Medical Genetics Commons^™

Overall Survival With Daratumumab, Lenalidomide, And Dexamethasone In Previously Treated Multiple Myeloma (Pollux): A Randomized, Open-Label, Phase Iii Trial, Meletios A Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San-Miguel, Nizar J Bahlis, Neil Rabin, Kenshi Suzuki, Torben Plesner, Sung-Soo Yoon, Dina Ben Yehuda, Paul G Richardson, Hartmut Goldschmidt, Donna Reece, Tahamtan Ahmadi, Xiang Qin, Wendy Garvin Mayo, Xue Gai, Jodi Carey, Robin Carson, Philippe Moreau

Faculty, Staff and Student Publications

Purpose: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS).

Methods: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, …

Real-Time Liver Tumor Localization Via Combined Surface Imaging And A Single X-Ray Projection, Hua-Chieh Shao, Yunxiang Li, Jing Wang, Steve Jiang, You Zhang

Faculty, Staff and Student Publications

Objective. Real-time imaging, a building block of real-time adaptive radiotherapy, provides instantaneous knowledge of anatomical motion to drive delivery adaptation to improve patient safety and treatment efficacy. The temporal constraint of real-time imaging (< 500 milliseconds) significantly limits the imaging signals that can be acquired, rendering volumetric imaging and 3D tumor localization extremely challenging. Real-time liver imaging is particularly difficult, compounded by the low soft tissue contrast within the liver. We proposed a deep learning (DL)-based framework (Surf-X-Bio), to track 3D liver tumor motion in real-time from combined optical surface image and a single on-board x-ray projection.

Approach. Surf-X-Bio performs mesh-based deformable registration to track/localize liver tumors volumetrically via three steps. First, a DL model was built to estimate liver boundary motion from an optical surface image, using learnt motion correlations between the respiratory-induced external body surface and liver boundary. Second, the residual liver boundary motion estimation error was further corrected by a graph neural network-based DL model, using information extracted from a …

Applications And Clinical Trial Landscape Using Toll-Like Receptor Agonists To Reduce The Toll Of Cancer, Christian Rolfo, Elisa Giovannetti, Pablo Martinez, Shannon Mccue, Aung Naing

Faculty, Staff and Student Publications

Toll-like receptors (TLRs), which serve as a bridge between innate and adaptive immunity, may be viable treatment targets. TLRs are the first line of defense against microbes and activate signaling cascades that induce immune and inflammatory responses. Patients with "hot" versus "cold" tumors may respond more favorably to immune checkpoint inhibition, and through their downstream effects, TLR agonists have the potential to convert "cold tumors" into "hot tumors" making TLRs in combination with immune checkpoint inhibitors, potential targets for cancer therapies. Imiquimod is a topical TLR7 agonist, approved by the FDA for antiviral and skin cancer treatments. Other TLR adjuvants …

Treatment Outcomes For Newly Diagnosed, Treatment-Naïve Tp53-Mutated Acute Myeloid Leukemia: A Systematic Review And Meta-Analysis, Naval G Daver, Shahed Iqbal, Camille Renard, Rebecca J Chan, Ken Hasegawa, Preston Tse, Michael J Zoratti, Feng Xie, Giridharan Ramsingh

Faculty, Staff and Student Publications

Background: TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).

Methods: We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), …

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, Megumi Kai, 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 …

Molecularly Targeted Therapy In Acute Myeloid Leukemia: Current Treatment Landscape And Mechanisms Of Response And Resistance, Curtis A Lachowiez, Courtney D Dinardo, Sanam Loghavi

Faculty, Staff and Student Publications

Treatment for acute myeloid leukemia (AML) has evolved rapidly over the last decade as improved understanding of cytogenetic and molecular drivers of leukemogenesis refined survival prognostication and enabled development of targeted therapeutics. Molecularly targeted therapies are now approved for the treatment of FLT3 and IDH1/2-mutated AML and additional molecularly and cellularly targeted therapeutics are in development for defined patient subgroups. Alongside these welcome therapeutic advancements, increased understanding of leukemic biology and treatment resistance has resulted in clinical trials investigating combinations of cytotoxic, cellular, and molecularly targeted therapeutics resulting in improved response and survival outcomes in patients with AML. Herein, …

Immortalized B Cells Transfected With Mrna Of Antigen Fused To Mitd (Ibmam): An Effective Tool For Antigen-Specific T-Cell Expansion And Tcr Validation, Zhe Wang, Tiantian Zhang, Aaron Anderson, Vincent Lee, Szymon Szymura, Benjamin Kuang, Jingwei Liu, Sattva S Neelapu, Larry Kwak, Soung-Chul Cha

Faculty, Staff and Student Publications

Peripheral mononuclear blood cells (PBMCs) are the most widely used study materials for immunomonitoring and antigen-specific T-cell identification. However, limited patient PBMCs and low-frequency antigen-specific T cells remain as significant technical challenges. To address these limitations, we established a novel platform comprised of optimized HLA-matched immortalized B cells transfected with mRNA of a prototype viral or tumor antigen conjugated to MHC class-I trafficking domain protein (MITD) to increase the efficiency of epitope expression in antigen-presenting cells (APCs) essential to expanding antigen-specific T cells. When applied to CMV as a model, the IBMAM platform could successfully expand CMV-specific T cells from …

Bi-Allelic Tti1 Variants Cause An Autosomal-Recessive Neurodevelopmental Disorder With Microcephaly, Margaux Serey-Gaut, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M R Taylor, Ayat N Asleh, Mohamad A Dar, Amy Mcnamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R Roeder, Rebecca Okashah Littlejohn, Harpreet K Dibra, Philip J Byrd, Grant S Stewart, Bilgen B Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey-Anne Evans, Gabrielle Lemire, Grace E Vannoy, Anne O'Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F Buckley, Christel Thauvin, George K Essien Umanah, Lionel Van Maldergem, James R Lupski, Tony Roscioli, Valina L Dawson, Ted M Dawson, Stylianos E Antonarakis

Faculty, Staff and Student Publications

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of …

Epigenetic-Metabolic Interplay In The Dna Damage Response And Therapeutic Resistance Of Breast Cancer, Chandrima Das, Swagata Adhikari, Apoorva Bhattacharya, Sanjukta Chakraborty, Payel Mondal, Santanu Adhikary, Kamlesh K Yadav, Shruti Pandita, Siddhartha Roy, John A Tainer, Zamal Ahmed, Tej K Pandita

Faculty, Staff and Student Publications

Therapy resistance is imposing a daunting challenge on effective clinical management of breast cancer. Although the development of resistance to drugs is multifaceted, reprogramming of energy metabolism pathways is emerging as a central but heterogenous regulator of this therapeutic challenge. Metabolic heterogeneity in cancer cells is intricately associated with alterations of different signaling networks and activation of DNA damage response pathways. Here we consider how the dynamic metabolic milieu of cancer cells regulates their DNA damage repair ability to ultimately contribute to development of therapy resistance. Diverse epigenetic regulators are crucial in remodeling the metabolic landscape of cancer. This epigenetic-metabolic …

Egr1 Drives Cell Proliferation By Directly Stimulating Tfeb Transcription In Response To Starvation, Marcella Cesana, Gennaro Tufano, Francesco Panariello, Nicolina Zampelli, Susanna Ambrosio, Rossella De Cegli, Margherita Mutarelli, Lorenzo Vaccaro, Micheal J Ziller, Davide Cacchiarelli, Diego L Medina, Andrea Ballabio

Duncan NRI Faculty and Staff Publications

The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the …

New Mouse Models With Hypomorphic Sumf1 Variants Mimic Attenuated Forms Of Multiple Sulfatase Deficiency, Nicolina Cristina Sorrentino, Maximiliano Presa, Sergio Attanasio, Vincenzo Cacace, Martina Sofia, Aamir Zuberi, Jennifer Ryan, Somdatta Ray, Igor Petkovic, Karthikeyan Radhakrishnan, Lars Schlotawa, Andrea Ballabio, Cathleen Lutz, Nicola Brunetti-Pierri

Duncan NRI Faculty and Staff Publications

Multiple sulfatase deficiency (MSD) is an ultrarare lysosomal storage disorder due to deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the enzyme responsible for the post-translational modification and activation of all sulfatases. Most MSD patients carry hypomorph SUMF1 variants resulting in variable degrees of residual sulfatase activities. In contrast, Sumf1 null mice with complete deficiency in all sulfatase enzyme activities, have very short lifespan with significant pre-wean lethality, owing to a challenging preclinical model. To overcome this limitation, we genetically engineered and characterized in mice two commonly …

What Are Risk Factors For And Outcomes Of Late Amputation After Treatment For Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report, Erik J Geiger, Wei Liu, Deo Kumar Srivastava, Nicholas M Bernthal, Brent R Weil, Kirsten K Ness, Robert E Goldsby, Kevin C Oeffinger, Leslie L Robison, Bryan V Dieffenbach, Christopher B Weldon, Mark C Gebhardt, Rebecca Howell, Andrew J Murphy, Wendy M Leisenring, Gregory T Armstrong, Eric J Chow, Rosanna L Wustrack

Faculty, Staff and Student Publications

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.

Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What …

Mitochondrial Structure And Function Adaptation In Residual Triple Negative Breast Cancer Cells Surviving Chemotherapy Treatment, Mokryun L Baek, Junegoo Lee, Katherine E Pendleton, Mariah J Berner, Emily B Goff, Sara A Martinez, Tao Wang, Matthew D Meyer, Bora Lim, James P Barrish, Weston Porter, Philip L Lorenzi, Gloria V Echeverria

Faculty, Staff and Student Publications

Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in ~45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents …

An Extension Of Estimating Equations To Model Longitudinal Medical Cost Trajectory With Medicare Claims Data Linked To Seer Cancer Registry, Shikun Wang, Jing Ning, Ying Xu, Ya-Chen Tina Shih, Y U Shen

Faculty, Staff and Student Publications

Insurance claims data is an increasingly important health policy research resource, given its longitudinal assessment of cancer care clinical outcomes. Population-level information on medical cost trajectory from disease diagnosis to terminal events, such as death, specifically interests policy makers. Estimating the mean cost trajectory has statistical challenges. The shape of the trajectory is usually highly nonlinear with varying durations, depending on the diagnosis-to-death population time distribution. The terminal event may be right censored, resulting in missing subsequent costs. Medical costs often have skewed distributions with zero-inflation and heteroscedasticity, which may not fit well with the commonly used parametric family of …

Highly Synchronized Cortical Circuit Dynamics Mediate Spontaneous Pain In Mice, Weihua Ding, Lukas Fischer, Qian Chen, Ziyi Li, Liuyue Yang, Kun Hu, Xue Zhou, Wei Chao, Peter Hu, Tewodros Mulugeta Dagnew, Daniel M Dubreuil, Shiyu Wang, Suyun Xia, Caroline Bao, Shengmei Zhu, Lucy Chen, Changning Wang, Brian Wainger, Peng Jin, Jianren Mao, Guoping Feng, Mark T Harnett, Shiqian Shen

Faculty, Staff and Student Publications

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a "normal" operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized …

Prospective Study Of Pain Outcomes Associated With Breast Surgery In Women With Nonhereditary Breast Cancer, Demetria J Smith-Graziani, Patricia A Parker, Susan K Peterson, Isabelle Bedrosian, Y Shen, Sarah M Desnyder, Wenli Dong, Abenaa M Brewster

Faculty, Staff and Student Publications

Objective: To assess pain severity and interference with life in women after different types of breast cancer surgery and the demographic, treatment-related, and psychosocial variables associated with these pain outcomes.

Summary of background data: Data are conflicting regarding pain outcomes and quality of life (QOL) among women who undergo different types of breast surgery.

Methods: Women with nonhereditary breast cancer completed the brief pain inventory before surgery and at 1, 6, 12, and 18 months postsurgery. We assessed associations between pain outcomes and CPM status and mastectomy status using multivariable repeated measures models. We assessed associations between pain outcome and …

Stem Cell Mobilization Yields With Daratumumab- And Lenalidomide-Containing Quadruplet Induction Therapy In Newly Diagnosed Multiple Myeloma: Findings From The Master And Griffin Trials, Saurabh Chhabra, Natalie Callander, Nicole L Watts, Luciano J Costa, Bicky Thapa, Jacob Laubach, Brandi Reeves, Cesar Rodriguez, Ajai Chari, Rebecca Silbermann, Larry D Anderson, Susan Bal, Binod Dhakal, Nitya Nathwani, Nina Shah, Eva Medvedova, Naresh Bumma, Sarah A Holstein, Caitlin Costello, Andrzej Jakubowiak, Tanya M Wildes, Timothy Schmidt, Robert Z Orlowski, Kenneth H Shain, Andrew J Cowan, Bhagirathbhai Dholaria, R Frank Cornell, James H Jerkins, Huiling Pei, Annelore Cortoos, Sharmila Patel, Thomas S Lin, Saad Z Usmani, Paul G Richardson, Peter M Voorhees

Faculty, Staff and Student Publications

For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT. Therefore, we assessed stem cell mobilization in patients following frontline induction therapy in the MASTER and GRIFFIN phase 2 clinical studies by examining stem …

Clinical Outcomes Of Combined Cervical And Transthoracic Surgical Approaches In Patients With Advanced Thyroid Cancer, Jared A Shenson, Mark E Zafereo, Mark Lee, Kevin J Contrera, Lei Feng, Neil Gross, Anastasios Maniakas, Jennifer Rui Wang, Libby Grubbs, Ara Vaporciyan, Wayne Hofstetter, Stephen Swisher, Reza Mehran, David Rice, Boris Sepesi, Mara Antonoff, Maria Cabanillas, Naifa Busaidy, Ramona Dadu, Natalie L Silver

Faculty, Staff and Student Publications

Background: Advanced thyroid disease involving the mediastinum may be managed surgically with a combined transcervical and transthoracic approach. Contemporary analysis of this infrequently encountered cohort will aid the multidisciplinary team in personalizing treatment approaches.

Methods: Retrospective review of patients undergoing combined transcervical and transthoracic surgery for thyroid cancer at a single high-volume institution from 1994 to 2015.

Results: Thirty-eight patients with median age 59 years (range 28-76) underwent surgery without perioperative mortality. Most patients had primary disease. A majority had distant metastases outside the mediastinum but had locoregionally curable disease. Common complications were temporary (39%) and permanent (18%) hypoparathyroidism, and …

Treatment Of Cancer-Related-Fatigue In Acute Hematological Malignancies: Results Of A Feasibility Study Of Using Cognitive Behavioral Therapy, Sriram Yennurajalingam, Marina Konopleva, Cindy L Carmack, Courtney D Dinardo, Melissa Gaffney, Zhanni Lu, Jing Ning, Wei Qiao, Eduardo Bruera

Faculty, Staff and Student Publications

Background: Despite cancer related fatigue (CRF) being the most common, and debilitating symptom in patients with recently diagnosed acute hematological malignancies (HM), there are limited effective treatments for CRF in HM. The aim of this study was to determine the feasibility of cognitive behavioral therapy (CBT) for CRF in HM.

Methods: In this preliminary longitudinal prospective study, HM patients diagnosed a median of one month previously with moderate to severe fatigue were enrolled. Patients received CBT in seven weekly sessions for eight weeks. Change in Functional Assessment of Cancer Illness Therapy (FACIT) - Fatigue (primary), FACT-G, Pittsburg Sleep Quality Index …

Dysphagia And Shortness-Of-Breath As Markers For Treatment Failure And Survival In Oropharyngeal Cancer After Radiation, Jarey H Wang, Vivian Salama, Lance Mccoy, Cem Dede, Temitayo Ajayi, Abdallah S R Mohamed, Clifton David Fuller, Lisanne V Van Dijk, Md Anderson Head And Neck Symptom Working Group

Faculty, Staff and Student Publications

Background: Post-treatment symptoms are a focal point of follow-up visits for head and neck cancer patients. While symptoms such as dysphagia and shortness-of-breath early after treatment may motivate additional work up, their precise association with disease control and survival outcomes is not well established.

Methods: This prospective data cohort study of 470 oropharyngeal cancer patients analyzed patient-reported swallowing, choking and shortness-of-breath symptoms at 3-to-6 months following radiotherapy to evaluate their association with overall survival and disease control. Associations between the presence of moderate-to-severe swallowing, choking and mild-to-severe shortness-of-breath and treatment outcomes were analyzed via Cox regression and Kaplan-Meier. The main …

Burn Resuscitation Practices In North America: Results Of The Acute Burn Resuscitation Multicenter Prospective Trial (Abrupt), David G Greenhalgh, Robert Cartotto, Sandra L Taylor, Jeffrey R Fine, Giavonni M Lewis, Michael A Marano, Lucy A Wibbenmeyer, James H Holmes, Julie A Rizzo, Kevin N Foster, Anjay Khandelwal, Sarah Fischer, Mark R Hemmila, David Hill, Ariel M Aballay, Edward E Tredget, Jeremy Goverman, Herbert Phelan, Carlos J Jimenez, Anthony Baldea, Rajiv Sood

Faculty, Staff and Student Publications

Objectives: ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial.

Summary background data: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation.

Methods: Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols.

Results: Of 379 enrollees, two-thirds (253) were resuscitated with …

On Target Methods To Induce Abscopal Phenomenon For Off-Target Effects: From Happenstance To Happenings, Blessie Elizabeth Nelson, Jacob J Adashek, Steven H Lin, Vivek Subbiah

Faculty, Staff and Student Publications

Although the "abscopal phenomenon" has been described several decades ago, this phenomenon lately has been obtaining momentous traction with the dawn of immune-based therapies. There has been increased cross talk among radiation oncologists, oncologists and immunologists and consequently a surge in the number of prospective clinical trials. This must be coupled with translation work from these clinical trials to aid in eventual identification of patients who may benefit. Abscopal effects may be induced by local and systemic methods, conventional radiotherapy, particle radiation, radionucleotide methods, cryoablation and brachytherapy. These approaches have all been reported to be stimulate abscopal effect. Immune induction …

Systemic Lupus Erythematosus And Mortality In Elderly Patients With Early Breast Cancer, Sebastian Bruera, Xiudong Lei, Xerxes Pundole, Hui Zhao, Sharon H Giordano, Maria E Suarez-Almazor

Faculty, Staff and Student Publications

Objective: Patients with cancer and systemic lupus erythematosus (SLE) may have worse outcomes than those without SLE, given their comorbidities. We examined survival in elderly women with breast cancer (BC) and SLE and hypothesized that survival would be decreased compared with women with BC but without SLE.

Methods: We identified patients with BC and SLE and patients with BC without SLE in the Texas Cancer Registry and Surveillance, Epidemiology, and End Results, linked to Medicare claims. Overall survival (OS) was estimated after matching (age and cancer stage) and in multivariable Cox proportional hazards models adjusting for other cancer characteristics, treatment, …

A Phase 1 Study Of Idh305 In Patients With Idh1 R132-Mutant Acute Myeloid Leukemia Or Myelodysplastic Syndrome, Courtney D Dinardo, Andreas Hochhaus, Mark G Frattini, Karen Yee, Thomas Zander, Xueying Chen, Nehal S Parikh, Joanne Choi, Andrew H Wei

Faculty, Staff and Student Publications

Purpose: Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Methods: IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting …

Elastic Priors To Dynamically Borrow Information From Historical Data In Clinical Trials, Liyun Jiang, Lei Nie, Ying Yuan

Faculty, Staff and Student Publications

Use of historical data and real-world evidence holds great potential to improve the efficiency of clinical trials. One major challenge is to effectively borrow information from historical data while maintaining a reasonable type I error and minimal bias. We propose the elastic prior approach to address this challenge. Unlike existing approaches, this approach proactively controls the behavior of information borrowing and type I errors by incorporating a well-known concept of clinically significant difference through an elastic function, defined as a monotonic function of a congruence measure between historical data and trial data. The elastic function is constructed to satisfy a …

Frontline Combination Of Ponatinib And Hyper-Cvad In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: 80-Months Follow-Up Results, Hagop Kantarjian, Nicholas J Short, Nitin Jain, Koji Sasaki, Xuelin Huang, Issa Khouri, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Partow Kebriaei, Rebecca Garris, Sanam Loghavi, Jeffrey Jorgensen, Monica Kwari, Susan O'Brien, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

Background:

The combination of ponatinib, a third generation BCR::ABL1 tyrosine kinase inhibitor (TKI), with Hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for SCT in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients followed with longer follow-up would establish this regimen as a new standard of care.

Methods:

Adults with newly diagnosed Ph-positive ALL were treated with the Hyper-CVAD regimen. Ponatinib was added as 45 mg daily x 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily …

Effect Of Neoadjuvant Chemotherapy On Intraoperative Core Temperature In Patients With Breast Cancer: A Retrospective Cohort Study, Daniel D Kim, Sarah M Desnyder, Patrick M Dougherty, Juan P Cata

Faculty, Staff and Student Publications

Background: Clinical evidence suggests that chemotherapeutic agents are associated with neuropathy and peripheral autonomic dysfunction. However, the possible effects of neoadjuvant chemotherapy on intraoperative temperature remain poorly characterised.

Methods: We evaluated patients who underwent a mastectomy for breast cancer between April 2016 and July 2020. Propensity scores were used to match patients who received neoadjuvant chemotherapy with those who did not, and intraoperative core temperature patterns were analysed in the matched cohort. The independent associations between vasopressor use and heart rate during general anaesthesia in the matched cohort were also analysed.

Results: Data from 1764 patients were analysed (882 patients …

Predictors Of Emergency Room Visits After Ambulatory Breast Cancer Surgery In The Medicare Population, Susie X Sun, Zhigang Duan, Henry M Kuerer, Sarah M Desnyder, Carrie Cunningham, Sharon H Giordano

Faculty, Staff and Student Publications

Background: Emergency department (ED) overuse is a large contributor to healthcare spending in the USA. We examined the rate of and risk factors for ED visits following outpatient breast cancer surgery.

Patients and methods: Using linked data from the Surveillance, Epidemiology, and End Results (SEER) program and Medicare, we identified women who underwent curative breast cancer surgery between 2003 and 2015. Our outcome of interest was ED visits within 30 days of surgery. Multivariate regression was used to evaluate the odds of ED visit while controlling for clinical and socioeconomic variables. Secondary analyses assessed admission from the ED as well …

Integrative Bioinformatic Analysis Of P53 And Pathway Alterations In Two Different Lung Cancer Subtypes, Yun Zhang, Abie Williams-Villalobo, Jyotsna D Godavarthi, Faith Shakoor, Shunbin Xiong

Faculty, Staff and Student Publications

Whether p53, either wild type (WT) or mutant, plays cell-specific or uniform role remains controversial. Using The Cancer Genome Atlas, we examined p53 in the lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), two lung cancers with different cellular origins and frequent p53 mutation (52% and 83%, respectively). Mutant p53 more strongly correlates with different genomic alteration and protein expression profiles in LUAD than in LUSC. p53 mutation in LUAD and LUSC is associated with multiple exacerbated clinical outcomes. Although the presence of p53 mutation does not change the survival of LUAD patients, LUSC patients containing p53 mutation exhibit …

Common Kinase Mutations Do Not Impact Optimal Molecular Responses In Core Binding Factor Acute Myeloid Leukemia Treated With Fludarabine, Cytarabine, And G-Csf Based Regimens, Jayastu Senapati, Tareq Abuasab, Fadi G Haddad, Farhad Ravandi, Tapan Kadia, Naval Daver, Yesid Alvarado, Mark A Brandt, Hagop Kantarjian, Gautam Borthakur

Faculty, Staff and Student Publications

No abstract provided.