Integrated MRI–Immune–Genomic Features Enclose a Risk Stratification Model in Patients Affected by Glioblastoma

Simple Summary: Despite crucial scientific advances, Glioblastoma (GB) remains a fatal disease with limited therapeutic options and a lack of suitable biomarkers. The unveiled competence of the brain immune system together with the breakthrough advent of immunotherapy has shifted the present translational research on GB towards an immune-focused perspective. Several clinical trials targeting the immunosuppressive GB background are ongoing. So far, results are inconclusive, underpinning our partial understanding of the complex cancer-immune interplay in brain tumors. High throughput Magnetic Resonance (MR) imaging has shown the potential to decipher GB heterogeneity, including pathologic and genomic clues. However, whether distinct GB immune contextures can be deciphered at an imaging scale is still elusive, leaving unattained the non-invasive achievement of prognostic and predictive biomarkers. Along these lines, we integrated genetic, immunopathologic and imaging features in a series of GB patients. Our results suggest that multiparametric approaches might offer new efficient risk stratification models, opening the possibility to intercept the critical events implicated in the dismal prognosis of GB. Abstract: Background: The aim of the present study was to dissect the clinical outcome of GB patients through the integration of molecular, immunophenotypic and MR imaging features. Methods: We enrolled 57 histologically proven and molecularly tested GB patients (5.3% IDH-1 mutant). Two- Dimensional Free ROI on the Biggest Enhancing Tumoral Diameter (TDFRBETD) acquired by MRI sequences were used to perform a manual evaluation of multiple quantitative variables, among which we selected: SD Fluid Attenuated Inversion Recovery (FLAIR), SD and mean Apparent Diffusion Coefficient (ADC). Characterization of the Tumor Immune Microenvironment (TIME) involved the immunohistochemical analysis of PD-L1, and number and distribution of CD3+, CD4+, CD8+ Tumor Infiltrating Lymphocytes (TILs) and CD163+ Tumor Associated Macrophages (TAMs), focusing on immune-vascular localization. Genetic, MR imaging and TIME descriptors were correlated with overall survival (OS). Results: MGMT methylation was associated with a significantly prolonged OS (median OS = 20 months), while no impact of p53 and EGFR status was apparent. GB cases with high mean ADC at MRI, indicative of low cellularity and soft consistency, exhibited increased OS (median OS = 24 months). PD-L1 and the overall number of TILs and CD163+TAMs had a marginal impact on patient outcome. Conversely, the density of vascular-associated (V) CD4+ lymphocytes emerged as the most significant prognostic factor (median OS = 23 months in V-CD4high vs. 13 months in V-CD4low, p = 0.015). High V-CD4+TILs also characterized TIME of MGMTmeth GB, while p53mut appeared to condition a desert immune background. When individual genetic (MGMTunmeth), MR imaging (mean ADClow) and TIME (V-CD4+TILslow) negative predictors were combined, median OS was 21 months (95% CI, 0–47.37) in patients displaying 0–1 risk factor and 13 months (95% CI 7.22–19.22) in the presence of 2–3 risk factors (p = 0.010, HR = 3.39, 95% CI 1.26–9.09). Conclusion: Interlacing MRI–immune–genetic features may provide highly significant risk-stratification models in GB patients

Computed Tomography Measurement of Rib Cage Morphometry in Emphysema

Background: Factors determining the shape of the human rib cage are not completely understood. We aimed to quantify the contribution of anthropometric and COPD-related changes to rib cage variability in adult cigarette smokers. Methods: Rib cage diameters and areas (calculated from the inner surface of the rib cage) in 816 smokers with or without COPD, were evaluated at three anatomical levels using computed tomography (CT). CTs were analyzed with software, which allows quantification of total emphysema (emphysema%). The relationship between rib cage measurements and anthropometric factors, lung function indices, and %emphysema were tested using linear regression models. Results: A model that included gender, age, BMI, emphysema%, forced expiratory volume in one second (FEV1)%, and forced vital capacity (FVC)% fit best with the rib cage measurements (R2  = 64% for the rib cage area variation at the lower anatomical level). Gender had the biggest impact on rib cage diameter and area (105.3 cm2; 95% CI: 111.7 to 98.8 for male lower area). Emphysema% was responsible for an increase in size of upper and middle CT areas (up to 5.4 cm2; 95% CI: 3.0 to 7.8 for an emphysema increase of 5%). Lower rib cage areas decreased as FVC% decreased (5.1 cm2; 95% CI: 2.5 to 7.6 for 10 percentage points of FVC variation). Conclusions: This study demonstrates that simple CT measurements can predict rib cage morphometric variability and also highlight relationships between rib cage morphometry and emphysema

Effect of iterative reconstruction on image quality of low-dose chest computed tomography

AIM: To assess quality and radiologists' preference of low-dose computed tomography (LDCT) reconstructed with filtered back projection (FBP) or Iterative Reconstruction. METHODS: Thin-section LDCTs (1-mm thick contiguous images; 120 kVp; 30 mAs) of 38 consecutive unselected patients, evaluated for various clinical indications, were reconstructed by four different reconstruction algorithms: FBP and Sinogram-AFfirmed Iterative Reconstruction (SAFIRE) with three different strengths, from 2 to 4 (i.e. S2, S3, S4). The image noise was recorded. Two thoracic radiologists visually compared both anatomic structures (interlobular septa, lung fissures, centrilobular artery, bronchial wall, and small vessels) and lung abnormalities (intralobular reticular opacities, nodules, emphysema, cystic lung disease, decreased-attenuation areas related to constrictive obliterans bronchiolitis, patchy ground-glass opacity, consolidation, and bronchiectasis) using a qualitative four-point scale grading system of the image quality. RESULTS: A lower amount of noise was recorded for LDCTs reformatted with any SAFIRE algorithm, as compared to FBP (P < 0.0001). The noise levels decreased as the SAFIRE strength increased from S2 to S4. The visual score of the subsegmental/segmental bronchial wall was greater for the FBP datasets compared to any SAFIRE dataset (P < 0.0001 for reviewer 1; P < 0.02 for reviewer 2). The decreased lung attenuation pattern score was lower on the S4 images for one reviewer, as compared to the other LDCT datasets (P = 0.003). No other differences in terms of radiologists' preference were recorded among FBP, S2, S3, and S4. Interobserver agreement was moderate only for fissures and bronchial wall, and good to excellent for the remainders. CONCLUSION: Iterative reconstructions showed lower image noise but did not provide any real improvement for the radiologists' evaluation of thin-section LDCT of the lung

Computed tomography measurement of rib cage morphometry in emphysema

Background: Factors determining the shape of the human rib cage are not completely understood. We aimed to quantify the contribution of anthropometric and COPD-related changes to rib cage variability in adult cigarette smokers. Methods: Rib cage diameters and areas (calculated from the inner surface of the rib cage) in 816 smokers with or without COPD, were evaluated at three anatomical levels using computed tomography (CT). CTs were analyzed with software, which allows quantification of total emphysema (emphysema%). The relationship between rib cage measurements and anthropometric factors, lung function indices, and % emphysema were tested using linear regression models. Results: A model that included gender, age, BMI, emphysema%, forced expiratory volume in one second (FEV1)%, and forced vital capacity (FVC)% fit best with the rib cage measurements (R-2 = 64% for the rib cage area variation at the lower anatomical level). Gender had the biggest impact on rib cage diameter and area (105.3 cm(2); 95% CI: 111.7 to 98.8 for male lower area). Emphysema% was responsible for an increase in size of upper and middle CT areas (up to 5.4 cm(2); 95% CI: 3.0 to 7.8 for an emphysema increase of 5%). Lower rib cage areas decreased as FVC% decreased (5.1 cm(2); 95% CI: 2.5 to 7.6 for 10 percentage points of FVC variation). Conclusions: This study demonstrates that simple CT measurements can predict rib cage morphometric variability and also highlight relationships between rib cage morphometry and emphysema

Differences between left and right side of each measures in all subjects, with the p-value of the difference.

<p>Notes: SD = standard deviation;</p>*<p>p-value was estimated by paired t-test.</p

Baseline study population characteristics.

<p>Notes: D = diameter; U = upper; M = middle; L = lower;</p>*<p>p-value indicates the probability of the null hypothesis when comparing patients with COPD, MILD subjects with modified COPD (mCOPD), and normal MILD subjects by using one-way ANOVA analysis.</p

Partial regression coefficient (β) and 95% confidence intervals (95%CI) of area variation at different lung sections by selected variables.

<p>Notes: numbers in bold characters are statistically significant;</p>§<p>male as compared with female;</p>*<p>5 percentage points variation;</p>**<p>10 percentage points variation.</p