tbuckley/cabot-search huggingface dataset:
NPM1 Variant Allele Frequency and Outcomes in AML
Authors: Maja Rothenberg-Thurley, Tobias Herold, Dennis Görlich, Cristina Sauerland, Hanna Janke, Victoria V Prassek, Nikola P Konstandin, Annika Maria Dufour, Stephanie Schneider, Bianka Ksienzyk, Evelyn Packeiser, Marion Subklewe, Michael von Bergwelt, Stefan K. Bohlander, Andreas Faldum, Jan Braess, Bernhard J. Wörmann, Wolfgang E. Berdel, Utz Krug, Wolfgang Hiddemann, Karsten Spiekermann, Klaus H. Metzeler
Journal: Blood (2018)
ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism
Authors: David H. Peng, Samrat T. Kundu, Jared J. Fradette, Lixia Diao, Pan Tong, Lauren A. Byers, Jing Wang, Jaime Rodriguez Canales, Pamela A. Villalobos, Barbara Mino, Yanan Yang, Rosalba Minelli, Michael D. Peoples, Christopher A. Bristow, Timothy P. Heffernan, Alessandro Carugo, Ignacio I. Wistuba, Don L. Gibbons
Journal: Science Translational Medicine (2019)

Suppression of ZEB1 through miR-200 expression or HDAC inhibition with mocetinostat sensitizes resistant KRAS mutant lung cancers to MEK inhibition.
Project Data Sphere: A first look at prostate cancer including concomitant medication use, prognosis, and toxicity.
Authors: Anthony M. Joshua, Bethany Gill, Leila Khoja, Melania Pintilie, Kald Abdallah
Journal: Journal of Clinical Oncology (2015)

5022 Background: PDS (www.projectdatasphere.org) enables patient-level analyses of control arms of cancer trials. We aimed to include the use of concomitant medications (CM) to (i) validate and improve established prognostic metastatic prostate cancer (mCRPC) models (ii) establish novel predictive factors of toxicity. Methods: Data was obtained for 2,747 control subjects with mCRPC from 7 Phase III clinical trials (1962 subjects were available for OS analyses from 5 studies). OS was estimated using the Kaplan-Meier method. Cox-proportional hazards models, stratified by trial, were used to estimate hazard ratios. Results: Of 23 medication classes examined patients taking proton pump inhibitors (HR: 1.17, p = 0.017) and Erythropoietin (HR: 1.45, p < .001) had worse OS. Patients taking fish oil (HR: 0.67, p = 0.025) and non-lipophilic statins (HR: 0.67, p = .0.017) had improved OS. Initially, metastatic site was significant for OS (predicted median: Node 24.61m, Bone 22.77 m, Lung 21.39 m, Liver 15.18 m; p < 0.001). After adjusting for metastatic site, these medication classes remained significant (HR 1.15, p = 0.017; HR 1.493, p < 0.01; HR 0.68, p = 0.03; HR 0.68, p = 0.0278 respectively). We then validated and combined 2 multi-variate prognostic models for OS (Templeton et al, Sonpavde et al) after inclusion of CM. Patients taking metformin (HR = 0.729, p = .008) and Cox2 inhibitors (HR = 0.708, p = .015) had improved OS whilst those taking low molecular weight heparin (HR = 1.352, p = .004) had worse OS. Thereafter, a simplified prognostic model based on albumin and LDH alone, equivalent in prognostication was established. For docetaxel trials from baseline, baseline neutrophil to lymphocyte ratio was the best predictor of any toxicity (OR 4.23, p = .004) after accounting for number of cycles, whilst the lymphocyte count had an inverse relationship with the occurence of any severe AE (OR 0.31, p = 0.03). The incidence of toxicity after cycle 1 was the best predictor of subsequent adverse events (OR 5.82, p < 0.01) Conclusions: Initial analyses of PDS data in mCRPC allowed for insights into prognostic models and predictors of docetaxel toxicity. Expansion of trials and quality of data will facilitate future analyses.
Racial disparity (RD) in cancer risk: Lessons from the global epidemiology of childhood acute lymphoblastic leukemia.
Authors: Christopher Kwesi Oladipupo Williams
Journal: Journal of Clinical Oncology (2015)

e12606 Background: Race affects various aspects of cancer control (CC), including risk and access to care. Genotypic studies confirm race as a societal construct without a biological basis, revealing the US population as a 500-year-old mosaic of genetic admixture of diverse origins, and questioning the role of ancestral genetic markers in cancer risk and predisposition. 65% of cancers occur through random and stochastic effects of DNA mutations, while 35% are related to environmental factors (EF) or inherited predisposition (5%-10%). Virus associated cancers and subtypes of CHALL relate to the latter. Methods: In 1978-83, CHALL/lymphoma were studied in the Nigerian (N) city of Ibadan (population: 1-2x106), inhabited by people of socioeconomic status (SES) of high (annual income - AI- US$ > 5x103-104) (HSES), medium (AI: US$ 2x103-3.5x102) and low (AI: US$ < 103-1.5x102) (LSES). Results: Common acute lymphoblastic leukemia (c-ALL) incidence (INC) (x10-5) was 0.75-1.51 in HSES and 0.25-0.50 in LSES; Burkitt's lymphoma INC: 0.00 in HSES and 1.81-3.62 in LSES. Comparison of SES influence on CHALL from global reports, correlating EF surrogate markers, e.g. hepatitis A seroprevalence/infant mortality, with leukemia INC/mortality in 2-4 year olds (0-5 for N and South Africans [SA]), revealed the following pairings: N - 1982-84: 91.4/0.5; SA Blacks - 1974-82: 85.7/0.9; SA Whites: 45.5/5.9; Okinawa, Japan (OJ) before 1960: 90.0/2.3; United Kingdom 1983-89: 28.0/6.9; OJ 1980-84; US Caucasians (USC) 1921-25: 80.0/1.9; USC 1956-60: 50.0/5.9; USC 1976-80: 38.0/6.7; US Non-Caucasians (USNC) 1946-50: 67.0/2.0; Bangalore, India 1988-92: 84.0/3.0; Manila, Philippines 1988-92: 56.3/5.8; Cali, Colombia 1987-91: 70.0/5.5; Lima, Peru: 1990-91: 70.04.3. (Pearson r: -0.8565; 95% confidence interval: -0.9606 to -0.6479; p [two-tailed]: 0.0001). Conclusions: Global and temporal trends in c-ALL INC in diverse ethnicities indicate a greater role of EF than genetic differences, thus suggesting that public health measures in CC should address SES rather than RD.
Abstract P107: Thirty-Year Risk of Incident and Recurrent Ischemic Stroke in Individuals With Sickle Cell Trait and Modification by Midlife Risk Factors: The Atherosclerosis Risk in Communities Study
Authors: Melissa C Caughey, Vimal K Derebail, Nigel S Key, Alexander P Reiner, Rebecca F Gottesman, Abhijit V Kshirsagar, Gerardo Heiss
Journal: Circulation (2019)

Introduction: Sickle cell trait (SCT) has been associated with ischemic stroke in some, but not all, epidemiologic cohorts. Heterogeneity of the association may be related to differences in demographic subgroups or midlife risk factors. Methods: The ARIC study is an observational cohort based on 4 US communities. Participation has included 6 clinical visits and ongoing surveillance of acute cardiovascular events. Black participants were genotyped for SCT, excluding any with sickle cell anemia or hemoglobin SC disease. Global genetic ancestry was determined from whole genome variation. Midlife factors were ascertained at ARIC visit 1 (1987-1989), or if missing imputed from visit 2 (1990-1992). Acute ischemic stroke was classified by physician review of the medical record. Associations between SCT and ischemic stroke were analyzed using repeat-events Cox regression with robust estimators, counting all occurrences of ischemic stroke per participant. Models were adjusted for sex, age, global genetic ancestry, and midlife factors (smoking, hypertension, hyperlipidemia, diabetes, chronic kidney disease, and previous myocardial infarction). Effect modification was tested by the multiplicative interaction of SCT with each midlife factor. Results: Our population was composed of 3,827 black adults with complete midlife data (32 [0.8%] excluded). SCT was identified in 255 (7%). The mean age at visit 1 was 53 years; the median follow-up time was 26 years. Most (63%) were women. At midlife, individuals with SCT had a greater prevalence of hyperlipidemia (32% vs. 26%; P =0.04) and chronic kidney disease (20% vs. 13%; P =0.003). From 1987-2016, 579 ischemic strokes occurred in 456 individuals. SCT was more strongly associated with ischemic stroke in participants with chronic kidney disease [HR=2.01 (1.13 - 3.60)] than those without [HR=1.10 (0.77 - 1.57)], P for interaction = 0.05, Figure 1 . Conclusions: The association between SCT and ischemic stroke is heterogeneous and appears to be stronger in those with chronic kidney disease.
Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study.
Authors: Scott T. Tagawa, Bishoy Morris Faltas, Elaine Tat Lam, Philip James Saylor, Aditya Bardia, Julio Hajdenberg, Alicia K. Morgans, Emerson A. Lim, Kevin Kalinsky, Pamela S. Simpson, Matt D. Galsky, Trishna Goswam, William A. Wegener, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2019)

354 Background: Patients (pts) with mUC who progress after platinum (PLT)-based chemotherapy and immune checkpoint inhibitor (CPI) therapy have poor outcomes and limited treatment options. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate. It consists of a monoclonal antibody targeting Trop-2, an epithelial cell surface antigen overexpressed in UC, conjugated to the active metabolite of irinotecan (SN38). Methods: We performed a phase I/II basket study in pts with advanced solid tumors receiving intravenous SG administered on day 1 and 8 of 21-day cycles, until progression or unacceptable toxicity. CT/MRI scans were obtained at 8-week intervals for response assessment. We evaluated pts with mUC who progressed after ≥1 prior systemic therapy and were treated with SG at the 10 mg/kg dose level. Endpoints included safety, objective response rate (ORR) by RECIST 1.1, clinical benefit rate (CBR; complete response [CR], partial response [PR], or else SD ≥6-mo), and Kaplan-Meier estimated duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: 45 pts (41M/4F; median age 67, range 49-90; ECOG 0/1: 31%/69%) received a median of 2 (range: 1-6) prior treatment lines, including PLT-based chemotherapy (95%) and CPI (38%). 33 had visceral metastases involving liver (n=15), lung (n=27), and other organs (n=5). The ORR was 31% (14/45), with 2 CR and 12 PR. In pts with visceral involvement, the ORR was 27% (9/33). The ORR in CPI-treated pts was 23% (4/17). The median DOR was 12.6 mo (2 pts continuing &gt;2 y), and the CBR was 47% (21/45). Median PFS and OS were 7.3 mo and 18.9 mo, respectively. The AE profile was consistent with prior reports. Grade ≥3 AEs in ≥5% of pts were neutropenia/neutrophil count decreased (38%), anemia (11%), hypophosphatemia (11%), diarrhea (9%), fatigue (9%), and febrile neutropenia (7%). Conclusions: SG demonstrated clinical activity in pts with relapsed/refractory mUC, including CPI-treated pts and pts with visceral disease. A single-arm, open-label, global phase 2 trial is underway to evaluate antitumor activity and safety of SG in advanced UC.(TROPHY-U-01; NCT03547973). Clinical trial information: NCT03547973.
Glia-Neuron Interactions in <i>Caenorhabditis elegans</i>
Authors: Aakanksha Singhvi, Shai Shaham
Journal: Annual Review of Neuroscience (2019)

Glia are abundant components of animal nervous systems. Recognized 170 years ago, concerted attempts to understand these cells began only recently. From these investigations glia, once considered passive filler material in the brain, have emerged as active players in neuron development and activity. Glia are essential for nervous system function, and their disruption leads to disease. The nematode Caenorhabditis elegans possesses glial types similar to vertebrate glia, based on molecular, morphological, and functional criteria, and has become a powerful model in which to study glia and their neuronal interactions. Facile genetic and transgenic methods in this animal allow the discovery of genes required for glial functions, and effects of glia at single synapses can be monitored by tracking neuron shape, physiology, or animal behavior. Here, we review recent progress in understanding glia-neuron interactions in C. elegans. We highlight similarities with glia in other animals, and suggest conserved emerging principles of glial function.
Risk of subsequent dementia from androgen deprivation therapy (ADT) versus orchiectomy among men with prostate cancer.
Authors: Ravi Bharat Parikh, Sumedha Chhatre, S. Bruce Malkowicz, Bingnan Li, Ravishankar Jayadevappa
Journal: Journal of Clinical Oncology (2019)

239 Background: Retrospective studies have suggested an association between ADT and cognitive dysfunction among men with prostate cancer. This association may be mediated directly by ADT or indirectly by long-term decreased androgen levels. We hypothesized that there would be no difference in rates of subsequent dementia among elderly men who received ADT vs orchiectomy for treatment of prostate cancer. Methods: We conducted a retrospective cohort study using the SEER-Medicare database of men ≥66 years old diagnosed with localized or advanced prostate cancer between 1996 and 2003 who were treated with ADT (n = 60146) or orchiectomy (n = 1760), either alone or as part of combined therapy. We used propensity score-adjusted regression to study the association between ADT or orchiectomy and subsequent risk of Alzheimer’s disease or dementia. We excluded patients diagnosed with dementia before or within 2 years of therapy. Results: Men receiving ADT were younger and less likely to be married than men receiving orchiectomy (Table). There was no difference in ethnicity, comorbidity index, or socioeconomic status (SES) between the two groups. ADT did not carry a higher risk of subsequent Alzheimer’s (HR 1.10, 95% CI 0.95-1.28) or dementia (HR 0.93, 95% CI 0.83-1.05) compared to orchiectomy. Conclusions: Among a large cohort of elderly men with prostate cancer, ADT and orchiectomy carried similar long-term risks of subsequent dementia. [Table: see text]
Abstract P200: Unsaturated Fat Replacing Carbohydrate or Protein Affects Protein-Based HDL Subspecies of Different Functionality
Authors: Bo Zhang, Barry Guglielmo, Jeremy D Furtado, Frank M Sacks
Journal: Circulation (2019)

Introduction: HDL is a heterogeneous group of protein-lipid complexes comprised of stable subspecies defined by their protein content whose functions and associations with cardiovascular disease (CVD) are likely driven by their proteome. The Optimal Macronutrient Intake Trial to Prevent Heart Disease (OMNI Heart) found that unsaturated fat replacing carbohydrate or protein increased HDL cholesterol, but nothing is known about the effect of macronutrient composition on HDL subspecies concentrations. Hypothesis: Dietary unsaturated fat (UNSAT) replacing carbohydrate (CARB) or protein (PROT) affects protein-based HDL subspecies. Methods: The OMNI Heart Trial employed a randomized cross-over design that fed sequentially each of three study diets emphasizing CARB, PROT, or UNSAT to the participants. The apolipoprotein (apo) A1 concentrations of 16 HDL subspecies, selected to represent the major functions of HDL, were measured in plasma samples from 141 participants collected after 4 weeks on each diet. Results and Conclusions: UNSAT replacing CARB or PROT affected the levels of different HDL subspecies involved in lipid metabolism, anti-oxidation, anti-inflammation, and homeostasis (figure). UNSAT replacing PROT increased HDL that contains apoC1, apoL1, PON1, or plasminogen. UNSAT replacing CARB increased HDL that contains apoC1 and HDL that contains apoE, an HDL subspecies associated with protection against CVD. PROT replacing CARB decreased HDL that contains apoE. UNSAT replacing CARB or PROT increased HDL cholesterol, total apoA1, and HDL that contains apoA2, as expected. In conclusion, macronutrients affect HDL subspecies that vary in their functionality, which may contribute to the effects of dietary inventions on the risk of cardiovascular and other diseases.
Molecular and clinical profile of Li-Fraumeni Syndrome in a Brazilian cohort.
Authors: Maria Nirvana Cruz Formiga, Amanda Franca Nobrega, Karina Miranda Santiago, Maria Isabel Waddington Achatz
Journal: Journal of Clinical Oncology (2015)

e12533 Background: Li-Fraumeni syndrome (LFS), an autosomal dominant highly penetrant cancer predisposition syndrome, is associated with germline mutations in TP53 gene and characterized by a variety of early onset tumors. Core LFS tumors are soft-tissue and bone sarcomas (SBS), breast cancer (BC), adrenal cortical carcinoma (ACC) and brain tumors (BT). DNA-biding domain TP53 mutation carriers have a 90% lifetime risk of developing a cancer. In Brazil, a variant form of LFS is exceedingly frequent due to a founder TP53 mutation, p.R337H, detected in 0.3% of South and Southeastern Brazilian population. This mutation occurs outside the DNA-binding domain (exon 10), in TP53 oligomerization domain. TP53 p.R337H carriers have lower cumulative lifetime cancer risk, with a number of mutation carriers being cancer-free. Methods: From a cohort of 172 Brazilian germline TP53 mutation carrier families, pedigrees, medical records, histopathological reports and death certificates were retrospectively accessed. Clinical features of TP53 carriers were based on types of cancer, number of tumors and age of cancer diagnosis. The cancer pattern in p.R337H carriers and other mutation carriers was compared. Results: TP53 p.R337H was present in 76.7% of carriers . From all TP53 mutation carriers, 57.5% have developed at least one cancer (53.8% for p.R337H, 70% for other mutations), 36% of all cancer patients had two or more tumors. Mean age at first cancer diagnosis was 30.3 years old (32.7yo for p.R337H carriers, 24.2yo for other mutation carriers). In p.R337H patients, BC, SBS, ACC and BT account for 70.2% of all tumors. In this subgroup, we identified high occurrence of tumors that are not described as part of LFS spectrum, including thyroid, lung and kidney cancers. In other mutations carriers, a similar profile was found, including SBS, BC, BT and ACC, diagnosed in 72.4% of the tumors. Conclusions: Brazilian p.R337H founder mutation carriers have a similar tumor profile than typical TP53 mutations carriers. The high occurrence of the syndrome in Brazil may constitute a public health issue. The understanding of the tumors spectrum and the age of cancer onset in this population may help defining personalized follow-up strategies in p.R337H Brazilian carriers.
Abstract P309: The High Risk of Venous Thromboembolism in Black Americans
Authors: H. Nicole Tran, Natalia Udaltsova, Stanton Siu, Jeanne Darbinian, Arthur L Klatsky
Journal: Circulation (2019)

Background: Reports suggest a higher risk of venous thromboembolism (VTE) in Black persons compared to Whites. The major clinical presentations of VTE, pulmonary embolism (PE) and deep venous thrombosis (DVT) are considered parts of the same pathological process and generally share the same risk factors. Sparse data raise the possibility of additional Black/White disparity in clinical VTE presentation; specifically, larger proportions of presentation with PE in Blacks than Whites and vice versa with DVT in Whites compared to Blacks. We present here relevant data from a new study with 4,674 VTE subjects. Hypothesis: The Black/White disparity in VTE may be concentrated in greater risk of Blacks for PE. Methods: We studied composite VTE risk in 61,459 members of a comprehensive health plan, who had supplied self-classified ethnicity data on prior health examinations between 1978 and 1985 and remained plan members in 1996, when out-patient diagnoses were added to electronic health records. Subjects were 28% Black, (n = 17,442), and 53% White (n = 32,557). From 1996 through 2015, at least one diagnosis of VTE was made during an outpatient visit or hospitalization for 4,675 persons (1,554 Black and 2,576 White). With Whites as referent we performed logistic regressions with 5 covariates. Models stratified by race were performed to explore traits of specific VTE codes and circumstances of diagnosis (hospitalization, out-patient, etc.). Results: The table shows HRs (95% CI) of Blacks vs Whites. Increased VTE risk of Blacks in each sex was entirely concentrated in subjects with PE and with hospitalization diagnoses. Among covariates sex, education, and smoking were unrelated to VTE risk while BMI was directly associated; results were similar in Whites, Blacks and race-stratified models within the diagnosis code and location of diagnosis groups. Conclusion: Compared to Whites, Black persons have an unexplained increased risk of PE but not of DVT.
Single agent versus doublet chemotherapy as second-line therapy of metastatic urothelial carcinoma (UC): A meta-analysis.
Authors: Daniele Raggi, Rosalba Miceli, Guru Sonpavde, Patrizia Giannatempo, Nicola Nicolai, Gurudatta Naik, Roberto Salvioni, Giuseppe Procopio, Filippo G. De Braud, Luigi Mariani, Andrea Necchi
Journal: Journal of Clinical Oncology (2015)

e15527 Background: The efficacy and safety of adding a second chemotherapeutic agent to single agent chemotherapy (CT), i.e. taxanes or vinflunine, in the second-line setting of UC is unclear. We compared the efficacy and safety of these two strategies through a trial level meta-analysis. Methods: PubMed, EMBASE, and ASCO abstracts were searched for trials including single agent or doublet CT in the second-line setting of UC following platinum-based CT. Random-effects models were used to pool trial level data according to treatment arm, including median PFS and OS, objective reponse-rate (ORR), and G3-4 toxicities. Multivariable analyses (MVA) were performed to compare single agent vs doublet CT, overall and by subgroups, adjusting for percentage of patients (pts) with ECOG performance status 2 and visceral metastases. Model weights were estimators inverse variances for ORR and toxicities; the logarithm of the trial sample sizes were used for OS and PFS. Results: 47 arms of phase II and III trials including 1964 pts were selected: 22 with single agent [n = 1202], including 3 (n = 486) vinflunine and 6 paclitaxel/docetaxel (n = 232). Of the 25 arms with doublets (n = 762), 6 were with cis- or carboplatin (n = 423), 21 (n = 656) with a taxane. The pooled ORR with single agents was 0.14 (95%CI: 0.11-0.18) vs 0.32 (95%CI: 0.28-0.37) with doublets. Pooled median PFS was 3.02 months (mo) and 5.03 mo, respectively. Pooled median OS was 7.5 mo and 9.33 mo. Multivariably, ORR odds ratio of doublet vs single agent was 2.95 (95%CI: 2.11-4.12, p < 0.001), pooled median difference was 2.21 mo (95%CI: 0.99, 3.43, p < 0.001) for PFS, and 1.92 mo (95%CI: 0.44-3.39, p = 0.011) for OS. There were no significant differences in G3-4 anemia (p = 0.392), neutropenia (p = 0.487), and thrombocytopenia (p = 0.822) in MVA. No differences were found between vinflunine and taxanes, and between different doublets for any outcome. Conclusions: In this meta-analysis, doublet CT regimens improved ORR and extended PFS and OS compared to single agents in pts receiving second-line CT for UC. The prospective evaluation of potent combinations of second-line CT may be rational in order to improve outcomes and serve as the foundation to combine with biologic agents.
Left Ventricular Contractility and Wall Stress in Patients With Aortic Stenosis With Preserved or Reduced Ejection Fraction
Authors: Saki Ito, Cristina Pislaru, William R. Miranda, Vuyisile T. Nkomo, Heidi M. Connolly, Sorin V. Pislaru, Patricia A. Pellikka, Bradley R. Lewis, Blase A. Carabello, Jae K. Oh
Journal: JACC. Cardiovascular imaging (2019)