Bayer AG.

B a c k g r o u n d : I n t h e p h a s e I I I C h e c k M a t e 2 2 7 s t u d y , fi r s t-l i n e nivolumab þ ipilimumab significantly prolonged progression-free survival (co-primary endpoint) versus chemotherapy in patients with advanced nonesmall-cell lung cancer (NSCLC) and high tumour mutational burden (TMB; !10 mutations/megabase). Aim: To evaluate patient-reported outcomes (PROs) in this population. Methods: Disease-related symptoms and general health status were assessed using the validated PRO questionnaires Lung Cancer Symptom Scale (LCSS) and EQ-5D, respectively. LCSS average symptom burden index (ASBI) and three-item global index (3-IGI) and EQ-5D visual analogue scale (VAS) and utility index (UI) scores and changes from baseline were analysed descriptively. Longitudinal changes were assessed by mixed-effect model repeated measures (MMRMs) and time to first deterioration/improvement analyses. Results: In the high TMB population, PRO questionnaire completion rates were w90% at baseline and >80% for most on-treatment assessments. During treatment, mean changes from baseline with nivolumab þ ipilimumab showed early, clinically meaningful improvements in LCSS ASBI/3-IGI and EQ-5D VAS/UI; with chemotherapy, symptoms and health-related quality of life remained stable (LCSS ASBI/3-IGI, EQ-5D UI) or improved following induction (EQ-5D VAS). MMRM-assessed changes in symptom burden were improved with nivolumab þ ipilimumab versus chemotherapy. Symptom deterioration by week 12 was lower with nivolumab þ ipilimumab versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% confidence interval 2.4e22.5]), irrespective of discontinuation. Time to first deterioration was delayed with nivolumab þ ipilimumab versus chemotherapy across LCSS and EQ-5D summary measures. Conclusion: First-line nivolumab þ ipilimumab demonstrated early, sustained improvements in PROs versus chemotherapy in patients with advanced NSCLC and high TMB. Clinical trial registration: NCT02477826.

IMPORTANCEIt is important to develop a surgical technique to reduce dissemination of tumor cells into the blood during surgery.OBJECTIVE To compare the outcomes of different sequences of vessel ligation during surgery on the dissemination of tumor cells and survival in patients with non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTSThis multicenter, randomized clinical trial was conducted from December 2016 to March 2018 with patients with non-small cell lung cancer who received thoracoscopic lobectomy in West China Hospital, Daping Hospital, and Sichuan Cancer Hospital. To further compare survival outcomes of the 2 procedures, we reviewed the Western China Lung Cancer database (2005-2017) using the same inclusion criteria.INTERVENTIONS Vein-first procedure vs artery-first procedure. MAIN OUTCOMES AND MEASURESChanges in folate receptor-positive circulating tumor cells (FR + CTCs) after surgery and 5-year overall, disease-free, and lung cancer-specific survival.RESULTS A total of 86 individuals were randomized; 22 patients (25.6%) were younger and 64 (74.4%) older than 60 years. Of these, 78 patients were analyzed. After surgery, an incremental change in FR + CTCs was observed in 26 of 40 patients (65.0%) in the artery-first group and 12 of 38 (31.6%) in the vein-first group (P = .003) (median change, 0.73 [interquartile range (IQR), −0.86 to 1.58] FU per 3 mL vs −0.50 [IQR, −2.53 to 0.79] FU per 3 mL; P = .006). Multivariate analysis confirmed that the artery-first procedure was a risk factor for FR + CTC increase during surgery (hazard ratio [HR], 4.03 [95% CI,]; P = .005). The propensity-matched analysis included 420 patients (210 with vein-first procedures and 210 with artery-first procedures). The vein-first group had significantly better outcomes than the artery-first group for 5-year overall survival (73.6% [95% CI, 64.4%-82.8%] vs 57.6% [95% CI, 48.4%-66.8%]; P = .002), disease-free survival (63.6% [95% CI, 55.4%-73.8%] vs 48.4% [95% CI, 40.0%-56.8%]; P = .001), and lung cancer-specific survival (76.4% [95% CI, 67.6%-85.2%] vs 59.9% [95% CI, 50.5%-69.3%]; P = .002). Multivariate analyses revealed that the artery-first procedure was a prognostic factor of poorer 5-year overall survival (HR, 1.65 [95% CI, 1.07-2.56]; P = .03), disease-free survival (HR, 1.43 [95% CI, 1.01-2.04]; P = .05) and lung cancer-specific survival (HR = 1.65 [95% CI, 1.04-2.61]; P = .03). CONCLUSIONS AND RELEVANCELigating effluent veins first during surgery may reduce tumor cell dissemination and improve survival outcomes in patients with non-small cell lung cancer.TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03436329

Risk factors other than physician- or patient-reported reasons play a role in discontinuation of initial HAART regimens. Identification of these risk factors and simplification of treatment regimens in those at high risk for discontinuation appear to be necessary in order to maximize the effectiveness of HAART regimens.

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ObjectivesTo study the relationship between exposure to protease inhibitor (PI) therapy and increased risk of cardiovascular events in HIV-infected patients. MethodsWe estimated the risk of cardiovascular disease (CVD) events with PI exposure in a cohort of HIVinfected patients using a time-dependent Cox proportional hazards model adjusting for the major CVD risk factors. Only the first CVD event for each subject was counted. ResultsOf a total of 7542 patients, 77% were exposed to PIs. CVD event rates were 9.8/1000 and 6.5/1000 person-years of follow-up (PYFU) in the PI-exposed and nonexposed groups, respectively (P 5 0.0008). PI exposure 60 days was associated with an increased risk of CVD event [adjusted hazards ratio (HR adj ) 1.71; 95% confidence interval (CI) 1.08-2.74; P 5 0.03]. Results from a subgroup of patients aged between 35 and 65 years were similar (HR adj 1.90; 95% CI 1.13-3.20; P 5 0.02). Other significant risk factors included smoking status, age, hypertension, diabetes mellitus and pre-existing CVD. ConclusionsPatients exposed to PI therapy had an increased risk of CVD events. Clinicians should evaluate the risk of CVD when making treatment decisions for HIV-infected patients.Keywords: antiretroviral therapy, cardiovascular disease, HAART, protease inhibitors, treatment complications IntroductionHighly active antiretroviral therapy (HAART) has resulted in dramatic declines in progression to AIDS and AIDS mortality in HIV-infected persons [1][2][3][4][5][6]. In some reports, death from nonAIDS-related causes exceed those attributed to AIDS in this patient population [2,[7][8][9], and cardiovascular deaths are increasing in these patients [1,2]. Recent reports suggest a shift in the relative cause of death among HIV-infected individuals, with cardiovascular deaths accounting for fewer than 4% of all deaths pre-1997 [1,10], and for 7-10% in more recent years [8,10,11].Reports from large observational studies demonstrate that considerable controversy exists over the association of HAART, particularly protease inhibitor (PI) therapies, with increased cardiovascular disease (CVD) risk [12][13][14][15][16][17]. PIs have been associated with alterations in surrogate markers of CVD, including coronary calcium scores and endothelial function [18,19], as well as with metabolic complications such as hyperlipidaemia, fat redistribution, insulin resistance, hypertension and diabetes mellitus [19][20][21][22][23][24]. Also, HIV-infected patients may have a higher prevalence of traditional CVD risk factors such as smoking than the general population [20,21]. In addition, as the mean age of the HIV-infected patient population has increased as a result of longer life expectancy with the disease, the consequent cardiovascular risk has also increased. 37These changes in patient demographics and the increasing prevalence of traditional CVD risk factors such as smoking, along with the increasing prevalence of PIassociated metabolic complications, have clearly increased the risk of CVD in HIV-infected individuals. ...

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Platelet inhibition with clopidogrel in patients for up to one year after presentation with an acute coronary syndrome is both effective and cost-effective.