Medical Genetics Commons^™

Eliminating Breast Surgery For Invasive Cancer With Exceptional Response To Neoadjuvant Systemic Therapy: Prospective Multicenter Clinical Trial Planned Initial Feasibility Endpoint, Helen M Johnson, Vicente Valero, Wei T Yang, Benjamin D Smith, Savitri Krishnamurthy, Yu Shen, Heather Lin, Anthony Lucci, Gaiane M Rauch, Henry M Kuerer

Faculty, Staff and Student Publications

Background: Response to neoadjuvant systemic therapy (NST) for breast cancer enables tailoring of subsequent therapy. Image-guided breast biopsy after NST can accurately predict a pathologic complete response (pCR). The feasibility phase of the clinical trial reported here assesses omission of breast surgery followed by radiotherapy in terms of local recurrence before trial expansion.

Study design: Women with unicentric, cT1-2 N0-1 M0 triple-negative (TNBC) or human epidermal growth factor receptor 2-positive breast cancer (HER2+BC) cancer with < 2 cm residual disease on post-NST imaging were eligible to enroll. If no residual invasive or in situ disease was identified by image-guided, vacuum-assisted core biopsy (VACB), breast surgery was omitted, and radiotherapy delivered. The primary endpoint for the feasibility phase was ipsilateral breast tumor recurrence at 6 months. If any recurrence occurred during the feasibility phase the trial would halt.

Results: Thirteen patients were enrolled from March 2017 to October 2018. The mean age was 60.8 years (range 51 to 75) and most patients were …

Carboplatin Dosing In The Treatment Of Ovarian Cancer: An Nrg Oncology Group Study, Aaron M Praiss, Austin Miller, Judith Smith, Stuart M Lichtman, Michael Bookman, Carol Aghajanian, Paul Sabbatini, Floor Backes, David E Cohn, Peter Argenta, Michael Friedlander, Michael J Goodheart, David G Mutch, David M Gershenson, Krishnansu S Tewari, Robert M Wenham, Andrea E Wahner Hendrickson, Roger B Lee, Heidi Gray, Angeles Alvarez Secord, Linda Van Le, Roisin E O'Cearbhaill

Faculty, Staff and Student Publications

Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl).

Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity …

Association Of Second-Generation Antiandrogens With Cognitive And Functional Toxic Effects In Randomized Clinical Trials: A Systematic Review And Meta-Analysis, Malgorzata K Nowakowska, Rachel M Ortega, Mackenzie R Wehner, Kevin T Nead

Faculty, Staff and Student Publications

Importance: The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed.

Objective: To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects.

Data sources: PubMed, EMBASE, and Scopus (inception to September 12, 2022).

Study selection: Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, …

Prognostic Factors For Pediatric, Adolescent, And Young Adult Patients With Non-Dipg Grade 4 Gliomas: A Contemporary Pooled Institutional Experience, Jennifer K Matsui, Pamela K Allen, Haley K Perlow, Jason M Johnson, Arnold C Paulino, Mary Frances Mcaleer, Maryam Fouladi, David R Grosshans, Amol J Ghia, Jing Li, Wafik T Zaky, Murali M Chintagumpala, Joshua D Palmer, Susan L Mcgovern

Faculty, Staff and Student Publications

Purpose: WHO grade 4 gliomas are rare in the pediatric and adolescent and young adult (AYA) population. We evaluated prognostic factors and outcomes in the pediatric versus AYA population.

Methods: This retrospective pooled study included patients less than 30 years old (yo) with grade 4 gliomas treated with modern surgery and radiotherapy. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis.

Results: Ninety-seven patients met criteria with median age 23.9 yo at diagnosis. Seventy-seven patients were ≥ 15 yo (79%) and 20 patients were < 15 yo (21%). Most had biopsy-proven glioblastoma (91%); the remainder had H3 K27M-altered diffuse midline glioma (DMG; 9%). All patients received surgery and radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection (GTR) was associated with better PFS in multivariate analysis [HR 2.00 (1.01-3.62), p = 0.023]. Age ≥ 15 yo was associated with improved OS [HR 0.36 (0.16-0.81), p = 0.014] while female gender [HR 2.12 (1.08-4.16), p = 0.03] and DMG histology [HR 2.79 (1.11-7.02), p = 0.029] were associated with worse OS. Only 7% of patients experienced grade 2 toxicity. 62% of patients experienced tumor progression (28% local, 34% distant). Analysis of salvage treatment found that second surgery and systemic therapy significantly improved survival.

Conclusion: Age is a significant prognostic factor in WHO grade …

Route Of Delivery Does Not Impact Postnatal Surgical Morbidity In Pregnancies Affected By Fetal Achondroplasia, Bobby K Brar, Michael B Bober, Ethan Gough, S Shahrukh Hashmi, Jacqueline T Hecht, Lorena Dujmusic, Mary E Little, Peggy Modaff, Richard M Pauli, David F Rodriguez-Buritica, Maria E Serna, Cory Smid, Janet M Legare, Julie E Hoover-Fong

Faculty, Staff and Student Publications

Purpose: Pregnancies affected by maternal or fetal achondroplasia present unique challenges. The optimal route of delivery in fetuses with achondroplasia has not been established. Our objective was to determine whether the route of delivery affects postnatal achondroplasia-related surgical burden.

Methods: We conducted a secondary analysis of Achondroplasia Natural History Study (CLARITY), which is a multicenter natural history cohort study of patients with achondroplasia. Achondroplasia-related surgical morbidity, which we defined as the need for one or more postnatal achondroplasia-related surgeries, was assessed in relation to the route of delivery and whether the mother also had achondroplasia. Rate of each individual surgery …

A Cre Driver Line For Genetic Targeting Of Kappa Opioid Receptor Expressing Cells, Franciely Paliarin, Chelsea Duplantis, Andrea F Jones, Jessica Cucinello-Ragland, Samhita Basavanhalli, Emily Blaze, Evan Doré, Anna Isabella Neel, Haiguo Sun, Rong Chen, Scott Edwards, Nicholas W Gilpin, Robert O Messing, Rajani Maiya

Faculty, Staff and Student Publications

Here we describe the generation and characterization of a Cre knock-in mouse line that harbors a Cre insertion in the 3′UTR of the κ opioid receptor gene (Oprk1) locus and provides genetic access to populations of κ opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre …

Pontocerebellar Hypoplasia Associated With Parg183trp Homozygous Variant In Exosc1 Gene: A Case Report, Nadirah S Damseh, Ali N Obeidat, Khondakar Sayef Ahammed, Motee Al-Ashhab, Motee Abu Awad, Ambro Van Hoof

Faculty, Staff and Student Publications

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders characterized by a wide phenotypic range including severe motor and cognitive impairments, microcephaly, distinctive facial features, and other features according to the type. Several classes of PCH1 have been linked to mutations in the evolutionarily conserved RNA exosome complex that consists of nine subunits (EXOSC1 to EXOSC9) and facilitates the degradation and processing of cytoplasmic and nuclear RNA from the 3' end. Only a single individual with an EXOSC1 mutation was reported with clinical features of PCH type 1 (PCH1F). Here, we report a 3-month-old female with PCH and …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Yan Wang, Roger Lopez-Bellido, Xiaojiao Huo, Annemieke Kavelaars, Michael J Galko

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent …

Clinical Significance And Biology Of Circulating Tumor Dna In High-Risk Early-Stage Her2-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy, Mark Jesus M Magbanua, Lamorna Brown Swigart, Ziad Ahmed, Rosalyn W Sayaman, Derrick Renner, Ekaterina Kalashnikova, Gillian L Hirst, Christina Yau, Denise M Wolf, Wen Li, Amy L Delson, Smita Asare, Minetta C Liu, Kathy Albain, A Jo Chien, Andres Forero-Torres, Claudine Isaacs, Rita Nanda, Debu Tripathy, Angel Rodriguez, Himanshu Sethi, Alexey Aleshin, Matthew Rabinowitz, Jane Perlmutter, W Fraser Symmans, Douglas Yee, Nola M Hylton, Laura J Esserman, Angela M Demichele, Hope S Rugo, Laura J Van 'T Veer

Faculty, Staff and Student Publications

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival …

Leveraging Mid-Infrared Spectroscopic Imaging And Deep Learning For Tissue Subtype Classification In Ovarian Cancer, Chalapathi Charan Gajjela, Matthew Brun, Rupali Mankar, Sara Corvigno, Noah Kennedy, Yanping Zhong, Jinsong Liu, Anil K Sood, David Mayerich, Sebastian Berisha, Rohith Reddy

Faculty, Staff and Student Publications

Mid-infrared spectroscopic imaging (MIRSI) is an emerging class of label-free techniques being leveraged for digital histopathology. Modern histopathologic identification of ovarian cancer involves tissue staining followed by morphological pattern recognition. This process is time-consuming and subjective and requires extensive expertise. This paper presents the first label-free, quantitative, and automated histological recognition of ovarian tissue subtypes using a new MIRSI technique. This optical photothermal infrared (O-PTIR) imaging technique provides a 10× enhancement in spatial resolution relative to prior instruments. It enables sub-cellular spectroscopic investigation of tissue at biochemically important fingerprint wavelengths. We demonstrate that the enhanced resolution of sub-cellular features, combined …

Targeting Cxcr4 Abrogates Resistance To Trastuzumab By Blocking Cell Cycle Progression And Synergizes With Docetaxel In Breast Cancer Treatment, Shuying Liu, Shelly M Xie, Wenbin Liu, Mihai Gagea, Ariella B Hanker, Nguyen Nguyen, Akshara Singareeka Raghavendra, Gloria Yang-Kolodji, Fuliang Chu, Sattva S Neelapu, Adriano Marchese, Samir Hanash, Johann Zimmermann, Carlos L Arteaga, Debasish Tripathy

Faculty, Staff and Student Publications

Background: Although trastuzumab and other HER2-targeted therapies have significantly improved survival in patients with HER2 overexpressed or amplified (HER2+) breast cancer, a significant proportion of patients do not respond or eventually develop clinical resistance. Strategies to reverse trastuzumab resistance remain a high clinical priority. We were the first to report the role of CXCR4 in trastuzumab resistance. The present study aims to explore the therapeutic potential of targeting CXCR4 and better understand the associated mechanisms.

Methods: Immunofluorescent staining, confocal microscopy analysis, and immunoblotting were used to analyze CXCR4 expression. BrdU incorporation assays and flow cytometry were used to analyze dynamic …

17Β-Estradiol Promotes Extracellular Vesicle Release And Selective Mirna Loading In Erα-Positive Breast Cancer, Rares Drula, Barbara Pardini, Xiao Fu, Mireia Cruz De Los Santos, Ancuta Jurj, Lan Pang, Sherien M El-Daly, Linda Fabris, Erik Knutsen, Mihnea P Dragomir, Recep Bayraktar, Yongfeng Li, Meng Chen, Filippo Del Vecchio, Léa Berland, Jessica Dae, Daniel Fan, Masayoshi Shimizu, Anh M Tran, Mercedes Barzi, Carlotta Pioppini, Angelica M Gutierrez, Cristina Ivan, Salyna Meas, Carolyn S Hall, Suresh K Alahari, Ioana Berindan-Neagoe, Muller Fabbri, Anthony Lucci, Banu Arun, Simone Anfossi, George A Calin

Faculty, Staff and Student Publications

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor-positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7's miRNAs into EVs. In multiple patient cohorts, …

Tubectomy With Delayed Oophorectomy As An Alternative To Risk-Reducing Salpingo-Oophorectomy In High-Risk Women To Assess The Safety Of Prevention: The Tuba-Wisp Ii Study Protocol, Miranda P Steenbeek, Majke H D Van Bommel, Joanna Inthout, Christine B Peterson, Michiel Simons, Kit C B Roes, Marleen Kets, Barbara M Norquist, Elizabeth M Swisher, Rosella P M G Hermens, Tuba-Wisp Ii Consortium, Karen H Lu, Joanne A De Hullu

Faculty, Staff and Student Publications

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) …

Machine Learning Reveals Lipidome Remodeling Dynamics In A Mouse Model Of Ovarian Cancer, Olatomiwa O Bifarin, Samyukta Sah, David A Gaul, Samuel G Moore, Ruihong Chen, Murugesan Palaniappan, Jaeyeon Kim, Martin M Matzuk, Facundo M Fernández

Faculty, Staff and Students Publications

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. …

Clinical Implications Of Tumor-Based Next-Generation Sequencing In High-Grade Epithelial Ovarian Cancer, Katherine I Foster, Kenna R M Shaw, Jeff Jin, Shannon N Westin, Timothy A Yap, Deanna M Glassman, Amir A Jazaeri, Jose A Rauh-Hain, Sanghoon Lee, Bryan M Fellman, Zhenlin Ju, Yuexin Liu, Nicole D Fleming, Anil K Sood

Faculty, Staff and Student Publications

Background: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer.

Methods: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox …

Cumulative Burden Of Late, Major Surgical Intervention In Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study (Ccss) Cohort, Bryan V Dieffenbach, Andrew J Murphy, Qi Liu, Duncan C Ramsey, Erik J Geiger, Lisa R Diller, Rebecca M Howell, Kevin C Oeffinger, Leslie L Robison, Yutaka Yasui, Gregory T Armstrong, Eric J Chow, Brent R Weil, Christopher B Weldon

Faculty, Staff and Student Publications

Background: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions.

Methods: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in …

Society For Immunotherapy Of Cancer (Sitc) Clinical Practice Guideline On Immunotherapy For The Treatment Of Gynecologic Cancer, Mary L Disis, Sarah F Adams, Jyoti Bajpai, Marcus O Butler, Tyler Curiel, Shelley A Dodt, Laura Doherty, Leisha A Emens, Claire F Friedman, Margaret Gatti-Mays, Melissa A Geller, Amir Jazaeri, Veena S John, Katherine C Kurnit, John B Liao, Haider Mahdi, Anne Mills, Emese Zsiros, Kunle Odunsi

Faculty, Staff and Student Publications

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, …

Lenvatinib Plus Pembrolizumab In Previously Treated Advanced Endometrial Cancer: Updated Efficacy And Safety From The Randomized Phase Iii Study 309/Keynote-775, Vicky Makker, Nicoletta Colombo, Antonio Casado Herráez, Bradley J Monk, Helen Mackay, Alessandro D Santin, David S Miller, Richard G Moore, Sally Baron-Hay, Isabelle Ray-Coquard, Kimio Ushijima, Kan Yonemori, Yong Man Kim, Eva M Guerra Alia, Ulus A Sanli, Steven Bird, Robert Orlowski, Jodi Mckenzie, Chinyere Okpara, Gianmaria Barresi, Domenica Lorusso

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

We report the final prespecified analysis for overall survival (OS), along with updated progression-free survival (PFS) and objective response rate (ORR), and safety from the open-label, randomized, phase III Study 309/KEYNOTE-775. In total, 827 patients with advanced, …

2021 Aapm Equity, Diversity, And Inclusion Climate Survey Executive Summary, Kristi R G Hendrickson, Stephen M Avery, Richard Castillo, Laura Cervino, Ashley Cetnar, Nolan L Gagne, Wendy Harris, Amirh Johnson, Megan E Lipford, Nadia Octave, Kelly C Paradis, Angélica Pérez-Andújar, Surendra Prajapati, Julianne Pollard-Larkin

Faculty, Staff and Student Publications

Purpose: The American Association of Physicists in Medicine (AAPM) shares the results, conclusions, and recommendations from the initial Equity, Diversity, and Inclusion Climate Survey conducted in 2021.

Methods and materials: The climate survey targeted medical physicists who are full members of the AAPM and included demographic inquiries and questions intended to assess the working environmental climate in terms of a sense of belonging and inclusion, experiences of discrimination and harassment, and obstacles to participation within the AAPM. The survey invitation was sent to 5,500 members. Responses were collected from 1385 members (response rate of 25%) between January and February 2021. …

X-Linked Variations In Shroom4 Are Implicated In Congenital Anomalies Of The Urinary Tract And The Anorectal, Cardiovascular And Central Nervous Systems, Caroline M. Kolvenbach, Tim Felger, Luca Schierbaum, Isabelle Thiffault, T Pastinen, Maria Szczepańska, Marcin Zaniew, Piotr Adamczyk, Allan Bayat, Öznur Yilmaz, Tobias T. Lindenberg, Holger Thiele, Friedhelm Hildebrandt, Katrin Hinderhofer, Ute Moog, Alina C Hilger, Bonnie Sullivan, Lauren E. Bartik, Piotr Gnyś, Phillip Grote, Benjamin Odermatt, Heiko M. Reutter, Gabriel C. Dworschak

Manuscripts, Articles, Book Chapters and Other Papers

Background: SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system.

Methods: Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development.

Results: In this study, we identified putative …

Targeting Chemotherapy Resistance In Mesenchymal Triple-Negative Breast Cancer: A Phase Ii Trial Of Neoadjuvant Angiogenic And Mtor Inhibition With Chemotherapy, Nour Abuhadra, Ryan Sun, Roland L Bassett, Lei Huo, Jeffrey T Chang, Mediget Teshome, Alyson R Clayborn, Jason B White, Elizabeth E Ravenberg, Beatriz E Adrada, Rosalind P Candelaria, Wei Yang, Qingqing Ding, W Fraser Symmans, Banu Arun, Senthil Damodaran, Kimberly B Koenig, Rachel M Layman, Bora Lim, Jennifer K Litton, Alastair Thompson, Naoto T Ueno, Helen Piwnica-Worms, Gabriel N Hortobagyi, Vicente Valero, Debu Tripathy, Gaiane M Rauch, Stacy Moulder, Clinton Yam

Faculty, Staff and Student Publications

Background:: Metaplastic histology and mesenchymal differentiation have been associated with chemotherapy resistance in triple-negative breast cancer (TNBC). In the neoadjuvant setting, suboptimal on-treatment clinical response to chemotherapy is associated with low rates of pathological complete response (pCR). Given the previously demonstrated activity of pegylated liposomal doxorubicin, bevacizumab, and mTOR inhibition with temsirolimus (DAT) or everolimus (DAE) in metastatic, metaplastic TNBC, we conducted a phase II study of DAT/DAE as the second phase of neoadjuvant therapy in patients with metaplastic and/or mesenchymal TNBC experiencing suboptimal clinical response to neoadjuvant doxorubicin and cyclophosphamide (AC) (NCT02456857).

Patients and Methods:: Patients received …

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 …

A Phase Ii Study Of Neoadjuvant Atezolizumab And Nab-Paclitaxel In Patients With Anthracycline-Resistant Early-Stage Triple-Negative Breast Cancer, Clinton Yam, Elizabeth A Mittendorf, Haven R Garber, Ryan Sun, Senthil Damodaran, Rashmi K Murthy, David Ramirez, Meghan Karuturi, Rachel M Layman, Nuhad Ibrahim, Gaiane M Rauch, Beatriz E Adrada, Rosalind P Candelaria, Jason B White, Elizabeth Ravenberg, Alyson Clayborn, Qing Qing Ding, W Fraser Symmans, Sabitha Prabhakaran, Alastair M Thompson, Vicente Valero, Debu Tripathy, Lei Huo, Stacy L Moulder, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489).

Methods: Patients …

Mini-Hyper-Cvd Plus Inotuzumab Ozogamicin, With Or Without Blinatumomab, In The Subgroup Of Older Patients With Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphocytic Leukaemia: Long-Term Results Of An Open-Label Phase 2 Trial, Elias Jabbour, Nicholas J Short, Jayastu Senapati, Nitin Jain, Xuelin Huang, Naval Daver, Courtney D Dinardo, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Guillermo Montalban Bravo, Koji Sasaki, Tapan M Kadia, Joseph Khoury, Sa A Wang, Fadi G Haddad, Jovitta Jacob, Rebecca Garris, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

Background: The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients.

Methods: For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The …

Implication Of Chromosomal Microarray Analysis Prior To In-Utero Repair Of Fetal Open Neural Tube Defect, R Zemet, E Krispin, R M Johnson, N R Kumar, L E Westerfield, S Stover, D G Mann, J Castillo, H A Castillo, A A Nassr, M Sanz Cortes, R Donepudi, J Espinoza, W E Whitehead, M A Belfort, A A Shamshirsaz, I B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Objective: In-utero repair of open neural tube defects (ONTD) is an accepted treatment option with demonstrated superior outcome for eligible patients. While current guidelines recommend genetic testing by chromosomal microarray analysis (CMA) when a major congenital anomaly is detected prenatally, the requirement for an in-utero repair, based on the Management of Myelomeningocele Study (MOMS) criteria, is a normal karyotype. In this study, we aimed to evaluate if CMA should be recommended as a prerequisite for in-utero ONTD repair.

Methods: This was a retrospective cohort study of pregnancies complicated by ONTD that underwent laparotomy-assisted fetoscopic repair or open-hysterotomy fetal surgery at …

Racial/Ethnic Disparities In Cervical Cancer Stage At Diagnosis: Mediating Effects Of Neighborhood-Level Socioeconomic Deprivation, Itunu O Sokale, Abiodun O Oluyomi, Jane R Montealegre, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND: Mortality from cervical cancer has declined steadily in the United States over the past several decades due to widespread screening for precancerous and early-stage cervical cancer (ECC), which are significantly easier to treat compared with late-stage cervical cancer (LCC). Unequal screening access continues to cause significant racial/ethnic disparities in cervical cancer diagnosis stage. This study examined the underlying role of neighborhood-level socioeconomic disadvantage as a potential mediator of the association between race/ethnicity and cervical cancer diagnosis stage.

METHODS: We analyzed Texas Cancer Registry data for cervical cancer cases diagnosed among women ages 18 or older from 2010 to 2018. …

Functional Variants Identify Sex-Specific Genes And Pathways In Alzheimer’S Disease, Thomas Bourquard, Kwanghyuk Lee, Ismael Al-Ramahi, Minh Pham, Dillon Shapiro, Yashwanth Lagisetty, Shirin Soleimani, Samantha Mota, Kevin Wilhelm, Maryam Samieinasab, Young Won Kim, Eunna Huh, Jennifer Asmussen, Panagiotis Katsonis, Juan Botas, Olivier Lichtarge

Faculty, Staff and Students Publications

The incidence of Alzheimer's Disease in females is almost double that of males. To search for sex-specific gene associations, we build a machine learning approach focused on functionally impactful coding variants. This method can detect differences between sequenced cases and controls in small cohorts. In the Alzheimer's Disease Sequencing Project with mixed sexes, this approach identified genes enriched for immune response pathways. After sex-separation, genes become specifically enriched for stress-response pathways in male and cell-cycle pathways in female. These genes improve disease risk prediction in silico and modulate Drosophila neurodegeneration in vivo. Thus, a general approach for machine learning on …

Srsf1 Haploinsufficiency Is Responsible For A Syndromic Developmental Disorder Associated With Intellectual Disability, Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus Leblanc, Emma Van Reempts, Frederic Tran Mau-Them, Ingrid M Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J Louie, Michael J Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley Mcconkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R Roeder, Tadahiro Mitani, Jennifer E Posey, Daniel Calame, Hagith Yonath, Jill A Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello

Faculty, Staff and Students Publications

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals …

Vestigial-Like 1 (Vgll1): An Ancient Co-Transcriptional Activator Linking Wing, Placenta, And Tumor Development, Heather M Sonnemann, Barbara Pazdrak, Dinler A Antunes, Jason Roszik, Gregory Lizée

Faculty, Staff and Student Publications

Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEAD transcription factors in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as …

Late-Onset Cognitive Impairment And Modifiable Risk Factors In Adult Childhood Cancer Survivors, Nicholas S Phillips, Kayla L Stratton, Annalynn M Williams, Tim Ahles, Kirsten K Ness, Harvey Jay Cohen, Kim Edelstein, Yutaka Yasui, Kevin Oeffinger, Eric J Chow, Rebecca M Howell, Leslie L Robison, Gregory T Armstrong, Wendy M Leisenring, Kevin R Krull

Faculty, Staff and Student Publications

Importance: Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood.

Objective: To determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments.

Design, setting, and participants: Participants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was …