Medical Genetics Commons^™

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 …

Genome-Wide Association Analysis Identifies Ancestry-Specific Genetic Variation Associated With Acute Response To Metformin And Glipizide In Sugar-Mgh, Josephine H Li, Laura N Brenner, Varinderpal Kaur, Katherine Figueroa, Philip Schroeder, Alicia Huerta-Chagoya, Miriam S Udler, Aaron Leong, Josep M Mercader, Jose C Florez

Faculty, Staff and Student Publications

AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes.

METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping …

Ethical, Legal, And Social Implications Of Genomics Research: Implications For Building A More Racially Diverse Bioethics Workforce, Faith E Fletcher

Center for Medical Ethics and Health Policy Staff Publications

No abstract provided.

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

Faculty, Staff and Student Publications

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

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

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

A Mendelian Randomization Study Of Genetic Liability To Post-Traumatic Stress Disorder And Risk Of Ischemic Stroke, Opeyemi Soremekun, Clarisse Musanabaganwa, Annette Uwineza, Maddalena Ardissino, Skanda Rajasundaram, Agaz H Wani, Stefan Jansen, Jean Mutabaruka, Eugene Rutembesa, Chisom Soremekun, Cisse Cheickna, Mamadou Wele, Joseph Mugisha, Oyekanmi Nash, Eugene Kinyanda, Dorothea Nitsch, Myriam Fornage, Tinashe Chikowore, Dipender Gill, Derek E Wildman, Leon Mutesa, Monica Uddin, Segun Fatumo

Faculty, Staff and Student Publications

Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a threshold P value (P) of <5 >× 10

Genome-Wide Association Study Of Thoracic Aortic Aneurysm And Dissection In The Million Veteran Program, Derek Klarin, Poornima Devineni, Anoop K Sendamarai, Anthony R Angueira, Sarah E Graham, Ying H Shen, Michael G Levin, James P Pirruccello, Ida Surakka, Purushotham R Karnam, Tanmoy Roychowdhury, Yanming Li, Minxian Wang, Krishna G Aragam, Kaavya Paruchuri, Verena Zuber, Gabrielle E Shakt, Noah L Tsao, Renae L Judy, Ha My T Vy, Shefali S Verma, Daniel J Rader, Ron Do, Joseph E Bavaria, Girish N Nadkarni, Marylyn D Ritchie, Stephen Burgess, Dong-Chuan Guo, Patrick T Ellinor, Scott A Lemaire, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Philip S Tsao, Saiju Pyarajan, Scott M Damrauer

Faculty, Staff and Student Publications

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and …

Invited Commentary: Mri Clear Cell Likelihood Score For Indeterminate Solid Renal Masses: Is There A Path For Broad Clinical Adoption?, Ivan Pedrosa

Faculty, Staff and Student Publications

No abstract provided.

The Promise And Future Of Radiomics For Personalized Radiotherapy Dosing And Adaptation, Rachel B Ger, Lise Wei, Issam El Naqa, Jing Wang

Faculty, Staff and Student Publications

Quantitative image analysis, also known as radiomics, aims to analyze large-scale quantitative features extracted from acquired medical images using hand-crafted or machine-engineered feature extraction approaches. Radiomics has great potential for a variety of clinical applications in radiation oncology, an image-rich treatment modality that utilizes computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) for treatment planning, dose calculation, and image guidance. A promising application of radiomics is in predicting treatment outcomes after radiotherapy such as local control and treatment-related toxicity using features extracted from pretreatment and on-treatment images. Based on these individualized predictions of treatment outcomes, radiotherapy …

Characteristics, Treatment, And Outcome Of Diverticulitis After Immune Checkpoint Inhibitor Treatment In Patients With Malignancies, Austin R Thomas, Mostafa Eyada, Miho Kono, Krishnavathana Varatharajalu, Yang Lu, Guofan Xu, Kavea Panneerselvam, Malek Shatila, Mehmet Altan, Jennifer Wang, John A Thompson, Hao Chi Zhang, Muhammad Ali Khan, Gottumukkala S Raju, Anusha S Thomas, Yinghong Wang

Faculty, Staff and Student Publications

Purpose: Immune checkpoint inhibitors (ICIs) are efficacious for treating various malignancies. In addition to immune-related adverse events (irAEs), growing evidence suggests that ICIs might also be associated with diverticulitis. We aim to assess the clinical presentations and management of colonic diverticulitis among cancer patients after ICI treatment.

Methods: A retrospective study was conducted on ICI-treated adult cancer patients between 01/2010 and 06/2020. Patients were grouped based on when diverticulitis developed relative to ICI treatment, either before (controls) or after (cases). Patient clinical characters, treatment, and outcomes were compared between both groups.

Results: 77 eligible patients were included: 63 patients developed …

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 …

Mrtx-500 Phase 2 Trial: Sitravatinib With Nivolumab In Patients With Nonsquamous Nsclc Progressing On Or After Checkpoint Inhibitor Therapy Or Chemotherapy, Kai He, David Berz, Shirish M Gadgeel, Wade T Iams, Debora S Bruno, Collin M Blakely, Alexander I Spira, Manish R Patel, David M Waterhouse, Donald A Richards, Anthony Pham, Robert Jotte, David S Hong, Edward B Garon, Anne Traynor, Peter Olson, Lisa Latven, Xiaohong Yan, Ronald Shazer, Ticiana A Leal

Faculty, Staff and Student Publications

Introduction: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity.

Methods: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) …

Snakes And Ladders: A Potential Therapy Of Hepatocyte Growth Factor And Pigment Epithelium-Derived Factor In Pulmonary Hypertension, Joseph M Zambelas, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

No abstract provided.

Early Stage Gastric Adenocarcinoma: Clinical And Molecular Landscapes, Yuki Hirata, Ayesha Noorani, Shumei Song, Linghua Wang, Jaffer A Ajani

Faculty, Staff and Student Publications

Gastric adenocarcinoma, even when diagnosed at an early (localized) disease stage, poses a major health-care burden with cure rates that remain unsatisfactorily low, particularly in Western countries. This lack of progress reflects, among other aspects, the impracticality of early diagnosis, considerable variations in therapeutic approaches that is partly based on regional preferences, and the ingrained heterogeneity of gastric adenocarcinoma cells and their associated tumour microenvironment (TME). Clinical trials have long applied empirical interventions with the assumption that all early stage gastric adenocarcinomas are alike. Despite certain successes, the shortcomings of these approaches can potentially be overcome by targeting the specific …

The Genetics Of Primary Ciliary Dyskinesia In Puerto Rico, Paolo Zanoni, Katharina Steindl, Heinrich Sticht, Beatrice Oneda, Pascal Joset, Ivan Ivanovski, Anselm H C Horn, Elena M Cabello, Julia Laube, Markus Zweier, Alessandra Baumer, Anita Rauch, Nadia Khan

Faculty, Staff and Student Publications

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA …

Neoadjuvant Immunotherapy For Advanced, Resectable Non-Small Cell Lung Cancer: A Systematic Review And Meta-Analysis, Yajing Wu, Vivek Verma, Carl M Gay, Yujia Chen, Fei Liang, Qiang Lin, Jianing Wang, Wei Zhang, Zhouguang Hui, Min Zhao, Jun Wang, Joe Y Chang

Faculty, Staff and Student Publications

Background: Neoadjuvant immunotherapy (nIT) is a rapidly emerging paradigm for advanced resectable non-small cell lung cancer (NSCLC). The objectives of this PRISMA/MOOSE/PICOD-guided systematic review and meta-analysis were (1) to assess the safety and efficacy of nIT, (2) to compare the safety and efficacy of neoadjuvant chemoimmunotherapy (nCIT) versus chemotherapy alone (nCT), and (3) to explore predictors of pathologic response with nIT and their association with outcomes.

Methods: Eligibility was resectable stage I-III NSCLC and the receipt of programmed death-1/programmed cell death ligand-1 (PD-L1)/cytotoxic T-lymphocyte-associated antigen-4 inhibitors before resection; other forms and modalities of neoadjuvant and/or adjuvant therapies were allowed. For …

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 …

Transplantation Referral Patterns For Patients With Newly Diagnosed Higher-Risk Myelodysplastic Syndromes And Acute Myeloid Leukemia At Academic And Community Sites In The Connect® Myeloid Disease Registry: Potential Barriers To Care, Benjamin Tomlinson, Marcos De Lima, Christopher R Cogle, Michael A Thompson, David L Grinblatt, Daniel A Pollyea, Rami S Komrokji, Gail J Roboz, Michael R Savona, Mikkael A Sekeres, Mehrdad Abedi, Guillermo Garcia-Manero, Sandra E Kurtin, Jaroslaw P Maciejewski, Jay L Patel, Dennis A Revicki, Tracy I George, E Dawn Flick, Pavel Kiselev, Chrystal U Louis, Irene S Degutis, Melissa Nifenecker, Harry P Erba, David P Steensma, Bart L Scott

Faculty, Staff and Student Publications

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to …

Nivolumab And Ipilimumab With Concurrent Stereotactic Radiosurgery For Intracranial Metastases From Non-Small Cell Lung Cancer: Analysis Of The Safety Cohort For Non-Randomized, Open-Label, Phase I/Ii Trial, Mehmet Altan, Yan Wang, Juhee Song, James Welsh, Chad Tang, Nandita Guha-Thakurta, George R Blumenschein, Brett W Carter, Jeffrey S Wefel, Amol J Ghia, Debra N Yeboa, Mary Frances Mcaleer, Caroline Chung, Kristina D Woodhouse, Susan L Mcgovern, Chenyang Wang, Betty Y S Kim, Jeffrey S Weinberg, Tina M Briere, Yasir Y Elamin, Xiuning Le, Tina Cascone, Marcelo V Negrao, Ferdinandos Skoulidis, Renata Ferrarotto, John V Heymach, Jing Li

Faculty, Staff and Student Publications

BACKGROUND: Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC.

PATIENTS AND METHODS: This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered …

Therapeutic Potential Of Salicylamide Derivatives For Combating Viral Infections, Jimin Xu, Yu Xue, Andrew A Bolinger, Jun Li, Mingxiang Zhou, Haiying Chen, Hongmin Li, Jia Zhou

Faculty, Staff and Student Publications

Since time immemorial human beings have constantly been fighting against viral infections. The ongoing and devastating coronavirus disease 2019 pandemic represents one of the most severe and most significant public health emergencies in human history, highlighting an urgent need to develop broad-spectrum antiviral agents. Salicylamide (2-hydroxybenzamide) derivatives, represented by niclosamide and nitazoxanide, inhibit the replication of a broad range of RNA and DNA viruses such as flavivirus, influenza A virus, and coronavirus. Moreover, nitazoxanide was effective in clinical trials against different viral infections including diarrhea caused by rotavirus and norovirus, uncomplicated influenza A and B, hepatitis B, and hepatitis C. …

Venetoclax Consolidation In High-Risk Cll Treated With Ibrutinib For ≥1 Year Achieves A High Rate Of Undetectable Mrd, Philip A Thompson, Michael J Keating, Alessandra Ferrajoli, Nitin Jain, Christine B Peterson, Naveen Garg, Sa A Wang, Jeffrey L Jorgensen, Tapan M Kadia, Prithviraj Bose, Naveen Pemmaraju, Nicholas J Short, William G Wierda

Faculty, Staff and Student Publications

Patients receiving ibrutinib for CLL rarely achieve undetectable measurable residual disease (U-MRD), necessitating indefinite therapy, with cumulative risks of treatment discontinuation due to progression or adverse events. This study added venetoclax to ibrutinib for up to 2 years, in patients who had received ibrutinib for ≥12 months (mo) and had ≥1 high risk feature (TP53 mutation and/or deletion, ATM deletion, complex karyotype or persistently elevated β2-microglobulin). The primary endpoint was U-MRD with 10−4 sensitivity (U-MRD4) in bone marrow (BM) at 12mo. Forty-five patients were treated. On intention-to-treat analysis, 23/42 (55%) patients improved their response to CR (2 pts were …

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, …

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome, Melissa R Hines, Tristan E Knight, Kevin O Mcnerney, Mark B Leick, Tania Jain, Sairah Ahmed, Matthew J Frigault, Joshua A Hill, Michael D Jain, William T Johnson, Yi Lin, Kris M Mahadeo, Gabriela M Maron, Rebecca A Marsh, Sattva S Neelapu, Sarah Nikiforow, Amanda K Ombrello, Nirav N Shah, Aimee C Talleur, David Turicek, Anant Vatsayan, Sandy W Wong, Marcela V Maus, Krishna V Komanduri, Nancy Berliner, Jan-Inge Henter, Miguel-Angel Perales, Noelle V Frey, David T Teachey, Matthew J Frank, Nirali N Shah

Faculty, Staff and Student Publications

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal …

Prevalence Of Ddc Genotypes In Patients With Aromatic L-Amino Acid Decarboxylase (Aadc) Deficiency And In Silico Prediction Of Structural Protein Changes, Nastassja Himmelreich, Mariarita Bertoldi, Majid Alfadhel, Malak Ali Alghamdi, Yair Anikster, Xinhua Bao, Fahad A Bashiri, Bruria Ben Zeev, Giovanni Bisello, Ahmet Cevdet Ceylan, Yin-Hsiu Chien, Yew Sing Choy, Sarah H Elsea, Lisa Flint, Àngels García-Cazorla, Charul Gijavanekar, Emel Yılmaz Gümüş, Muddathir H Hamad, Burcu Hişmi, Tomas Honzik, Oya Kuseyri Hübschmann, Wuh-Liang Hwu, Salvador Ibáñez-Micó, Kathrin Jeltsch, Natalia Juliá-Palacios, Çiğdem Seher Kasapkara, Manju A Kurian, Katarzyna Kusmierska, Ning Liu, Lock Hock Ngu, John D Odom, Winnie Peitee Ong, Thomas Opladen, Mari Oppeboen, Phillip L Pearl, Belén Pérez, Roser Pons, Agnieszka Magdalena Rygiel, Tan Ee Shien, Robert Spaull, Jolanta Sykut-Cegielska, Brahim Tabarki, Trine Tangeraas, Beat Thöny, Tessa Wassenberg, Yongxin Wen, Yusnita Yakob, Jasmine Goh Chew Yin, Jiri Zeman, Nenad Blau

Faculty, Staff and Students Publications

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, …

Withdrawing Extra Corporeal Membrane Oxygenation (Ecmo) Against A Family’S Wishes: Three Permissible Scenarios, Trevor M Bibler, Asma Zainab

Center for Medical Ethics and Health Policy Staff Publications

The ethical permissibility of unilaterally withdrawing life-sustaining technologies has been a perennial topic in transplant and critical care medicine, often focusing on CPR and mechanical ventilation. The permissibility of unilateral withdrawal of extracorporeal membrane oxygenation (ECMO) has been discussed sparingly. When addressed, authors have appealed to professional authority rather than substantive ethical analysis. In this Perspective, we argue that there are at least three (3) scenarios wherein healthcare teams would be justified in unilaterally withdrawing ECMO, despite the objections of the patient's legal representative. The ethical considerations that provide the groundwork for these scenarios are, primarily: equity, integrity, and the …

Machine Learning For Ecg Diagnosis And Risk Stratification Of Occlusion Myocardial Infarction, Salah S Al-Zaiti, Christian Martin-Gill, Jessica K Zègre-Hemsey, Zeineb Bouzid, Ziad Faramand, Mohammad O Alrawashdeh, Richard E Gregg, Stephanie Helman, Nathan T Riek, Karina Kraevsky-Phillips, Gilles Clermont, Murat Akcakaya, Susan M Sereika, Peter Van Dam, Stephen W Smith, Yochai Birnbaum, Samir Saba, Ervin Sejdic, Clifton W Callaway

Faculty, Staff and Students Publications

Patients with occlusion myocardial infarction (OMI) and no ST-elevation on presenting electrocardiogram (ECG) are increasing in numbers. These patients have a poor prognosis and would benefit from immediate reperfusion therapy, but, currently, there are no accurate tools to identify them during initial triage. Here we report, to our knowledge, the first observational cohort study to develop machine learning models for the ECG diagnosis of OMI. Using 7,313 consecutive patients from multiple clinical sites, we derived and externally validated an intelligent model that outperformed practicing clinicians and other widely used commercial interpretation systems, substantially boosting both precision and sensitivity. Our derived …

De Novo Variants In Cnot9 Cause A Neurodevelopmental Disorder With Or Without Epilepsy, Lydia Von Wintzingerode, Bruria Ben-Zeev, Claudia Cesario, Katie M Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V Kelley, Marie-Cécile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L Thompson, Marina Trivisano, Julia Hentschel, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann

Faculty, Staff and Students Publications

Purpose: The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.

Methods: Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.

Results: We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have …

Remote Neuronal Activity Drives Glioma Progression Through Sema4f, Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm Mcdonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael R Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen

Faculty, Staff and Students Publications

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform …

Ywhae Loss Of Function Causes A Rare Neurodevelopmental Disease With Brain Abnormalities In Human And Mouse, Anne-Sophie Denommé-Pichon, Stephan C Collins, Ange-Line Bruel, Anna Mikhaleva, Christel Wagner, Valerie E Vancollie, Quentin Thomas, Martin Chevarin, Mathys Weber, Carlos E Prada, Alexis Overs, María Palomares-Bralo, Fernando Santos-Simarro, Marta Pacio-Míguez, Tiffany Busa, Eric Legius, Carlos A Bacino, Jill A Rosenfeld, Gwenaël Le Guyader, Matthieu Egloff, Xavier Le Guillou, Maria Antonietta Mencarelli, Alessandra Renieri, Salvatore Grosso, Jonathan Levy, Blandine Dozières, Isabelle Desguerre, Antonio Vitobello, Yannis Duffourd, Christopher J Lelliott, Christel Thauvin-Robinet, Christophe Philippe, Laurence Faivre, Binnaz Yalcin

Faculty, Staff and Students Publications

Purpose: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.

Methods: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae.

Results: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions < 1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans.

Conclusion: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.