and reproducibility (multi-day) of whole-prostate and focal-lesion ADC assessment in a multi-site setting.

Study type: Prospective multi-institutional.

Subjects: Twenty-nine males, ages 53 to 80 (median 63) …

Urgent Cytoreduction For Newly Diagnosed Acute Myeloid Leukemia Patients Allows Acquisition Of Pretreatment Genomic Data And Enrollment On Investigational Clinical Trials, Kunhwa Kim, Marina Konopleva, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Guilin Tang, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Caitlin R Rausch, Musa Yilmaz, Koji Sasaki, Nicholas J Short, Nitin Jain, Mark Brandt, Sherry Pierce, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did …

Combined Il-2, Agonistic Cd3 And 4–1bb Stimulation Preserve Clonotype Hierarchy In Propagated Non-Small Cell Lung Cancer Tumor-Infiltrating Lymphocytes, Parin Shah, Marie-Andrée Forget, Meredith L Frank, Peixin Jiang, Donastas Sakellariou-Thompson, Lorenzo Federico, Roohussaba Khairullah, Chantal Alexia Neutzler, Ignacio Wistuba, Chi-Wan B Chow, Yan Long, Junya Fujimoto, Shiaw-Yih Lin, Anirban Maitra, Marcelo V Negrao, Kyle Gregory Mitchell, Annikka Weissferdt, Ara A Vaporciyan, Tina Cascone, Jack A Roth, Jianjun Zhang, Boris Sepesi, Don L Gibbons, John V Heymach, Cara L Haymaker, Daniel J Mcgrail, Alexandre Reuben, Chantale Bernatchez

Faculty, Staff and Student Publications

Background: Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) yielded clinical benefit in patients with checkpoint blockade immunotherapy-refractory non-small cell lung cancer (NSCLC) prompting a renewed interest in TIL-ACT. This preclinical study explores the feasibility of producing a NSCLC TIL product with sufficient numbers and enhanced attributes using an improved culture method.

Methods: TIL from resected NSCLC tumors were initially cultured using (1) the traditional method using interleukin (IL)-2 alone in 24-well plates (TIL 1.0) or (2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). TIL subsequently underwent a rapid expansion …

Single-Nuclei Rna-Seq On Human Retinal Tissue Provides Improved Transcriptome Profiling, Qingnan Liang, Rachayata Dharmat, Leah Owen, Akbar Shakoor, Yumei Li, Sangbae Kim, Albert Vitale, Ivana Kim, Denise Morgan, Shaoheng Liang, Nathaniel Wu, Ken Chen, Margaret M Deangelis, Rui Chen

Faculty, Staff and Students Publications

Single-cell RNA-seq is a powerful tool in decoding the heterogeneity in complex tissues by generating transcriptomic profiles of the individual cell. Here, we report a single-nuclei RNA-seq (snRNA-seq) transcriptomic study on human retinal tissue, which is composed of multiple cell types with distinct functions. Six samples from three healthy donors are profiled and high-quality RNA-seq data is obtained for 5873 single nuclei. All major retinal cell types are observed and marker genes for each cell type are identified. The gene expression of the macular and peripheral retina is compared to each other at cell-type level. Furthermore, our dataset shows an …

Aging And Environmental Exposures Alter Tissue-Specific Dna Methylation Dependent Upon Cpg Island Context, Brock C. Christensen, E Andres Houseman, Carmen J. Marsit, Shichun Zheng, Margaret R. Wrensch, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas

Dartmouth Scholarship

Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci …