Medicine and Health Sciences Commons^™

Improved Survival And Tumor Control With Interleukin-2 Is Associated With The Development Of Immune-Related Adverse Events: Data From The Proclaim, Brendan Curti, Gregory A Daniels, David F Mcdermott, Joseph I Clark, Howard L Kaufman, Theodore F Logan, Jatinder Singh, Meenu Kaur, Theresa L Luna, Nancy Gregory, Michael A Morse, Michael K K Wong, Janice P Dutcher

Articles, Abstracts, and Reports

BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL-2) documented in the PROCLAIM

METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC …

A Pilot Study Of An Autologous Tumor-Derived Autophagosome Vaccine With Docetaxel In Patients With Stage Iv Non-Small Cell Lung Cancer., Rachel E Sanborn, Helen J Ross, Sandra Aung, Anupama Acheson, Tarsem Moudgil, Sachin Puri, Traci Hilton, Brenda Fisher, Todd Coffey, Christopher Paustian, Michael Neuberger, Edwin Walker, Hong-Ming Hu, Walter Urba, Bernard A Fox

Articles, Abstracts, and Reports

BACKGROUND: Tumor-derived autophagosome vaccines (DRibbles) have the potential to broaden immune response to poorly immunogenic tumors.

METHODS: Autologous vaccine generated from tumor cells harvested from pleural effusions was administered to patients with advanced NSCLC with the objectives of assessing safety and immune response. Four patients were vaccinated and evaluable for immune response; each received two to four doses of vaccine. Study therapy included two cycles of docetaxel 75 mg/m

RESULTS: Three of four patients had tumor cells available for testing. Autologous tumor-specific immune response was seen in two of the three, manifested by IL-5 (1 patient after 3 doses), and …

Common Tdp1 Polymorphisms In Relation To Survival Among Small Cell Lung Cancer Patients: A Multicenter Study From The International Lung Cancer Consortium, Pawadee Lohavanichbutr, Lori C. Sakoda, Christopher I. Amos, Susanne M. Arnold, David C. Christiani, Michael P. A. Davies, John K. Field, Eric B. Haura, Rayjean J Hung, Takashi Kohno, Maria Teresa Landi, Geoffrey Liu, Yi Liu, Michael W. Marcus, Grainne M. O'Kane, Matthew B. Schabath, Kouya Shiraishi, Stacey A. Slone, Adonina Tardón, Ping Yang, Kazushi Yoshida, Ruyang Zhang, Xuchen Zong, Gary E. Goodman, Noel S. Weiss, Chu Chen

Internal Medicine Faculty Publications

Background—DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients.

Methods—Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage. …

Ecog-Acrin (E4805) Randomized Phase Ii Study To Determine The Effect Of 2 Different Doses Of Aflibercept In Patients With Metastatic Renal Cell Carcinoma, Roberto Pili, Opeyemi Jegede, Michael A. Carducci, Judith Manola, David L. Groteluschen, Leonard L. Appleman, Glenn Liu, James C. Shanks, Shaker R. Dakhil, Janice Dutcher, Robert S. Dipaola

Internal Medicine Faculty Publications

Background—Aflibercept is a recombinantly-produced fusion protein that has potent anti-VEGF activity. We tested whether aflibercept has clinical activity in clear cell renal cell carcinoma (ccRCC). The recommended Phase 2 dose was 4 mg/kg but several patients treated at 1 mg/kg demonstrated prolonged progression-free survival (PFS). We therefore tested both doses in a parallel group randomized trial.

Methods—Eligible patients (pts) had histologically confirmed advanced or metastatic ccRCC and previous treatments including prior exposure to a VEGF RTKI. Patients received aflibercept (either 1 mg/kg or 4 mg/kg) day 1 of a 14-day cycle until progression. Patients randomized to 1 mg/kg …

Influence Of Dietary Salt Knowledge, Perceptions, And Beliefs On Consumption Choices After Stroke In Uganda, Martin N. Kaddumukasa, Elly Katabira, Martha Sajatovic, Svetlana Pundik, Mark Kaddumukasa, Larry B. Goldstein

Neurology Faculty Publications

Background

Previous research on Uganda's poststroke population revealed that their level of dietary salt knowledge did not lead to healthier consumption choices.

Purpose

Identify barriers and motivators for healthy dietary behaviors and evaluate the understanding of widely accepted salt regulation mechanisms among poststroke patients in Uganda.

Methods

Convergent parallel mixed methods triangulation design comprised a cross-sectional survey (n = 81) and 8 focus group discussions with 7-10 poststroke participants in each group. We assessed participant characteristics and obtained insights into their salt consumption attitudes, perceptions, and knowledge. Qualitative responses were analyzed using an inductive approach with thematic analytic procedures. Relationships …

Cognitive Trajectory Changes Over 20 Years Before Dementia Diagnosis: A Large Cohort Study., Ge Li, Eric B Larson, Jane B Shofer, Paul K Crane, Laura E Gibbons, Wayne Mccormick, J D Bowen, Mary Lou Thompson

Articles, Abstracts, and Reports

BACKGROUND/OBJECTIVES: Longitudinal studies have shown an increase in cognitive decline many years before clinical diagnosis of dementia. We sought to estimate changes, relative to "normal" aging, in the trajectory of scores on a global cognitive function test-the Cognitive Abilities Screening Instrument (CASI).

DESIGN: A prospective cohort study.

SETTING: Community-dwelling members of a U.S. health maintenance organization.

PARTICIPANTS: Individuals aged 65 and older who had no dementia diagnosis at baseline and had at least two visits with valid CASI test score (N = 4,315).

MEASUREMENTS: Average longitudinal trajectories, including changes in trajectory before clinical diagnosis in those who would be diagnosed …

Incidence Of Cognitively Defined Late-Onset Alzheimer's Dementia Subgroups From A Prospective Cohort Study., Paul K Crane, Emily Trittschuh, Shubhabrata Mukherjee, Andrew J Saykin, R Elizabeth Sanders, Eric B Larson, Susan M Mccurry, Wayne Mccormick, J D Bowen, Thomas Grabowski, Mackenzie Moore, Julianna Bauman, Alden L Gross, C Dirk Keene, Thomas D Bird, Laura E Gibbons, Jesse Mez

Articles, Abstracts, and Reports

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia.

METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments.

RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), …

Linkage, Whole Genome Sequence, And Biological Data Implicate Variants In Rab10 In Alzheimer's Disease Resilience., Perry G Ridge, Celeste M Karch, Simon Hsu, Ivan Arano, Craig C Teerlink, Mark T W Ebbert, Josue D Gonzalez Murcia, James M Farnham, Anna R Damato, Mariet Allen, Xue Wang, Oscar Harari, Victoria M Fernandez, Rita Guerreiro, Jose Bras, John Hardy, Ronald Munger, Maria Norton, Celeste Sassi, Andrew Singleton, Steven G Younkin, Dennis W Dickson, Todd E Golde, Nathan D Price, Nilüfer Ertekin-Taner, Carlos Cruchaga, Alison M Goate, Christopher Corcoran, Joann Tschanz, Lisa A Cannon-Albright, John S K Kauwe

Articles, Abstracts, and Reports

BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.

METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs …

Multisite Evaluation Of The Bd Max Extended Enteric Bacterial Panel For Detection Of Yersinia Enterocolitica, Enterotoxigenic Escherichia Coli, Vibrio, And Plesiomonas Shigelloides From Stool Specimens., Patricia J Simner, Margret Oethinger, Kathleen A Stellrecht, Dylan R Pillai, Ram Yogev, Helene Leblond, Joel Mortensen

Articles, Abstracts, and Reports

The purpose of this study was to perform a multisite evaluation to establish the performance characteristics of the BD Max extended enteric bacterial panel (xEBP) assay directly from unpreserved or Cary-Blair-preserved stool specimens for the detection of Yersinia enterocolitica, enterotoxigenic Escherichia coli (ETEC), Vibrio, and Plesiomonas shigelloides The study included prospective, retrospective, and prepared contrived specimens from 6 clinical sites. BD Max xEBP results were compared to the reference method, which included standard culture techniques coupled with alternate PCR and sequencing, except for ETEC, for which the reference method was two alternate PCRs and sequencing. Alternate PCR was …

Rapid Rest/Stress Regadenoson Ungated Perfusion Cmr For Detection Of Coronary Artery Disease In Patients With Atrial Fibrillation., Erik T Bieging, I Haider, G Adluru, L Chang, P Suksaranjit, D Likhite, A Shaaban, L Jensen, B D Wilson, C J Mcgann, E Dibella

Articles, Abstracts, and Reports

Cardiovascular magnetic resonance (CMR) perfusion has been established as a useful imaging modality for the detection of coronary artery disease (CAD). However, there are several limitations when applying standard, ECG-gated stress/rest perfusion CMR to patients with atrial fibrillation (AF). In this study we investigate an approach with no ECG gating and a rapid rest/stress perfusion protocol to determine its accuracy for detection of CAD in patients with AF. 26 patients with AF underwent a rapid rest/regadenoson stress CMR perfusion imaging protocol, and all patients had X-ray coronary angiography. An ungated radial myocardial perfusion sequence was used. Imaging protocol included: rest …

Efficacy And Safety Of Pembrolizumab In Patients Enrolled In Keynote-030 In The United States: An Expanded Access Program., Tara C Gangadhar, Wen-Jen Hwu, Michael A Postow, Omid Hamid, Adil Daud, Roxana Dronca, Richard Joseph, Steven J O'Day, F S Hodi, Anna C Pavlick, Harriet Kluger, Romina P Oxborough, Aiming Yang, Mihaela Gazdoiu, Debra A Kush, Scot Ebbinghaus, April K S Salama

Articles, Abstracts, and Reports

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. …

Intravesical Rad-Ifnα/Syn3 For Patients With High-Grade, Bacillus Calmette-Guerin-Refractory Or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase Ii Randomized Study., Neal D Shore, Stephen A Boorjian, Daniel J Canter, Kenneth Ogan, Lawrence I Karsh, Tracy M Downs, Leonard G Gomella, Ashish M Kamat, Yair Lotan, Robert S Svatek, Trinity J Bivalacqua, Robert L Grubb, Tracey L Krupski, Seth P Lerner, Michael E Woods, Brant A Inman, Matthew I Milowsky, Alan Boyd, F Peter Treasure, Gillian Gregory, David G Sawutz, Seppo Yla-Herttuala, Nigel R Parker, Colin P N Dinney

Department of Medicine Faculty Papers

Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10(11) viral particles (vp)/mL or 3 × 10(11) vp/mL). Patients who responded at months 3, …

A Two-Biomarker Model Predicts Mortality In The Critically Ill With Sepsis., Carmen Mikacenic, Brenda L Price, Susanna Harju-Baker, D Shane O'Mahony, Cassianne Robinson-Cohen, Frank Radella, William O Hahn, Ronit Katz, David C Christiani, Jonathan Himmelfarb, W Conrad Liles, Mark M Wurfel

Articles, Abstracts, and Reports

RATIONALE: Improving the prospective identification of patients with systemic inflammatory response syndrome (SIRS) and sepsis at low risk for organ dysfunction and death is a major clinical challenge.

OBJECTIVES: To develop and validate a multibiomarker-based prediction model for 28-day mortality in critically ill patients with SIRS and sepsis.

METHODS: A derivation cohort (n = 888) and internal test cohort (n = 278) were taken from a prospective study of critically ill intensive care unit (ICU) patients meeting two of four SIRS criteria at an academic medical center for whom plasma was obtained within 24 hours. The validation cohort (n = …

Clinically Silent Alzheimer's And Vascular Pathologies Influence Brain Networks Supporting Executive Function In Healthy Older Adults, Brian T. Gold, Christopher A. Brown, Jonathan G. Hakun, Leslie M. Shaw, John Q. Trojanowski, Charles D. Smith

Neuroscience Faculty Publications

Aging is associated with declines in executive function. We examined how executive functional brain systems are influenced by clinically silent Alzheimer’s disease (AD) pathology and cerebral white matter hyperintensities (WMHs). Twenty-nine younger adults and thirty-four cognitively normal older adults completed a working memory paradigm while functional magnetic resonance imaging (fMRI) was performed. Older adults further underwent lumbar cerebrospinal fluid (CSF) draw for assessment of AD pathology and FLAIR imaging for assessment of WMHs. Accurate working memory performance in both age groups was associated with high fronto-visual functional connectivity (fC). However, in older adults, higher expression of fronto-visual fC was linked …

Randomized Phase Ii Study Comparing Prophylactic Cranial Irradiation Alone To Prophylactic Cranial Irradiation And Consolidative Extracranial Irradiation For Extensive-Disease Small Cell Lung Cancer (Ed Sclc): Nrg Oncology Rtog 0937, Elizabeth M. Gore, Chen Hu, Alexander Y. Sun, Daniel F. Grimm, Suresh S. Ramalingam, Neal E. Dunlap, Kristin A. Higgins, Maria Werner-Wasik, Aaron M. Allen, Puneeth Iyengar, Gregory M. M. Videtic, Russell K. Hales, Ronald C. Mcgarry, James J. Urbanic, Anthony T. Pu, Candice A. Johnstone, Volker W. Stieber, Rebecca Paulus, Jeffrey D. Bradley

Radiation Medicine Faculty Publications

Introduction—RTOG-0937 is a randomized phase-II trial evaluating 1-year OS with PCI or PCI plus consolidative radiation therapy (cRT) to intra-thoracic disease and extracranial metastases for ED-SCLC.

Methods—Patients with 1–4 extracranial metastases were eligible after CR or PR to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included PR vs CR after chemotherapy and 1 vs 2–4 metastases; age < 65 vs ≥ 65 was added after an observed imbalance. PCI was 25GY/10 fractions. cRT was 45GY/15 fractions. To detect an OS improvement from 30% to 45% with a 34% hazard reduction (HR=0·66) under a 0.1 type-1 error (1-sided) and 80% power, 154 patients were required.

Results—Ninety-seven patients were randomized between March, 2010 and February, 2015. Eleven patients were ineligible (nine PCI, two PCI+cRT), leaving 42 randomized to PCI and 44 to PCI+cRT. At planned interim analysis the study …

Association Of Disease Location And Treatment With Survival In Diffuse Large B-Cell Lymphoma Of The Eye And Ocular Adnexal Region., Aseef H H. Ahmed, C. Stephen Foster, Carol L. Shields

Wills Eye Hospital Papers

Importance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved.

Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL.

Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1-72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, …

Ibrutinib Unmasks Critical Role Of Bruton Tyrosine Kinase In Primary Cns Lymphoma., Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S. Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan-Ying Hsieh, Dan Rohle, Marc Rosenblum, Agnes Viale, Viviane S. Tabar, Cameron W. Brennan, Igor T. Gavrilovic, Thomas J. Kaley, Craig P. Nolan, Antonio Omuro, Elena Pentsova, Alissa A. Thomas, Elina Tsyvkin, Ariela Noy, M. Lia Palomba, Paul Hamlin, Craig S. Sauter, Craig H. Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C. Lallana, Vaios Hatzoglou, Anne S. Reiner, Philip H. Gutin, Jason T. Huse, Katherine S. Panageas, Thomas G. Graeber, Nikolaus Schultz, Lisa M. Deangelis, Ingo K. Mellinghoff

Department of Neurology Faculty Papers

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated …

Nrg Oncology-Radiation Therapy Oncology Group Study 1014: 1-Year Toxicity Report From A Phase 2 Study Of Repeat Breast-Preserving Surgery And 3-Dimensional Conformal Partial-Breast Reirradiation For In-Breast Recurrence., Douglas W. Arthur, Kathryn A. Winter, Henry M. Kuerer, Bruce G. Haffty, Laurie W. Cuttino, Dorin A. Todor, Nicole L. Simone, Shelly B. Hayes, Wendy A. Woodward, Beryl Mccormick, Randi J. Cohen, Walter M. Sahijdak, Daniel J. Canaday, Doris R. Brown, Adam D. Currey, Christine M. Fisher, Reshma Jagsi, Julia White

Department of Radiation Oncology Faculty Papers

PURPOSE: To determine the associated toxicity, tolerance, and safety of partial-breast reirradiation.

METHODS AND MATERIALS: Eligibility criteria included in-breast recurrence occurring >1 year after whole-breast irradiation, <3 >cm, unifocal, and resected with negative margins. Partial-breast reirradiation was targeted to the surgical cavity plus 1.5 cm; a prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments was used. The primary objective was to evaluate the rate of grade ≥3 treatment-related skin, fibrosis, and/or breast pain adverse events (AEs), occurring ≤1 year from re-treatment completion. A rate of ≥13% for these AEs in a cohort of 55 patients was …

Brain Microvascular Injury And White Matter Disease Provoked By Diabetes-Associated Hyperamylinemia, Han Ly, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses …

Impact Of Time Between Diagnosis And Slnb On Outcomes In Cutaneous Melanoma., Daniel W Nelson, Stacey Stern, David E Elashoff, Robert Elashoff, John F Thompson, Nicola Mozzillo, Omgo E Nieweg, Harald J Hoekstra, Alistair J Cochran, Mark B Faries

Articles, Abstracts, and Reports

BACKGROUND: Hypothetically, delay between melanoma diagnosis and SLNB could affect outcomes, either adversely by allowing growth and dissemination of metastases, or beneficially by allowing development of an anti-melanoma immune response. Available data are conflicting about the effect of SLNB delay on patient survival. Our objective was to determine whether delay between initial diagnosis and SLNB affects outcomes in patients with cutaneous melanoma.

STUDY DESIGN: We performed query and analysis of a large prospectively maintained database of patients with primary cutaneous melanomas undergoing SLNB. An independent dataset from MSLT-1 (Multicenter Selective Lymphadenectomy Trial-1) was used for validation. Primary outcomes included disease-free …

Mismatch Repair Deficiency Predicts Response Of Solid Tumors To Pd-1 Blockade., Dung T Le, Jennifer N Durham, Kellie N Smith, Hao Wang, Bjarne R Bartlett, Laveet K Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S Luber, Fay Wong, Nilofer S Azad, Agnieszka A Rucki, Dan Laheru, Ross Donehower, Atif Zaheer, George A Fisher, Todd S Crocenzi, James J Lee, Tim F Greten, Austin G Duffy, Kristen K Ciombor, Aleksandra D Eyring, Bao H Lam, Andrew Joe, S Peter Kang, Matthias Holdhoff, Ludmila Danilova, Leslie Cope, Christian Meyer, Shibin Zhou, Richard M Goldberg, Deborah K Armstrong, Katherine M Bever, Amanda N Fader, Janis Taube, Franck Housseau, David Spetzler, Nianqing Xiao, Drew M Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, James R Eshleman, Bert Vogelstein, Robert A Anders, Luis A Diaz

Articles, Abstracts, and Reports

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis …

Tumor-Treating Fields Plus Chemotherapy Versus Chemotherapy Alone For Glioblastoma At First Recurrence: A Post Hoc Analysis Of The Ef-14 Trial., Santosh Kesari, Zvi Ram

Articles, Abstracts, and Reports

BACKGROUND: This post hoc analysis of the EF-14 trial (NCT00916409) of tumor-treating fields (TTFields) plus temozolomide versus temozolomide alone in newly diagnosed glioblastoma compared the efficacy of TTFields plus chemotherapy (physician's choice) versus chemotherapy alone after first recurrence.

METHODS: Patients on TTFields plus temozolomide continued TTFields plus second-line chemotherapy after first recurrence. Some patients on temozolomide alone crossed over after approval of TTFields for recurrent GBM. The primary efficacy outcome was overall survival (OS).

RESULTS: After disease progression, 131 patients received TTFields plus chemotherapy and 73 chemotherapy alone. Thirteen patients in the original temozolomide-alone group crossed over to receive TTFields …

Risk Of Incident Clinical Diagnosis Of Alzheimer's Disease-Type Dementia Attributable To Pathology-Confirmed Vascular Disease, Hiroko H. Dodge, Jian Zhu, Randy Woltjer, Peter T. Nelson, David A. Bennett, Nigel J. Cairns, David W. Fardo, Jeffrey A. Kaye, Deniz-Erten Lyons, Nora Mattek, Julie A. Schneider, Lisa C. Silbert, Chengjie Xiong, Lei Yu, Frederick A. Schmitt, Richard J. Kryscio, Erin L. Abner, Smart Data Consortium

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD).

METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with …

A Phase Ib/Ii Study Of Cabozantinib (Xl184) With Or Without Erlotinib In Patients With Non-Small Cell Lung Cancer., Heather A Wakelee, Scott Gettinger, Jeffrey Engelman, Pasi A Jänne, Howard J. West, Deepa S Subramaniam, Joseph Leach, Michael Wax, Yifah Yaron, Dale R Miles, Primo N Lara

Articles, Abstracts, and Reports

PURPOSE: Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.

METHODS: This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent …

Association Of Magnet Status With Hospitalization Outcomes For Ischemic Stroke Patients., Kimon Bekelis, Symeon Missios, Todd A. Mackenzie

Department of Neurosurgery Faculty Papers

BACKGROUND: It is not clear whether Magnet recognition by the American Nurses Credentialing Center (nursing excellence program) is associated with improved patient outcomes. We investigated whether hospitalization in a Magnet hospital is associated with improved outcomes for patients with ischemic stroke.

METHODS AND RESULTS: We performed a cohort study of patients with ischemic stroke from 2009 to 2013, who were registered in the New York Statewide Planning and Research Cooperative System database. Propensity-score-adjusted multivariable regression models were used to adjust for known confounders, with mixed effects methods to control for clustering at the facility level. An instrumental variable analysis was …

Seroprevalence Of Poliovirus Antibodies In The Kansas City Metropolitan Area, 2012-2013., Gregory S. Wallace, Barbara A. Pahud, William C. Weldon, Aaron T. Curns, M Steven Oberste, Christopher J. Harrison

Manuscripts, Articles, Book Chapters and Other Papers

No indigenous cases of poliomyelitis have occurred in the US since 1979; however the risk of importation persists until global eradication is achieved. The seropositivity rate for different age cohorts with exposures to different poliovirus vaccine types and wild virus in the US are not presently known. A convenience sample was conducted in the Kansas City metropolitan area during 2012-2103 with approximately 100 participants enrolled for each of 5 age cohorts categorized based on vaccine policy changes over time in the US. Immunization records for poliovirus vaccination were required for participants90.7%, 94.4%, and 83.3%, for types 1, 2, and 3, …

Outcomes After Diagnosis Of Mild Cognitive Impairment In A Large Autopsy Series, Erin L. Abner, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Daniela C. Moga, Eseosa T. Ighodaro, Gregory A. Jicha, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Randall L. Woltjer, Julie A. Schneider, Nigel J. Cairns, David A. Bennett, Peter T. Nelson

Epidemiology and Environmental Health Faculty Publications

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).

METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States.

RESULTS: Mean follow‐up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical …

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

White Matter Hyperintensity Associations With Cerebral Blood Flow In Elderly Subjects Stratified By Cerebrovascular Risk, Ahmed A. Bahrani, David K. Powell, Guoqiang Yu, Eleanor S. Johnson, Gregory A. Jicha, Charles D. Smith

Biomedical Engineering Faculty Publications

Objective: This study aims to add clarity to the relationship between deep and periventricular brain white matter hyperintensities (WMHs), cerebral blood flow (CBF), and cerebrovascular risk in older persons. Methods: Deep white matter hyperintensity (dWMH) and periventricular white matter hyperintensity (pWMH) and regional gray matter (GM) and white matter (WM) blood flow from arterial spin labeling were quantified from magnetic resonance imaging scans of 26 cognitively normal elderly subjects stratified by cerebrovascular disease (CVD) risk. Fluidattenuated inversion recovery images were acquired using a high-resolution 3-dimensional (3-D) sequence that reduced partial volume effects seen with slicebased techniques. Results: dWMHs but not …

Natural History Of Gutter-Related Type Ia Endoleaks After Snorkel/Chimney Endovascular Aneurysm Repair., Brant W Ullery, Kenneth Tran, Nathan K Itoga, Ronald L Dalman, Jason T Lee

Articles, Abstracts, and Reports

OBJECTIVE: Alternative endovascular strategies using parallel or snorkel/chimney (chimney endovascular aneurysm repair [ch-EVAR]) techniques have been developed to address the lack of widespread availability and manufacturing limitations with branched/fenestrated aortic devices for the treatment of complex abdominal aortic aneurysms. Despite high technical success and midterm patency of snorkel stent configurations, concerns remain regarding the perceived increased incidence of early gutter-related type Ia endoleaks. We aimed to evaluate the incidence and natural history of gutter-related type Ia endoleaks following ch-EVAR.

METHODS: Review of medical records and available imaging studies, including completion angiography and serial computed tomographic angiography, was performed for all …