The Role of a Panel of Pro-Fibrogenic miRs in Fibrotic Lung Disorders

Rationale: Pulmonary idiopathic fibrosis (IPF), Cryptogenetic organizing pneumonia (COP) and bronchiolitis obliterans syndrome (BOS) are rare pulmonary disorders, linked by the presence of fibrotic lesions. In our previous work (Di Carlo, 2016) on BOS we computationally identified a panel of candidate miRNAs and demonstrated by in situ hybridization analysis (ISH) and qRT-PCR, a dysregulation of two highly ranked miRNAs, miR-21 and miR-34a;ISH confirmed abnormal miR-21 and miR-34a expression in BOS lesions; other miRNAs where indicated as potential candidates in BOS by computational analysis. Aim We extended our previous work by analyzing the expression of miR-21, miR-34a and three other highly ranked miRNAs (miR-145, miR-146b-5p and miR-381) in BOS and other lung diseases associated with fibroblast activation/proliferation and collagen deposition. Identifying a specific profile of dysregulated miRNAs could provide useful diagnostic markers and potential therapeutic target. Methods :We evaluated miRNAs expression profile by ISH and RT-PCR quantification in a series of formalin-fixed and paraffin-embedded lung samples obtained from patients with IPF (n. 8), OP (n. 8), BOS (n. 12) and normal lung from organ donors. Results In BOS, COP and IPF/UIP miR-21 and miR-145 were expressed in fibroblasts of BO lesions, OP plugs and in fibroblast foci respectively, and in reactive alveolar epithelia; miR-146b expression correlated to the amount of inflammatory cell infiltrates and epithelial activation in all cases, while a weak expression was evident in OP and IPF/UIP lesions. miR-34a overexpression was associated with the activation of alveolar epithelia and to a lesser extent with fibroblast lesions in OP. miR-381 showed a weak expression in all diseases, and was localized especially in inflammatory cells. ISH data have been confirmed by qRTPCR analysis obtained on same samples. Conclusions: miR-21, miR-145 and miR-146b are over-expressed in fibroblasts in all the cases analyzed, but their expression is not disease-specific, although some differences are observed in different diseases. This finding underlies their role in non-specific fibrotic lung processes.ISH complements the results of qPCR, allows the precise cellular localization of miR expression, and improves correlations with cell-specific pathway

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case-control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46-0.95], p\u2009=\u20090.0281), PFS (HR 0.65 [95% CI 0.48-0.89]; p\u2009=\u20090.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p\u2009=\u20090.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of\u2009 65\u20091 somatic DDR gene mutation was 20% and 24.5% (p\u2009=\u20090.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p\u2009=\u20090.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted

Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case–control matched analysis from a large multicenter study

Background: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy. Results: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. Conclusions: Among metastatic NSCLC patients with PD-L1 expression ≥50% receiving first-line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first-line chemotherapy

On the sampling distributions of the ml estimators in network effect models

The present contribution aims at describing the finite sample behaviour of ML estimators in network autocorrelation models, a class of auto-regressive models used to study the effect of networks on a variable of interest when the data points are interdependent. More specifically, through an extensive simulation study, it is investigated whether, and the conditions under which, the ML estimators are asymptotically normally distributed

On the sampling distribution of the ML estimators in Network Autocorrelation Models

This work investigates the finite sample properties of the maximum likelihood (ML) estimators for network autocorrelation models (NAMs), a class of auto-regressive models used to study the effect of networks on dependent variables of interest when the data points are interdependent. It is known that the estimated autocorrelation parameter has a finite sample negative bias, the amount of which is positively related with the network density (Mizruchi, Neuman, 2008, 2010). A recent study on the statistical power of a test on the same parameter is also available (Wang et al. 2014). We examine the whole finite sample distribution of both the ML estimator of the autocorrelation parameter and the regressor parameters. More specifically, through an extensive simulation study, this work investigates whether – and the conditions under which – the ML estimators are normally distributed. The finite sample distributions are evaluated with respect to the network density and topology, the distribution of error terms, and the strength of the autocorrelation parameter. It turns out that the ML estimators of the autocorrelation parameter and of the intercept are not normally distributed in case of small sample size, even in presence of normally distributed errors. Furthermore, the network density has some effect on the variability of the estimators. On the other hand, it seems that other features of the network topologies, in the main, have little effects on the estimator distributions. Also, proper methods to deal with the bias of autocorrelation parameter are introduced and studied. Particularly, a residual-based bootstrap is proposed, in line with a related literature (Lin et al., 2011; Yang, 2013). A further simulation study shows that the bootstrap based distributions are more accurate and should be preferred in case of low density and moderate network effects

Revisiting the Instrumented Romberg Test: Can Today's Technology Offer a Risk-of-Fall Screening Device for Senior Citizens? An Experience-Based Approach

Risk of fall (ROF) is a worldwide major concern for its prevalence and consequent dramatic outcomes in the elderly population. The growing age-related risk appears to be associated with increasing motor, sensory, and cognitive problems in the elderly population. There is a consensus on the need to screen for these balance dysfunctions, but the available methods are largely based on subjectively assessed performances. The instrumented Romberg test using a force plate represents a validated assessment process for the evaluation of balance performances. The purpose of this study is to propose an innovative instrumental method to identify balance deficits, assess their severity, and give an automated indication of the most likely etiology. The proposed new method was applied to the instrumented Romberg test, using force plate data recorded in a cohort of 551 females aged >65 participating in adapted physical activity courses. The method allowed us to identify 145 dysfunctional subjects and to determine the likely origin of their deficit: 21 central, 5 vestibular, 9 visual, 59 proprioceptive (musculoskeletal etiology), and 51 functional. Based on the preliminary findings of the study, this test could be an efficient and cost-effective mass screening tool for identifying subjects at risk of fall, since the procedure proves to be rapid, non-invasive, and apparently devoid of any contraindications