bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of comorbidities on mortality among men and women with COPD: report from the OLIN COPD study
Authors: Sawalha Sami , Hedman Linnea , Backman Helena , Stenfors Nikolai , Rönmark Eva , Lundbäck Bo , Lindberg Anne 
Published: July 2019

Background: Comorbidities probably contribute to the increased mortality observed among subjects with chronic obstructive pulmonary disease (COPD), but sex differences in the prognostic impact of comorbidities have rarely been evaluated in population-based studies. The aim of this study was to evaluate the impact of common comorbidities, cardiovascular disease (CVD), diabetes mellitus (DM), and anxiety/depression (A/D), on mortality among men and women with and without airway obstruction in a population-based study. Methods: All subjects with airway obstruction [forced expiratory volume in 1 second (FEV1)/(forced) vital capacity ((F)VC) <0.70, n = 993] were, together with age- and sex-matched referents, identified after examinations of population-based cohorts in 2002–2004. Spirometric groups: normal lung function (NLF) and COPD (post-bronchodilator FEV1/(F)VC <0.70) and additionally, LLN-COPD (FEV1/(F)VC <lower limit of normal). Mortality data was collected until December 2015. Results: In COPD, the prevalence of CVD and DM was higher in men, whereas the prevalence of A/D was higher in women. The cumulative mortality was significantly higher in COPD than NLF, and higher in men than women in both groups. Among women with COPD, CVD and A/D but not DM increased the risk of death independent of age, body mass index, smoking habits, and disease severity, whereas among men DM and A/D but not CVD increased the risk for death. When the LLN criterion was applied, the pattern was similar. Conclusion: There were sex-dependent differences regarding the impact of comorbidities on prognosis in COPD. Even though the prevalence of CVD was higher in men, the impact of CVD on mortality was higher in women, and despite higher prevalence of A/D in women, the impact on mortality was similar in both sexes. The reviews of this paper are available via the supplemental material section.
Total cholesterol/HDL-cholesterol ratio discordance with LDL-cholesterol and non-HDL-cholesterol and incidence of atherosclerotic cardiovascular disease in primary prevention: The ARIC study
Authors: Quispe Renato , Elshazly Mohamed B , Zhao Di , Toth Peter P , Puri Rishi , Virani Salim S , Blumenthal Roger S , Martin Seth S , Jones Steven R , Michos Erin D 
Published: July 2019

Aims The total cholesterol (TC)/high-density lipoprotein (HDL) cholesterol ratio may carry additional information not available in more commonly used single cholesterol measures. Analysis of discordance between lipid parameters might help assess the impact of such additional information on the risk of atherosclerotic cardiovascular disease. We aimed to investigate the role of the TC/HDL-cholesterol ratio in determining atherosclerotic cardiovascular disease risk when discordant with low-density lipoprotein (LDL) cholesterol and non-HDL-cholesterol. Methods We studied 14,403 Atherosclerosis Risk in Communities (ARIC) study participants who were free of atherosclerotic cardiovascular disease at baseline. TC/HDL-cholesterol discordance with LDL-cholesterol (estimated by the novel Martin/Hopkins method) and non-HDL-cholesterol was assessed at five visits and determined by being at or above the median for each lipid parameter. We constructed Cox proportional hazard models to estimate the risk for incident atherosclerotic cardiovascular disease events associated with each lipid concordance/discordance category using a time-varying approach. Results Mean age of participants was 54.1 years, 56% women and 25% black. There were 2634 atherosclerotic cardiovascular disease events over a median (interquartile range) follow-up of 24.2 (16.0–25.4) years. Among individuals with LDL-cholesterol and non-HDL-cholesterol less than the median, 26% and 21% had discordant TC/HDL-cholesterol at or above the median, respectively. These individuals had a 24% (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.09, 1.41) and 29% (HR 1.29, 95% CI 1.13, 1.46) greater risk of incident atherosclerotic cardiovascular disease, respectively, compared to those with TC/HDL-cholesterol less than the median after multivariable adjustment. In individuals with diabetes with LDL-cholesterol or non-HDL-cholesterol less than the median, discordant TC/HDL-cholesterol at or above the median was more prevalent at 48% and 38%, respectively. Conclusion Clinically significant discordance exists between TC/HDL-cholesterol, available from the standard lipid profile, and the routinely used non-HDL-cholesterol and LDL-cholesterol. Such discordance may help inform atherosclerotic cardiovascular disease risk management, particularly in individuals with diabetes in whom discordance is more common.
Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia
Authors: Lucena-Araujo Antonio R. , Coelho-Silva Juan L. , Pereira-Martins Diego A. , Silveira Douglas R. , Koury Luisa C. , Melo Raul A. M. , Bittencourt Rosane , Pagnano Katia , Pasquini Ricardo , Nunes Elenaide C. , Fagundes Evandro M. , Gloria Ana B. , Kerbauy Fábio , de Lourdes Chauffaille Maria , Bendit Israel , Rocha Vanderson , Keating Armand , Tallman Martin S. , Ribeiro Raul C. , Dillon Richard , Ganser Arnold , Löwenberg Bob , Valk P. J. M. , Lo-Coco Francesco , Sanz Miguel A. , Berliner Nancy , Rego Eduardo M. 
Published: July 2019

Abstract
Luceno-Araujo et al use assays of mutations associated with myeloid malignancy to propose an integrative prognostic score for acute promyelocytic leukemia (ISAPL) in patients treated with all-trans retinoic acid and anthracycline-based therapy. They demonstrate that the ISAPL is superior for predicting outcomes and identifying patients who may benefit from alternative therapies to maximize their chance of a cure.
Early progression as a predictor of survival in marginal zone lymphomas: an analysis from the FIL-NF10 study
Authors: Luminari Stefano , Merli Michele , Rattotti Sara , Tarantino Vittoria , Marcheselli Luigi , Cavallo Federica , Varettoni Marzia , Bianchi Benedetta , Merli Francesco , Tedeschi Alessandra , Cabras Giuseppina , Re Francesca , Visco Carlo , Torresan Delamain Marcia , Cencini Emanuele , Spina Michele , Ferrero Simone , Ferrari Angela , Deodato Marina , Mannina Donato , Annibali Ombretta , Rago Angela , Orsucci Lorella , Defrancesco Irene , Frigeni Marco , Cesaretti Marina , Arcaini Luca 
Published: July 2019

Abstract
Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome in MZL and identifies a high-risk population. This trial was registered at www.clinicaltrials.gov as #NCT02904577.
Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif
Authors: Zhou Peixun , Blain Alex E. , Newman Alexander M. , Zaka Masood , Chagaluka George , Adlar Filbert R. , Offor Ugonna T. , Broadbent Casey , Chaytor Lewis , Whitehead Amber , Hall Amy , O’Connor Hettie , Van Noorden Susan , Lampert Irvin , Bailey Simon , Molyneux Elizabeth , Bacon Chris M. , Bomken Simon , Rand Vikki 
Published: July 2019

Abstract
FOXO1 has an oncogenic role in adult germinal center–derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1, resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples, respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3, or members of the phosphatidylinositol 3-kinase signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.
Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Morgensztern Daniel , Bazhenova Lyudmila , Waqar Saiama Naheed , McDermott Lori , Hutchins Jeff , Harb Wael A. , Velcheti Vamsidhar , Cohen Roger B. 
Published: July 2019

101 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma (AD) cell line transfected with the gp96-Ig fusion protein. DURGA is a multi-cohort study evaluating the combination of HS-110 and immune checkpoint blockers (ICBs) in patients with advanced NSCLC. Here we report the initial two cohorts with the combination of HS-110 and nivolumab. Methods: Patients (pts) with previously treated NSCLC received 1 X 107 HS-110 cells weekly for the first 18 weeks and nivolumab 3 mg/kg or 240 mg every 2 weeks until intolerable toxicity or tumor progression. Tissue was tested at baseline for PD-L1 expression (≥ 1% or < 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined by more than 10% CD8+ lymphocytes in the tumor stroma. Pts in cohort A had never received, and pts in cohort B had received, prior ICBs. The primary objectives were safety and objective response rates (ORR). Results: As of the August 2018 data cut-off, there were 43 pts enrolled into cohort A (40 AD and 3 squamous cell carcinoma [SCC]) and 18 pts in cohort B (15 AD and 3 SCC). In cohort A, 14 pts (32.6%) were TIL high, 13 (30.2%) TIL low and 16 (37.2%) TIL unknown. ORR, disease control rate (DCR), median progression-free survival (PFS) and 1 year PFS were 18.6%, 48.8%, 1.9 months and 23.9% respectively in cohort A, with median follow up of 432 days. ORR, DCR, and PFS were 22%, 50% and 2.2 months respectively in cohort B, with median follow up of 43 days. The median overall survival (mOS) was not reached in either cohort. In cohort A, TIL low at baseline was associated with increased mOS compared to TIL high (not reached vs 13.8 months, hazard ratio [HR] 0.23, 95% CI 0.068-0.81, p = 0.04). There were no differences in mOS according to PD-L1 status in cohort A (p = 0.82). 57 (93%) pts experienced at least one adverse event (AE), of which 39 (64%) were grade 1 or 2. The most common AEs were fatigue (31%), cough and diarrhea (19.7% each). There were 2 grade 5 AEs (3.3%) caused by pulmonary embolism and tumor progression, neither considered to be treatment related. Conclusions: The combination of HS-110 and nivolumab is safe with encouraging preliminary efficacy data. The study is ongoing and additional populations are being explored. Clinical trial information: NCT02439450.
Nivolumab treatment in advanced non-small cell lung cancer (NSCLC): Retrospective analysis of real-life data in the Hospital Universitario Reina Sofía (HURS).
Authors: GarcÃa DurÃ¡n Carmen , Moreno-Vega Alberto L. , Sánchez Mauriño Pedro , López-González Javier , Barneto - Aranda Isidoro C. , De La Haba Juan , Aranda Aguilar Enrique 
Published: July 2019

108 Background: Recently, nivolumab has been approval as 2nd-line treatment of non-small cell lung cancer (NSCLC) in our country. Data regarding its effectiveness or safety in real-life setting are publishing daily. Methods: 27 patients with advanced NSCLC treated with nivolumab at HURS between February 2016 to November 2017, were evaluated for survival (overall survival OS, progression-free survival PFS), time to treatment failure (TTF), treatment discontinuation due to toxicity and demographics/clinicopathological characteristics, using SPSS v 8.0. Results: Median age was 62 years; 77,8% males. At closing data, 25,9% of patients were still receiving nivolumab treatment. 51,9 % had finished treatment due to disease progression and 7,4% to toxicity. 25,9% patients continued others chemotherapies schedules. Mean of cycles received was 11. 51,8% presented ORR to nivolumab (78% PR). The median TTF at nivolumab was 3 months. The median progression-free survival (PFS) was 6.93 months (6,2 months in the squamous histology vs 9,42 in adenocarcinoma). The median OS was 22.6 months. Neutrophil-lymphocyte ratio in a complete blood count did not decrease during nivolumab treatment in any patients (p < 0.05, McNemar test), no relation to survival rates (with a cut-off of 5 and 3). Conclusions: Effectiveness (OS and PFS) of nivoumab were high in our patients, slightly better than those observed with similar characteristics included in clinical trials. We have not found predictive survival markers.
A severe case of refractory esophageal stenosis induced by nivolumab and responding to personalized treatment.
Authors: Obeid Michel 
Published: July 2019

113 Background: The prevalence of esophageal stenosis caused by ICI in the context of induced immune mucositis and esophagitis is extremely rare. Methods: NA. Results: Case presentation: We report the case of a patient with stage IV pulmonary adenocarcinoma treated for 6 months with nivolumab who developed bilateral conjunctivitis followed by oropharyngeal mucositis and esophagitis complicated by a severe esophageal stenosis. The laryngeal margin and hypopharyngeal mucosa appeared highly inflammatory. Esophagogastroduodenoscopy revealed mucositis with a scar-like stricture immediately below the upper esophageal sphincter with nonulcerative mucosa and an inflammatory aspect of the entire esophagus. No involvement of the stomach was observed. Oropharynx biopsies displayed marked lymphocytic T cell-infiltration with several foci of monocellular necrosis in the squamous epithelium. A blood sample revealed a discrete increase in the ESR with no eosinophilia or leukocytosis. Liver and kidney function panel tests were normal. A CT scan reported no evidence of disease recurrence. Despite multiple boluses of methylprednisolone and high doses of prednisone continued for several months, the patient experienced very rapid symptomatological reappearance during three steroid tapering attempts and aggravation of his esophageal stenosis to an aphagic stage, requiring a nasogastric tube. This long course of high-dose corticosteroid treatment was complicated with osteoporosis-induced fractures with several spontaneous compressions of thoracolumbar vertebrae requiring an enlarged T10 to L5 cementoplasty. Anti-IL-6 blockade therapy with tocilizumab resulted in excellent response, allowing the total resolution of the irAEs leading to successful steroid tapering. Conclusions: Herein, we describe the first case of a patient who developed autoimmune mucositis and esophagitis complicated by a severe refractory esophageal stenosis induced during treatment by nivolumab, which completely resolved after personalized treatment with tocilizumab, suggesting a role of IL-6 blockade in the management of severe steroid refractory irAEs.
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Tun Aung , Thein Wai Lin , Elfiky Aymen , Gasperino James , Guevara Elizabeth 
Published: July 2019

117 Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥ grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Seven phase 2 & 3 RCTs (Keynote-021,189, 407, IMpower-131, 150, checkmate-227, and Govindan et al) including 3785 patients with advanced NSCLC were included in the analysis. IMpower 150 trial allowed EGFR or ALK mutated patients. The study arm used standard treatment regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab, while control arm used only standard treatment regimens. The pooled HR for PFS was 0.65 (95% CI: 0.56-0.77; P=0.00001), the pooled HR for OS was 0.73 (95% CI: 0.59-0.90; P=0.003), and the pooled RR for ORR was 1.45 (95 CI: 1.17-1.8; P=0.0007). The pooled RRs for all-grade AEs and high-grade AEs were 1.1 (95% CI: 1-1.21; P=0.05) and 1.28 (95% CI: 1.13-1.46; P=0.0001), respectively. Conclusions: Adding immunotherapy to standard regimen significantly improves PFS, OS, and ORR for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.
Estimated costs of grade 3–4 all-cause and treatment-related adverse events for stage IV or recurrent non-small cell lung cancer (NSCLC) in the CheckMate 227 (CM-227) trial.
Authors: Stenehjem David D. , Santi Irene , Gupte-Singh Komal , Penrod John R. , Venkatachalam Meena 
Published: July 2019

120 Background: In the ongoing phase 3 CM-227 trial, nivolumab + ipilimumab (N+I) showed significantly longer progression-free survival compared to chemotherapy (C) among patients with NSCLC and tumor mutational burden (TMB) ≥10 mutations/megabase (high) by Foundation One CDx. The frequencies of all-cause (AC) and treatment-related (TR) adverse events (AEs) including grade 3–4 AEs were similar between the N+I and C arms, although the types of AEs differed. This study estimated the costs of managing grade 3–4 ACAEs and TRAEs in the first year after treatment initiation in CM-227 patients with high TMB. Methods: The frequency, grade, and attribution of AEs were extracted from CM-227 patient-level data. Costs of managing each grade 3–4 ACAE and grade 3–4 TRAE were estimated using related codes of the International Classification of Disease, 10th Revision, as well as cost information from the Healthcare Cost and Utilization Project National Inpatient Sample data (2015). A sensitivity analysis accounting for treatment duration and a temporal trends analysis were conducted. Results: In patients treated with N+I (n = 135), 157 grade 3–4 ACAEs and 70 grade 3–4 TRAEs were observed compared to 153 and 74 respectively among the patients treated with C (n = 159). The cost of managing grade 3–4 ACAEs per treated patient for N+I was $19,602 and for C was $16,353 (difference $3,249; 95% CI $1,774–$4,723), while the cost of managing grade 3–4 TRAEs per treated patient was $6,921 and $8,925 for N+I and C, respectively (difference $2,004; 95% CI $878–$3,131). An analysis adjusting for treatment duration yielded lower cost per person-month for N+I compared to C for both grade 3–4 ACAEs ($2,886 and $3,521; difference $634; 95% CI $379–$889) and grade 3–4 TRAEs ($1,019 and $1,921, difference $902; 95% CI $696–$1,109). For both N+I and C, the cost of managing grade 3–4 ACAEs and grade 3–4 TRAEs per person-month was highest in the first 3 months and declined thereafter. Conclusions: The cost of ACAEs was somewhat higher for N+I than for C, while the cost of TRAEs was somewhat lower for N+I than for C. Adjusting for treatment duration, N+I had lower costs for both ACAEs and TRAEs compared to C. Clinical trial information: NCT02477826.
Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced squamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Tun Aung , Thein Wai Lin , Gasperino James , Elfiky Aymen , Guevara Elizabeth 
Published: July 2019

121 Background: Squamous Non-small cell lung cancer (NSCLC) accounts for ~30% of lung cancers, and long-term survival remains poor for advanced disease. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 3 RCTs (Keynote – 407, IMpower – 131, and Govindan et al) including 1991 patients with advanced squamous NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, or atezolizumab, while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.71 (95% CI: 0.56-0.9; P = 0.005), the pooled HR for OS was 0.84 (95% CI: 0.68-1.04; P = 0.11), and the pooled RR for ORR was 1.19 (95 CI: 0.9-1.56; P = 0.22). The pooled RRs for all-grade AEs and high-grade AEs were 1.17 (95% CI: 0.99-1.39; P = 0.07) and 1.36 (95% CI: 1.19-1.56; P = 0.0001), respectively. Conclusions: The combined chemo-immunotherapy improves PFS without significant improvement in OS & ORR compared to standard chemotherapy for the first-line treatment of advanced squamous NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.