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Characteristics, Treatment Patterns, and Outcomes in Primary Cutaneous Gamma Delta T Cell Lymphoma (PCGDTCL): A Real World Multi-Institutional Analysis of a Rare Malignancy
David, Kevin A. , Pulitzer, Melissa , Guitart, Joan , Martínez‐Escala, Maria Estela , Wang, Yaqun , Ristow, Kay M., Winchell, Nicole, Haun, Paul , Allen, Pamela B. , William, Basem M. , Denlinger, Nathan , Mehta–Shah, Neha , Feldman, Tatyana , Weller, Alex , Evens, Andrew M. , William, Basem , Evens, Andrew M , Geller, Shamir , Bennani, N. Nora , Landsburg, Daniel J. , Wilcox, Ryan A. , Hristov, Alexandra C. , Horwitz, Sarah McCue

Blood | November 14, 2019 | Volume: 134 | Issue: Supplement_1 | Pages: 4028-4028

10.1182/blood-2019-130223 Get It

Background: PCGTCL is a rare disorder, accounting for < 1% of all lymphomas. In part given the rarity, timely and accurate diagnosis (dx) remains challenging. Moreover, PCGTCL is typically characterized by a highly aggressive course. We conducted a multi-institutional, retrospective analysis to delineate pathology, patient (pt) characteristics, treatment patterns & outcomes of PCGDTCL in the modern era. Methods: We collected detailed information on pts with PCGDTCL dx between 2000 - 2017 across 10 academic centers. Pathologic data, including IHC & flow characteristics on de-identified pathology reports, were reviewed centrally by an expert dermatopathologist (MP). A pathologic tier was assigned to each case based on fidelity to the following pre-defined minimum criteria: flow cytometric evidence of gamma and/or delta protein-expressing lymphoma or histopathologic evidence of gamma and/or delta protein expression & at least 50% atypical lymphocytes positive for gamma/delta immunostain (IHC) with tissue representative of entire lesion. The presence of >25% CD30 positivity of malignant lymphocytes was an exclusion criterion. Further, PCR evidence of TCR gamma monoclonality or TCR beta/betaF1 negativity alone were inadequate for inclusion with confirmation of gamma/delta phenotype (especially IHC) being key for inclusion. A clinical tier was also assigned to each case based on group consensus. A composite score was derived by combining pathologic & clinical tiers, with those fitting a pre-determined score threshold included in the primary analysis. Univariate (UVA) associations were derived via Cox model for associations with survival. Results: Collectively, all centers submitted a total of 80 cases that were dx & treated locally as PCGDTCL. 48 (60%) cases met pre-defined criteria for inclusion of bona fide dx of PCGTCL. 26 (33%) cases had insufficient composite scores and were grouped in a 2nd tier & 6 cases had incomplete follow-up data and were unsuitable for analysis. The most common reason for placement in the 2nd tier was negativity for gamma/delta IHC or lack of documentation of such testing (n=16). Among the top tier of 48 veritable cases, 32 pts (67%) were male, 39 (81%) white & 4 (8%) black. Median age was 62 years (range 20-88). 19 (40%) pts had B symptoms at dx; ECOG performance status (PS) 0 in 12 pts (25%) & 1-3 in 22 cases (45%) (unknown 29%); anemia was present in 21 pts (44%) & LDH increased in 22 (46%). Bone marrow was involved in only 3 pts (6%) & hemophagocytic syndrome was present at dx in 6 pts (12%). Frontline therapy was heterogeneous (Table 1) with the most common therapies being bexarotene alone in 8 pts; UV therapy in 6 pts; and CHOP in 4 pts. Furthermore, there was inclusion of etoposide in 12 pts (25%), anthracyclines in 9 (19%) & platinum agents in 3 pts (6%). The overall response to 1st line therapy was 40% (19% complete response) with stable disease in 10%, progression in 35% & unknown in 15%. Seven pts (15%) received consolidative stem cell transplantation (SCT), which was allogeneic in all but 1 case. The 2-year PFS for the 48 bona fide pts was 39% (95% CI 0.26-0.59) (Fig 1A) & 2-year OS was 36% (95% CI 0.23-.56) (Fig 1B). The 26 cases in the 2nd tier had overall similar 2-year PFS of 41% (95% CI 0.15-67) and OS of 37% (95% CI 0.22-0.62). In terms of impact of therapy, use of consolidative SCT in 1st remission was associated with improved survival (P=0.02) (Fig 1C). No other therapeutic variable had significance. In UVA for baseline factors, PS (P=0.006) (Fig 1D) and increased vs. normal LDH (P=0.05) were significantly associated with OS. Median OS for pts with normal LDH was 25 months vs 12 months with increased LDH. Median OS for pts with ECOG PS 0 was not reached vs approximately 14 months for ECOG PS 1-3. Conclusions: To the best of our knowledge, this series represents one of the largest reported to date of PCGDTCL. Accurate diagnosis and classification of PCGDTCL need ongoing analysis and delineation. Using strict criteria, only 60% of cases across 10 academic centers were confirmed as bona fide PCGDTCL. Analysis of these pts treated in the modern era demonstrated modest survival. In addition, we identified several prognostic factors, in particular LDH and ECOG PS, associated with patient outcome. Furthermore, the incorporation of allogeneic SCT in 1st remission may contribute to improved long-term survival. Enhanced treatment options and continued collaboration are critically needed in this rare disease. Disclosures Bennani: Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Landsburg:Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haun:Karger, Inc.: Other: Royalties: Textbook. William:Techspert: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy. Mehta-Shah:Kiowa Hakka Kirin: Consultancy; Celgene: Research Funding; Roche/Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Verastem Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. Wilcox:Bristol-Myers Squibb: Research Funding; Millenium/Takeda: Research Funding; CTI Biopharma: Research Funding; Incyte: Research Funding. Feldman:AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Pfizer: Research Funding; Portola Pharma: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Roche: Research Funding; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Cell Medica: Research Funding; Amgen: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Corvus: Research Funding. Evens:Tesaro: Research Funding; Pharmacyclics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Horwitz:Affimed: Consultancy; Mundipharma: Consultancy; Forty-Seven: Research Funding; Astex: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Portola: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Aileron: Research Funding; Portola: Consultancy; Kura: Consultancy; Kura: Consultancy; Miragen: Consultancy; Miragen: Consultancy; Portola: Consultancy; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Forty-Seven: Research Funding; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Affimed: Consultancy; Astex: Consultancy; Trillium: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Research Funding; Mundipharma: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Kura: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Miragen: Consultancy; Portola: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Affimed: Consultancy; Trillium: Research Funding; Millennium/Takeda: Consultancy, Research Funding.
Parametric Hemodynamic 4D Flow MRI Maps for the Characterization of Chronic Thoracic Descending Aortic Dissection
Jarvis, Kelly , Pruijssen, Judith T. , Son, Andre Y. , Allen, Bradley D. , Soulat, Gilles , Vali, Alireza , Hoel, Andrew W. , Eskandari, Mark K. , Carr, James , Markl, Michael , Collins, Jeremy D. , Allen, Bradley A , Markl, Michael , Barker, Alex J. , Malaisrie, S. Chris

Journal of Magnetic Resonance Imaging | November 12, 2019 | Volume: 51 | Issue: 5 | Pages: 1357-1368

10.1002/jmri.26986 | PMID 31714648 Get It

BackgroundSystematic evaluation of complex flow in the true lumen and false lumen (TL, FL) is needed to better understand which patients with chronic descending aortic dissection (DAD) are predisposed to complications.PurposeTo develop quantitative hemodynamic maps from 4D flow MRI for evaluating TL and FL flow characteristics.Study TypeRetrospective.PopulationIn all, 20 DAD patients (age = 60 ± 11 years; 12 male) (six medically managed type B AD [TBAD], 14 repaired type A AD [rTAAD] now with ascending aortic graft [AAo] or elephant trunk [ET1] repair) and 21 age‐matched controls (age = 59 ± 10 years; 13 male) were included.Field Strength/Sequence1.5T, 3T, 4D flow MRI.Assessment4D flow MRI was acquired in all subjects. Data analysis included 3D segmentation of TL and FL and voxelwise calculation of forward flow, reverse flow, flow stasis, and kinetic energy as quantitative hemodynamics maps.Statistical TestsAnalysis of variance (ANOVA) or Kruskal–Wallis tests were performed for comparing subject groups. Correlation and Bland–Altman analysis was performed for the interobserver study.ResultsPatients with rTAAD presented with elevated TL reverse flow (AAo repair: P = 0.004, ET1: P = 0.018) and increased TL kinetic energy (AAo repair: P = 0.0002, ET1: P = 0.011) compared to controls. In addition, TL kinetic energy was increased vs. patients with TBAD (AAo repair: P = 0.021, ET1: P = 0.048). rTAAD was associated with higher FL kinetic energy and lower FL stasis compared to patients with TBAD (AAo repair: P = 0.002, ET1: P = 0.024 and AAo repair: P = 0.003, ET1: P = 0.048, respectively).Data ConclusionQuantitative maps from 4D flow MRI demonstrated global and regional hemodynamic differences between DAD patients and controls. Patients with rTAAD vs. TBAD had significantly altered regional TL and FL hemodynamics. These findings indicate the potential of 4D flow MRI‐derived hemodynamic maps to help better evaluate patients with DAD.Level of Evidence: 3Technical Efficacy Stage: 1J. Magn. Reson. Imaging 2020;51:1357–1368.
Incidence and Risk Factors of Postoperative Mortality and Morbidity After Elective Versus Emergent Abdominal Surgery in a National Sample of 8193 Patients With Cirrhosis
Johnson, Kay M. , Newman, Kira L. , Green, Pamela K., Cornia, Paul B. , Itani, Kamal , Harris, Alex H. S. , Kamath, Patrick S. , Ioannou, George N. , Newman, Kira L , Green, Pamela K. , Berry, Kristin , Wu, Peter , Beste, Lauren A. , Harris, A O

Annals of Surgery | November 12, 2019 | Volume: 274 | Issue: 4 | Pages: e345-e354

10.1097/sla.0000000000003674 | PMID 31714310 Get It

Objective: To describe the incidence and risk factors for mortality and morbidity in patients with cirrhosis undergoing elective or emergent abdominal surgeries. Background: Postoperative morbidity and mortality are higher in patients with cirrhosis; variation by surgical procedure type and cirrhosis severity remain unclear. Methods: We analyzed prospectively-collected data from the Veterans Affairs (VA) Surgical Quality Improvement Program for 8193 patients with cirrhosis, 864 noncirrhotic controls with chronic hepatitis B infection, and 5468 noncirrhotic controls without chronic liver disease, who underwent abdominal surgery from 2001 to 2017. Data were analyzed using random-effects models controlling for potential confounders. Results: Patients with cirrhosis had significantly higher 30-day mortality than noncirrhotic patients with chronic hepatitis B [4.4% vs 1.3%, adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.57–4.98] or with no chronic liver disease (0.8%, aOR 4.68, 95% CI 3.27–6.69); mortality difference was highest in patients with Model for End-stage Liver Disease (MELD) score ≥10. Among patients with cirrhosis, postoperative mortality was almost 6 times higher after emergent rather than elective surgery (17.2% vs. 2.1%, aOR 5.82, 95% CI 4.66–7.27). For elective surgeries, 30-day mortality was highest after colorectal resection (7.0%) and lowest after inguinal hernia repair (0.6%). Predictors of postoperative mortality included cirrhosis-related characteristics (high MELD score, low serum albumin, ascites, encephalopathy), surgery-related characteristics (emergent vs elective, type of surgery, intraoperative blood transfusion), comorbidities (chronic obstructive pulmonary disease, cancer, sepsis, ventilator dependence, functional status), and age. Conclusions: Accurate preoperative risk assessments in patients with cirrhosis should account for cirrhosis severity, comorbidities, type of procedure, and whether the procedure is emergent versus elective.
Development of an Objective Structured Clinical Examination as a Component of Assessment for Initial Board Certification in Anesthesiology
Isaak, Robert S. , Peterson-Layne, Cathleen, Lien, Cynthia A. , Menzies, Anna O., Cole, Daniel J. , Dainer, Rupa J., Fahy, Brenda G. , Macario, Alex, Suresh, Santhanam , Harman, Ann E., Warner, David O. , Sun, Huaping

Anesthesia & Analgesia | November 4, 2019 | Volume: 130 | Issue: 1 | Pages: 258-264

10.1213/ane.0000000000004496 | PMID 31688077 Get It

With its first administration of an Objective Structured Clinical Examination (OSCE) in 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate this type of assessment into its high-stakes certification examination system. The fundamental rationale for the ABA’s introduction of the OSCE is to include an assessment that allows candidates for board certification to demonstrate what they actually “do” in domains relevant to clinical practice. Inherent in this rationale is that the OSCE will capture competencies not well assessed in the current written and oral examinations—competencies that will allow the ABA to judge whether a candidate meets the standards expected for board certification more properly. This special article describes the ABA’s journey from initial conceptualization through first administration of the OSCE, including the format of the OSCE, the process for scenario development, the standardized patient program that supports OSCE administration, examiner training, scoring, and future assessment of reliability, validity, and impact of the OSCE. This information will be beneficial to both those involved in the initial certification process, such as residency graduate candidates and program directors, and others contemplating the use of high-stakes summative OSCE assessments.
Lack of association between modifiable exposures and glioma risk: A Mendelian randomisation analysis
Saunders, Charlie N. , Cornish, Alex J. , Kinnersley, Ben , Claus, Elizabeth B. , Schildkraut, Joellen M. , Barnholtz‐Sloan, Jill S. , Bernstein, Jonine L. , Lai, Rose , Rajaraman, Preetha , Johansen, Christoffer , Jenkins, Robert B. , Melin, Beatrice , Wrensch, Margaret , Sanson, Marc , Bondy, Melissa L. , Houlston, Richard S. , Houlston, Richard S , Barnholtz-Sloan, Jill S , Sanson, Marc , Law, Philip , Il’yasova, Dora , Olson, Sara H. , Chanock, Stephen Jacob

Neuro-Oncology | October 23, 2019 | Volume: No volume available | Issue: No issue available | Pages: No page available

10.1093/neuonc/noz209 | PMID 31665421 Get It

Abstract Background The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian Randomisation (MR) framework to examine if lifestyle, cardiometabolic and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation. Methods We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: lifestyle and dietary factors (height, plasma IGF-1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamin [A1, B12, B6, E and 25-hydroxyvitamin D], fatty acids levels [mono-unsaturated, omega-3 and omega-6] and circulating fetuin-A); cardiometabolic factors (birth weight, HDL cholesterol, LDL cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, HbA1C levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio) were included; inflammatory factors (C-reactive protein (CRP), plasma IL-6 sRa and serum IgE). Results After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism (SNP) no significant association with glioma risk was observed (i.e. PCorrected > 0.05). Conclusions This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.
O4‐03‐01: FRONTOTEMPORAL LOBAR DEGENERATION RESEARCH IN NORTH AMERICA: PROGRESS IN THE ARTFL/LEFFTDS CONSORTIA
Heuer, Hilary W. , Boxer, Adam L. , Rosen, Howard J. , Forsberg, Leah K. , Brushaber, Danielle , Bordelon, Yvette , Coppola, Giovanni , Dickerson, Brad C., Dickinson, Susan, Faber, Kelley, Fields, Julie A. , Gavrilova, Ralitza H. , Ghoshal, Nupur , Graff‐Radford, Jonathan , Graff-Radford, N. R., Grant, Ian , Huey, Edward D. , Karydas, Anna M., Kaufer, Daniel , Kramer, Joel H. , Ljubenkov, Peter A. , Lucente, Diane , Lungu, Codrin , Mackenzie, Ian R. , McGinnis, Scott M., Mendez, Mario F. , Onyike, Chiadi U. , Pantelyat, Alex, Pearlman, Rodney , Petrucelli, Leonard , Rademakers, Rosa , Ramos, Eliana Marisa , Rankin, Katherine P. , Rascovsky, Katya, Rogalskı, Emily , Shaw, Leslie M. , Sutherland, Margaret , Syrjanen, Jeremy A. , Tatton, Nadine , Taylor, Joanne, Weıntraub, Sandra , Consortia, ARTFL and LEFFTDS, Boeve, Bradley F. , Appleby, Brian S. , Brannelly, Patrick , Domoto‐Reilly, Kimiko , Fong, Jamie , Foroud, Tatiana , Goldman, Jill , Grossman, Murray , Hsiao, John , Hsiung, Ging‐Yuek Robin , Irwin, David J. , Kantarci, Kejal , Kerwin, Diana , Knopman, David S. , Kremers, Walter K. , Kukull, Walter A. , Litvan, Irene , Miller, Bruce L. , Roberson, Erik D. , Tartaglia, Maria Carmela , Toga, Arthur W. , Wong, Bonnie , Wszołek, Zbigniew K. , Consortia, ARTFL and LEFFTDS

Alzheimer's & Dementia | October 18, 2019 | Volume: 15 | Issue: 7S_Part_23 | Pages: No page available

10.1016/j.jalz.2019.06.4752 Get It

P2‐314: THE MULTIDOMAIN IMPAIRMENT RATING (MIR) SCALE: INITIAL RELIABILITY DATA ON A MULTIDIMENSIONAL SCALE DESIGNED FOR FTLD SPECTRUM DISORDERS
Forsberg, Leah K. , Boxer, Adam L. , Rosen, Howard J. , Kornak, John , Heuer, Hilary W. , Fields, Julie A. , Brushaber, Danielle , Sturm, Virginia E. , Staffaroni, Adam M. , Ljubenkov, Peter A. , Denver, Reilly, Ong, Elise, Bordelon, Yvette , Coppola, Giovanni, Dickerson, Brad C., Dickinson, Susan, Faber, Kelley, Gavrilova, Ralitza H. , Gearhart, Debra, Ghoshal, Nupur , Graff‐Radford, Jonathan , Graff-Radford, N. R., Huey, Edward D. , Karydas, Anna M., Kaufer, Daniel , Kraft, Ruth, Kramer, Joel H. , Lucente, Diane , Lungu, Codrin , Mackenzie, Ian R. , McGinnis, Scott M., Mendez, Mario F. , Onyike, Chiadi U. , Pantelyat, Alex, Pearlman, Rodney , Petrucelli, Leonard , Potter, Madeline, Rademakers, Rosa , Ramos, Eliana Marisa , Rankin, Katherine P. , Rascovsky, Katya, Rogalskı, Emily , Shaw, Leslie M. , Sutherland, M. Anne, Syrjanen, Jeremy A. , Tatton, Nadine , Taylor, Joanne, Trojanowski, John Q. , Weıntraub, Sandra , Boeve, Bradley F. , Machulda, Mary M. , Appleby, Brian S. , Brannelly, Patrick , Coppola, Giovanni, Domoto‐Reilly, Kimiko , Fong, Jamie , Foroud, Tatiana , Goldman, Jill , Grossman, Murray , Hsiung, Ging‐Yuek Robin , Irwin, David J. , Jones, David T. , Kantarci, Kejal , Kerwin, Diana , Knopman, David S. , Kremers, Walter K. , Kukull, Walter A. , Litvan, Irene , Miller, Bruce L. , Roberson, Erik D. , Sutherland, Marg, Tartaglia, Maria Carmela , Toga, Arthur W. , Wong, Bonnie , Wszołek, Zbigniew K.

Alzheimer's & Dementia | October 18, 2019 | Volume: 15 | Issue: 7S_Part_14 | Pages: No page available

10.1016/j.jalz.2019.06.2721 Get It

Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisulfite sequencing of plasma cell-free DNA (cfDNA).
Oxnard, Geoffrey R. , Seiden, Michael V., Venn, Oliver, Jamshidi, Arash , Beausang, John F., Gross, Samuel, Fung, Eric T. , Yecies, Jessica L., Shaknovich, Rita , Fields, Alexander P. , Richards, Donald , Aravanis, Alex, Hartman, Anne‐Renee , Liu, Minetta C. , Klein, Eric A. , Hubbell, Earl , Zhang, Nan , Gross, Samuel, Kurtzman, Kathryn N. , Sekeres, Mikkael A. , Yu, Peter Paul , Aravanis, Alexander M.

Journal of Global Oncology | October 15, 2019 | Volume: 5 | Issue: suppl | Pages: 44-44

10.1200/jgo.2019.5.suppl.44 Get It

44 Background: A noninvasive cfDNA blood test detecting multiple cancers at earlier stages could decrease cancer mortality. In earlier discovery work, whole-genome bisulfite sequencing outperformed whole-genome and targeted sequencing approaches for multi-cancer detection across stages at high specificity. Here, multi-cancer detection and TOO localization using bisulfite sequencing of plasma cfDNA to identify methylomic signatures was evaluated in preparation for clinical validation, utility, and implementation studies. Methods: 2301 analyzable participants (1422 cancer [ > 20 tumor types, all stages], 879 non-cancer) were included in this prespecified substudy from the Circulating Cell-free Genome Atlas (CCGA) (NCT02889978) study - a prospective, multi-center, observational, case-control study with longitudinal follow-up. Plasma cfDNA was subjected to a targeted methylation sequencing assay using high-efficiency methylation chemistry to enrich for methylation targets, and a machine learning classifier determined cancer status and tissue of origin (TOO). Observed methylation fragments characteristic of cancer and TOO were combined across targeted regions and assigned a relative probability of cancer and of a specific TOO. Results: Performance is reported at 99% specificity (ie, a combined false positive rate across all cancer types of 1%), a level required for population-level screening. Across cancer types, sensitivity ranged from 59 to 86%. Combined cancer detection (sensitivity [95% CI]) was 34% (27-43%) in stage I (n = 151), 77% (70-83%) in stage II (n = 171), 84% (79-89%) in stage III (n = 204), and 92% (88-95%) in stage IV (n = 281). TOO was provided for 94% of all cancers detected; of these, TOO was correct in > 90% of cases. Conclusions: Detection of multiple deadly cancers across stages using methylation signatures in plasma cfDNA was achieved with a single, fixed, low false positive rate, and simultaneously provided accurate TOO localization. This targeted methylation assay is undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic. Clinical trial information: NCT02889978.
2-Year Follow-up and High-Risk Subset Analysis of Zuma-1, the Pivotal Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory Large B Cell Lymphoma
Neelapu, Sattva S. , Jacobson, Caron A. , Miklos, David B. , Lekakis, Lazaros J. , Oluwole, Olalekan O. , Braunschweig, Ira , Hill, Brian T. , Timmerman, John M. , Deol, Abhinav , Stiff, Patrick J. , McSweeney, Peter A., Herrera, Alex F. , Xue, Allen , Jiang, Yizhou , Bot, Adrian , Rossi, John M. , Go, William Y., Oluwole, Olalekan O , Miklos, David B , Ghobadi, Armin , Lin, Yi , Reagan, Patrick Michael , Flinn, Ian W. , Farooq, Umar , Goy, Andre Henri , Muñoz, Javier , Siddiqi, Tanya , Chavez, Julio C , Kim, Jaeyeon , Locke, Frederick L.

Blood | October 14, 2019 | Volume: 132 | Issue: Supplement 1 | Pages: 2967-2967

10.1182/blood-2018-99-111368 Get It

Abstract Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of patients with relapsed or refractory large B cell lymphoma with ≥ 2 prior systemic therapies. This report focuses on high-risk patient populations as well as long-term durability of response, and B cell recovery. Methods: In ZUMA-1, eligible patients with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis and received low-dose conditioning followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu and Locke et al. NEJM. 2017; NCT02348216). Outcomes in patients with double-expressor B cell lymphoma (MYC [≥ 40%] and BCL-2 [≥ 50%] protein expression by immunohistochemistry [IHC]) or high-grade B cell lymphoma (HGBCL), defined as double- or triple-hit (MYC+ and BCL2+ and/or BCL6+ by fluorescence in situ hybridization) or not otherwise specified (MYC- and > 70% Ki67 by IHC) were examined by independent pathology review. Exploratory analyses, including normal B cell levels in peripheral blood over time and frequency of use of safety interventions of interest, were also performed. A long-term follow-up analysis will be conducted with a data cutoff of August 11, 2018 for all 108 patients, including the HGBCL subgroup. Results: As of August 11, 2017, all 108 patients had at least 1 year of follow-up, with a median follow-up of 15.4 months. The objective response rate (ORR) was 82% with a complete response (CR) rate or 58%. The CR rate was 53% (29/55) in patients with disease refractory to ≥ 2 consecutive prior lines of therapy and 72% (18/25) in patients who had relapsed within 12 months after autologous stem cell transplantation. High-risk genetics were assessed in the 47 evaluable pre-treatment tumor samples: 37 patients (79%) had HGBCL or double-expressor B cell lymphoma and had an ORR of 89% (33/37) including a CR rate of 68% (25/37). Forty-two percent of patients overall had ongoing responses with a median follow-up of 15.4 months including 49% (18/37) of patients with high-risk genetics. To investigate the relationship between B cell recovery and ongoing response, B cell levels were assessed over time. Overall, of the 87 evaluable patients, 47% had no detectable B cells at baseline, and the remainder had levels close to or below the lower level of quantification of the assay. In patients with ongoing responses at 12 months post axi-cel infusion, 19 of the 35 (54%) patients with evaluable samples had detectable B cells at 12 months. This suggests B cell recovery in some patients with ongoing response as only 6 of 40 (15%) patients with evaluable samples had detectable B cells at 3 months after axi-cel infusion. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) were generally reversible and reported for 12% and 31% of patients, respectively. Tocilizumab (45%) and/or steroids (28%) were used for the management of CRS and NE. The use of vasopressors, dialysis, and intubation were minimal, used in only 17%, 3%, and 3% of patients, respectively. Thirty-four percent of patients (37/108) had either no CRS/NE (6%) or only Grade 1 CRS with (12%) or without (16%) Grade 1 NE. For these 37 patients, the median onset of CRS and NE was 2 and 7 days after infusion, respectively. Patients with Grade 0 - 1 CRS/NE had similar efficacy (ORR, 86%; CR, 65%) but lower peak/AUC CAR T cell levels vs the overall population. Updated safety and efficacy results will be presented with a minimum follow-up of 2 years and a median follow-up of 27.1 months. Conclusion: High rates of durable response were observed in patients with HGBCL and double-expressor B cell lymphoma, with approximately half of these patients (18/37) maintaining CR at ≥ 1 year. Efficacy in these high-risk populations was comparable to the overall patient population in ZUMA-1. At 12 months, B-cell recovery was observed in over half the patients with ongoing remission. About one-third of patients had only Grades 0 - 1 CRS/NE yet showed comparable efficacy with the overall patient population. High-grade CRS/NE were largely managed with tocilizumab and steroids with very low use of intensive or invasive interventions. Updated outcomes with a minimum of 2 years of follow-up will be presented. Disclosures Neelapu: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Miklos:Adaptive Biotechnologies: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Kite - Gilead: Consultancy, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Research Funding. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Deol:Novartis: Consultancy; Kite Pharmaceuticals: Consultancy. Reagan:Seattle Genetics: Research Funding. Flinn:Agios: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Calithera: Research Funding; Portola: Research Funding; Kite: Research Funding; Forma: Research Funding; Genentech: Research Funding; Verastem: Research Funding; BeiGene: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Janssen: Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Infinity: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Curis: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy, Research Funding; Takeda: Research Funding; Pfizer: Research Funding. McSweeney:Kite, a Gilead Company: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Alexion: Consultancy; Genentech: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Janssen: Consultancy; Kite: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Herrera:Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding. Xue:Kite, a Gilead Company: Employment. Jiang:Kite, a Gilead Company: Employment. Bot:KITE: Employment. Rossi:KITE: Employment. Kim:Kite, a Gilead Company: Employment. Go:KITE: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor.
Thoracic Radiologists’ Versus Computer Scientists’ Perspectives on the Future of Artificial Intelligence in Radiology
Eltorai, Adam E. M. , Bratt, Alex , Guo, H. Henry , Bratt, Alexander K., Bratt, Alex

Journal of Thoracic Imaging | October 14, 2019 | Volume: 35 | Issue: 4 | Pages: 255-259

10.1097/rti.0000000000000453 | PMID 31609778 Get It

Background: There is intense interest and speculation in the application of artificial intelligence (AI) to radiology. The goals of this investigation were (1) to assess thoracic radiologists’ perspectives on the role and expected impact of AI in radiology, and (2) to compare radiologists’ perspectives with those of computer science (CS) experts working in the AI development. Methods: An online survey was developed and distributed to chest radiologists and CS experts at leading academic centers and societies, comparing their expectations of AI’s influence on radiologists’ jobs, job satisfaction, salary, and role in society. Results: A total of 95 radiologists and 45 computer scientists responded. Computer scientists reported having read more scientific journal articles on AI/machine learning in the past year than radiologists (mean [95% confidence interval]=17.1 [9.01-25.2] vs. 7.3 [4.7-9.9], P=0.0047). The impact of AI in radiology is expected to be high, with 57.8% and 73.3% of computer scientists and 31.6% and 61.1% of chest radiologists predicting radiologists’ job will be dramatically different in 5 to 10 years, and 10 to 20 years, respectively. Although very few practitioners in both fields expect radiologists to become obsolete, with 0% expecting radiologist obsolescence in 5 years, in the long run, significantly more computer scientists (15.6%) predict radiologist obsolescence in 10 to 20 years, as compared with 3.2% of radiologists reporting the same (P=0.0128). Overall, both chest radiologists and computer scientists are optimistic about the future of AI in radiology, with large majorities expecting radiologists’ job satisfaction to increase or stay the same (89.5% of radiologists vs. 86.7% of CS experts, P=0.7767), radiologists’ salaries to increase or stay the same (83.2% of radiologists vs. 73.4% of CS experts, P=0.1827), and the role of radiologists in society to improve or stay the same (88.4% vs. 86.7%, P=0.7857). Conclusions: Thoracic radiologists and CS experts are generally positive on the impact of AI in radiology. However, a larger percentage, but still small minority, of computer scientists predict radiologist obsolescence in 10 to 20 years. As the future of AI in radiology unfolds, this study presents a historical timestamp of which group of experts’ perceptions were closer to eventual reality.