tbuckley/cabot-search huggingface dataset:
Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
Authors: Brian D. Hobbs, Rachel K. Putman, Tetsuro Araki, Mizuki Nishino, Gunnar Gudmundsson, Vilmundur Gudnason, Gudny Eiriksdottir, Nuno Rodrigues Zilhao Nogueira, Josée Dupuis, Hanfei Xu, George T. O’Connor, Ani Manichaikul, Jennifer Nguyen, Anna J. Podolanczuk, Purnema Madahar, Jerome I. Rotter, David J. Lederer, R. Graham Barr, Stephen S. Rich, Elizabeth J. Ampleford, Victor E. Ortega, Stephen P. Peters, Wanda K. O’Neal, John D. Newell, Eugene R. Bleecker, Deborah A. Meyers, Richard J. Allen, Justin M. Oldham, Shwu-Fan Ma, Imre Noth, R. Gisli Jenkins, Toby M. Maher, Richard B. Hubbard, Louise V. Wain, Tasha E. Fingerlin, David A. Schwartz, George R. Washko, Ivan O. Rosas, Edwin K. Silverman, Hiroto Hatabu, Michael H. Cho, Gary M. Hunninghake
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
Point-of-care Ratiometric Fluorescence Imaging of Tissue for the Diagnosis of Ovarian Cancer
Authors: Xiaobo Zhou, Yawei Liu, Qiyu Liu, Luzhe Yan, Meng Xue, Wei Yuan, Mei Shi, Wei Feng, Congjian Xu, Fuyou Li
Journal: Theranostics (2019)

During a minimally invasive tumor resection procedure, it is still a challenge to rapidly and accurately trace tiny malignant tumors in real time. Fluorescent molecular imaging is considered an efficient method of localizing tumors during surgery due to its high sensitivity and biosafety. On the basis of the fact that γ-glutamyltranspeptidase (GGT) is overexpressed in ovarian cancer, we herein designed a highly sensitive ratiometric fluorescent GGT-responsive probe Py-GSH for rapid tumor detection.
David Gwyn Thomas
Authors: Martyn Thomas, Kieran J O’Flynn
Journal: BMJ (2019)

David Gwyn Thomas was born in Wells, Somerset, the only child of Welsh parents. A talented academic, sportsman, and pianist, he obtained a scholarship to read medicine at Middlesex Hospital in 1957. There he met his future wife, Eileen, a student nurse at University College Hospital next door. He worshipped at Westminster Chapel under the pastor, Martyn Lloyd-Jones, and developed a deep and abiding faith …
Evaluation of the effect of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR‐Reduced trial
Authors: Milton Packer, Javed Butler, Gerasimos S. Filippatos, Waheed Jamal, Afshin Salsali, Janet Schnee, Karen Kimura, Cordula Zeller, Jyothis George, Martina Brueckmann, Stefan D. Anker, Faiez Zannad
Journal: European Journal of Heart Failure (2019)

Drugs that inhibit the sodium-glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin-angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction.
Does multiple mutational analysis of the EGFR pathway have a prognostic role in advanced colorectal cancer (CRC)?
Authors: Luisa Foltran, Giuseppe Aprile, Giovanna De Maglio, Federica Edith Pisa, Mariaelena Casagrande, Laura Ferrari, Stefania Eufemia Lutrino, Micol Mazzer, Elena Masiero, Nicoletta Pella, Mariella Giovannoni, Emiliana Iaiza, Giovanni Cardellino, Paola Ermacora, Vittorio Durastante, Antonio Cristin, Roberto Petri, Stefano Pizzolitto, Gianpiero Fasola
Journal: Journal of Clinical Oncology (2012)

3612 Background: BRAF mutation is widely recognised as a strong negative prognostic factor in advanced CRC, while the prognostic value of KRAS mutations in codons 12-13 remains controversial. Exploring mutations in other downstream components of the EGFR pathway may have an impact on survival. Methods: A consecutive cohort of 201 metastatic CRC patients treated with systemic chemotherapy were analysed for KRAS (12-13-61-146), BRAF, PIK3CA and NRAS genotypes by pyrosequencing on PyroMarkTMQ96 ID instrument (Qiagen, Germany) with commercially available kits Anti-EGFR MoAb response (Diatech Pharmacogenetics, Italy). Accurate microdissection guaranteed more than 70% of cancer cells for each sample. For the purpose of the survival analysis 4 categories were created: (1) KRAS mutated (codons 12-13 only); (2) BRAF mutated; (3) any of KRAS codons 61-146, PIK3CA or NRAS mutations; (4) all-wild type. Log-rank and Cox proportional tests were applied for statistical analysis. Results: KRAS mutations were present in 96 (47.8%) patients: 86 (42.8%) were in codons 12-13. BRAF mutations were found in 11 (5.5%) samples while PIK3CA and NRAS in 33 (16.4%) and 7 (3.5%), respectively. All mutations were mutually exclusive except for 24 (11.9%) patients with concomitant KRAS/PIK3CA mutations. Median survivals for different categories are shown. Patients harbouring BRAF mutation had the worst outcome (p=0.0006). Mutations of any codon of KRAS (12-13-61-146) also negatively impacted on survival (p=0.026), while the all wild-type (KRAS/BRAF/PIK3CA/NRAS) patients had the longest survival (p=0.002). Conclusions: This study suggests the usefulness for early molecular profiling for advanced CRC patients. Mutational analysis of all EGFR pathway components may identify different prognostic subgroups. This information may drive treatment selection in clinical practice and stratification in clinical trials. [Table: see text]
Donor-derived cell-free DNA detects kidney transplant rejection during nivolumab treatment
Authors: Daan P. Hurkmans, Jeroen G. H. P. Verhoeven, Kitty de Leur, Karin Boer, Arjen Joosse, Carla C. Baan, Jan H. von der Thüsen, Ron H. N. van Schaik, Ron H. J. Mathijssen, Astrid A. M. van der Veldt, Dennis A. Hesselink
Journal: Journal for ImmunoTherapy of Cancer (2019)

In solid organ transplant (SOT) recipients, transplant rejection during immune checkpoint inhibitor (ICI) treatment for cancer is a clinical problem. Donor-derived cell-free DNA (dd-cfDNA) can be detected in blood and is a sensitive biomarker for diagnosis of acute rejection in SOT recipients. To our best knowledge, this is the first case report of a kidney transplant recipient with advanced cancer treated with ICI who was monitored with dd-cfDNA.A 72-year old female with a long-standing renal transplant was diagnosed with advanced melanoma in 2018 and was treated with the anti-PD1 antibody nivolumab. Within 12 days after the first administration of nivolumab, dd-cfDNA ratio increased to 23%, suggesting allograft rejection. Her kidney transplant function deteriorated and acute rejection was confirmed by renal transplant biopsy. As the rejection could not be controlled despite immunosuppressive treatment, a transplant nephrectomy was necessary and haemodialysis was started. Immunological analysis of the renal explant showed infiltration of alloreactive, nivolumab-saturated, PD1+ cytotoxic T cells. After transplant nephrectomy, she experienced nivolumab-related toxicity and rapid disease progression.Clinicians prescribing ICIs should be aware that SOT recipients are at risk of transplant rejection as a result of T cell activation. Dd-cfDNA is a sensitive biomarker and should be further studied for early detection of transplant rejection. Immunological analysis of the kidney explant showed marked graft infiltration with alloreactive PD-1+ cytotoxic T cells that were saturated with nivolumab.
Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).
Authors: Sattva Swarup Neelapu, Caron A. Jacobson, Olalekan O. Oluwole, Javier Munoz, Abhinav Deol, David Bernard Miklos, Nancy L. Bartlett, Ira Braunschweig, Yizhou Jiang, Jenny J. Kim, Lianqing Zheng, John M. Rossi, Frederick Lundry Locke
Journal: Journal of Clinical Oncology (2019)

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 10 6 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs &lt; 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs &lt; 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm 2 vs 3574 mm 2 . Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and &lt; 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts &lt; 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts &lt; 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts &lt; 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs &lt; 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs &lt; 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and &lt; 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.
Natural History of Myocardial Late Gadolinium Enhancement Predicts Adverse Clinical Events in Heart Transplant Recipients
Authors: Kongkiat Chaikriangkrai, Muhannad Aboud Abbasi, Roberto Sarnari, Daniel Lee, Allen S. Anderson, Kambiz Ghafourian, Sadiya S. Khan, Esther E. Vorovich, Jonathan D. Rich, Jane E. Wilcox, Julie A. Blaisdell, Clyde W. Yancy, James Carr, Michael Markl
Journal: JACC. Cardiovascular imaging (2019)
The role of high-dimensional profiling of the systemic immune response on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB).
Authors: Kevin Lee Min Chua, Michael Fehlings, Pek Lim Chu, Xiao-Tian Lin, Eugenia Yeo, Kar Perng Low, Dennis Poon, Enya Ong, Wai Yee Woo, Joseph Wee, Alessandra Nardin, N Gopalakrishna Iyer, Daniel Shao-Weng Tan, Khee Chee Soo, Evan Newell, Melvin Lee Kiang Chua
Journal: Journal of Clinical Oncology (2019)

13 Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB. Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N = 10). All patients received ablative RT (8-50 Gy/1-5 fr) for oligoprogression and/or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools. Results: Median follow-up of the overall cohort was 18 mo; median duration of ICB received in the ICB-RT-ICB arm was 15 mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P &lt;0.01). This clinical phenomenon corresponded to an increased % Ki67 high CD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P &lt;0.01). Deeper immunophenotyping of the Ki67 high subsets revealed associated high expression of GranzymeB and Eomes. Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB.
Chimeric Antigen Receptor T‐Cell Therapy Clinical Results in Pediatric and Young Adult B‐ALL
Authors: Amanda M. DiNofia, Shannon L. Maude
Journal: HemaSphere (2019)

Abstract Chimeric antigen receptor (CAR)‐modified T‐cell therapy has revolutionized the care of patients with relapsed and refractory B‐cell acute lymphoblastic leukemia (B‐ALL). Results from clinical trials across multiple institutions report remarkable remission rates with CD19‐directed CAR‐modified T‐cell therapy. These remissions are also proving to be durable in many patients with a relapse‐free survival (RFS) of approximately 50% to 60% at 1 year across several trials and institutions in this population that has been historically very difficult to treat. In addition, new products are being developed to enhance upon the original CAR T‐cell products, which include a humanized CAR, allogeneic CARs, and both CD22 and biallelic CD19 and CD22 constructs. Toxicity after CAR‐modified T‐cell therapy is characterized by cytokine release syndrome (CRS) and neurotoxicity in the acute post‐infusion period and B‐cell aplasia as a long‐term consequence of treatment. This review will summarize the published data thus far on the use of CAR‐modified T‐cell therapy in pediatric B‐ALL and outline the various CAR products now being developed for this population. Delivery of this therapy and the decision to pursue hematopoietic stem cell transplant (HSCT) after treatment will be discussed.
For-profit hospital ownership status and use of brachytherapy after breast-conserving surgery.
Authors: Sounok Sen, Pamela R. Soulos, Jeph Herrin, Kenneth B Roberts, James B. Yu, Beth-Ann Lesnikoski, Joseph S. Ross, Harlan Krumholz, Cary Philip Gross
Journal: Journal of Clinical Oncology (2013)

6511 Background: Because the benefits of adjuvant radiation therapy (RT) for breast cancer decrease with increasing age, the use of newer and more expensive RT modalities such as brachytherapy in the treatment of older women has been questioned. In particular, patients and policy makers may be concerned that for-profit hospitals might be more likely to use therapies with higher reimbursements. Among both younger and older Medicare beneficiaries with breast cancer, we examined whether hospital ownership status is associated with use of adjuvant brachytherapy. Methods: Using the Centers for Medicare and Medicaid Services Chronic Condition Warehouse database, we conducted a retrospective study of female Medicare beneficiaries aged 66-94 years old receiving breast-conserving surgery for invasive breast cancer in 2008 and 2009. We assessed the relationship between hospital ownership and receipt of brachytherapy, as well as overall RT (i.e. brachytherapy or whole breast irradiation) using hierarchical generalized linear models. Results: The sample consisted of 35,118 women, 8.0% of whom had undergone surgery at for-profit hospitals.Among patients who received RT, those who underwent surgery at for-profit hospitals were significantly more likely to receive brachytherapy (20.2%) than patients treated at not-for-profit hospitals (15.2%; OR for profit vs. not-for profit: 1.50; 95% CI: 1.23-1.84; p&lt;0.001). Among women 66-79 years old, there was no relation between hospital profit status and overall RT use. However, among women age 80-94 years old, receipt of surgery at a for-profit hospital was significantly associated with higher overall RT use (OR: 1.22; 95% CI: 1.03-1.45, p=0.03) and brachytherapy use (OR: 1.66; 95% CI: 1.18-2.34, p=0.003), but not whole breast irradiation use (OR: 1.14; 95% CI: 0.96-1.36, p=0.13) Conclusions: Medicare beneficiaries undergoing breast-conserving surgery at for-profit hospitals were more likely to receive brachytherapy, a newer, less proven, and more expensive technology. Among the oldest women, who are least likely to benefit from RT, care at a for-profit hospital was associated with higher overall RT use, with this difference largely driven by the use of brachytherapy.
SAT0592 THE IMPACT OF ORAL GLUCOCORTICOIDS ON THE DEVELOPMENT OF CATARACTS AND GLAUCOMA IN INCIDENT RHEUMATOID ARTHRITIS PATIENTS
Authors: Rachel Black, Susan Lester, Catherine Hill, Will Dixon
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Cataracts and glaucoma are recognised glucocorticoid (GC) adverse effects. However, the impact of GC use, dose and timing on the development of cataracts and glaucoma has not been well quantified. <h3>Objectives:</h3> 1. To determine the association between GC use and dose and the development of cataract and glaucoma in patients with incident RA, 2. To determine the lag effect of GC dose. <h3>Methods:</h3> Data were used from the Clinical Practice Research Datalink (CPRD), a large UK primary care database derived from an electronic medical record (Jan 1992- Dec 2017). RA patients were identified using a validated algorithm and only incident patients were included. Parametric log-logistic survival models were used to assess the impact of GC use, dose (prednisolone daily dose equivalent) and lagged dose (at 1, 3, 6 months, 1 &amp; 2 years). A square root transformation of dose was used for the cataract models. Smoking, gender and uveitis were included as covariates in the model and age was used as the timescale. Comorbidities on the causal pathway, such as diabetes and hypertension, were not included. Results were reported as odds ratios (OR) for the cumulative incidence. <h3>Results:</h3> There were 22607 patients with incident RA (median age 66, IQR 37-84, 68% female), of which 241 had cataracts and 164 had glaucoma on or before baseline. Median duration of follow up was 8.7 years (IQR 1.8-19.8) and 39% were ever GC users during follow up. The incidence rate, per 1000 patient-years was 12.3 (95% CI 11.8, 12.9) for cataracts and 3.1 (95% CI 2.8, 3.4) for glaucoma, and increased with age. Uveitis was an important predictor for both cataracts and glaucoma, and cataracts were more frequent in females. GC use and GC dose were associated with both cataracts and glaucoma (Table 1). In the multivariable lagged dose analysis, GC dose at 1-year prior had the greatest effect size for cataracts (OR 1.26, 95% CI 1.12, 1.42), whereas GC dose at 3-months prior had the greatest effect size for glaucoma (OR 1.06, 95% 1.01, 1.11). <h3>Conclusion:</h3> The quantification of the risk associated with GCs and the development of cataract and glaucoma is of clinical utility in daily practice. EULAR guidelines recommend patients are informed of the risks and benefits of GC treatment prior to commencement, however the risk of these potential adverse effects had not previously been quantified. This information will allow patients to make better-informed treatment choices in conjunction with their treating doctor. <h3>Disclosure of Interests:</h3> None declared