Ultrasound elastography (US-E) is a noninvasive, safe, cost-effective and reliable technique to assess the mechanical properties of soft tissue and provide imaging biomarkers for pathological processes. Many lung diseases such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and interstitial lung disease are associated with dramatic changes in mechanical properties of lung tissues. Nevertheless, US-E is rarely used to image the lung because it is filled with air. The large difference in acoustic impedance between air and lung tissue results in the reflection of the ultrasound wave at the lung surface and, consequently, the loss of most ultrasound energy. In recent years, there has been an increasing interest in US-E applications in evaluating lung diseases. This article provides a comprehensive review of the technological advances of US-E research on lung disease diagnosis. We introduce the basic principles and major techniques of US-E and provide information on various applications in lung disease assessment. Finally, the potential applications of US-E to the diagnosis of COVID-19 pneumonia is discussed.

BACKGROUND: It has been demonstrated that regular exercise improves the quality of life in patients undergoing treatment for lung cancer and has been associated with reductions in cancer-specific mortality in patients with colon and breast cancer. The direct effects of cardiovascular exercise on lung cancer tumor biology, however, remain unknown. The authors evaluated the effects of cardiovascular exercise in a mouse model of lung adenocarcinoma. METHODS: Luciferase-tagged A549 lung adenocarcinoma cells were injected through the tail vein of nude male mice. Then, the mice underwent weekly bioluminescent imaging until lung tumors were clearly identified. After lung tumors were identified, the mice were randomized to daily wheel running versus no wheel running, and they were imaged weekly. After 4 weeks, all mice were killed, and the lung tumors were harvested. Western blot and immunohistochemical analyses were conducted on tumor tissues to identify potential differences in protein expression levels in exercising mice versus sedentary mice. RESULTS: Lung tumors in exercising mice grew significantly more slowly relative to sedentary mice. There was no change in the development of metastatic lesions between the 2 groups. Protein analysis by Western blot or immunohistochemical analysis demonstrated increased p53 protein levels in exercising mice relative to sedentary mice as well as increased mediators of apoptosis, including Bax and active caspase 3, in tumor tissues. In both groups of mice, no normal tissue toxicity was observed in other organs. CONCLUSIONS: Daily cardiovascular exercise appears to mitigate the growth of lung adenocarcinoma tumors, possibly by activation of the p53 tumor suppressor function and increased apoptosis.

Survival rates of patients with either early and advanced stage non–small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015.

Purpose To evaluate nuclear hypoxia-inducible factor 1α (HIF-1α) expression as a prognostic factor for distant recurrence (DR) and local recurrence (LR) after pancreatic adenocarcinoma resection. Methods and Materials Tissue specimens were collected from 98 patients with pancreatic adenocarcinoma who underwent resection without neoadjuvant therapy between January 2000 and December 2011. Local recurrence was defined as radiographic or pathologic evidence of progressive disease in the pancreas, pancreatic bed, or associated nodal regions. Distant recurrence was defined as radiographically or pathologically confirmed recurrent disease in other sites. Immunohistochemical staining was performed and scored by an independent pathologist blinded to patient outcomes. High HIF-1α overall expression score was defined as high percentage and intensity staining and thus score > 1.33. Univariate analysis was performed for HIF-1α score with LR alone and with DR. Multivariate logistic regression was used to determine predictors of LR and DR. Results Median follow-up time for all patients was 16.3 months. Eight patients (8%) demonstrated isolated LR, 26 patients (26.5%) had isolated DR, and 13 patients had both LR and DR. Fifty-three patients (54%) had high HIF-1α expression, and 45 patients (46%) had low HIF-1α expression. High HIF-1α expression was significantly associated with DR (P=.03), and low HIF-1α expression was significantly associated with isolated LR (P=.03). On multivariate logistic regression analysis, high HIF-1α was the only significant predictor of DR (odds ratio 2.46 [95% confidence interval 1.06-5.72]; P=.03). In patients with a known recurrence, an HIF-1α score ≥2.5 demonstrated a specificity of 100% for DR. Conclusions High HIF-1α expression is a significant predictor of distant failure versus isolated local failure in patients undergoing resection of pancreatic adenocarcinoma. Expression of HIF-1α may have utility in determining candidates for adjuvant local radiation therapy and systemic chemotherapy.

Observing early metabolic changes in positron emission tomography (PET) is an essential tool to assess treatment efficiency in radiotherapy. However, for thoracic regions, the use of three-dimensional (3D) PET imaging is unfeasible because the radiotracer activity is smeared by the respiratory motion and averaged during the imaging acquisition process. This motion-induced degradation is similar in magnitude with the treatment-induced changes, and the two occurrences become indiscernible. We present a customized temporal-spatial deformable registration method for quantifying respiratory motion in a four-dimensional (4D) PET dataset. Once the motion is quantified, a motion-corrected (MC) dataset is created by tracking voxels to eliminate breathing-induced changes in the 4D imaging scan. The 4D voxel-tracking data is then summed to yield a 3D MC-PET scan containing only treatment-induced changes. This proof of concept is exemplified on both phantom and clinical data, where the proposed algorithm tracked the trajectories of individual points through the 4D datasets reducing motion to less than 4 mm in all phases. This correction approach using deformable registration can discern motion blurring from treatment-induced changes in treatment response assessment using PET imaging.

Background Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response. Methods We used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells. Results We show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8 + T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a 'stem-like' CD8 + T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8 + T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8 + and stem-like CD8 + T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8 + T-cells and stem-like CD8 + T-cells in both the irradiated and unirradiated tumor. Conclusions These correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8 + T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.

Magnetic resonance imaging (MRI) has been widely used in combination with computed tomography (CT) radiation therapy because MRI improves the accuracy and reliability of target delineation due to its superior soft tissue contrast over CT. The MRI-only treatment process is currently an active field of research since it could eliminate systematic MR-CT co-registration errors, reduce medical cost, avoid diagnostic radiation exposure, and simplify clinical workflow. The purpose of this work is to validate the application of a deep learning-based method for abdominal synthetic CT (sCT) generation by image evaluation and dosimetric assessment in a commercial proton pencil beam treatment planning system (TPS). This study proposes to integrate dense block into a 3D cycle-consistent generative adversarial networks (cycle GAN) framework in an effort to effectively learn the nonlinear mapping between MRI and CT pairs. A cohort of 21 patients with co-registered CT and MR pairs were used to test the deep learning-based sCT image quality by leave-one-out cross validation. The CT image quality, dosimetric accuracy and the distal range fidelity were rigorously checked, using side-by-side comparison against the corresponding original CT images. The average mean absolute error (MAE) was 72.87±18.16 HU. The relative differences of the statistics of the PTV dose volume histogram (DVH) metrics between sCT and CT were generally less than 1%. Mean 3D gamma analysis passing rate of 1mm/1%, 2mm/2%, 3mm/3% criteria with 10% dose threshold were 90.76±5.94%, 96.98±2.93% and 99.37±0.99%, respectively. The median, mean and standard deviation of absolute maximum range differences were 0.170 cm, 0.186 cm and 0.155 cm. The image similarity, dosimetric and distal range agreement between sCT and original CT suggests the feasibility of further development of an MRI-only workflow for liver proton radiotherapy.

Introduction: Neutrophil-to-lymphocyte ratio (NLR) is a surrogate for systemic inflammatory response and its elevation has been shown to be a poor prognostic factor in various malignancies. Stereotactic radiosurgery (SRS) can induce a leukocyte-predominant inflammatory response. This study investigates the prognostic impact of post-SRS NLR in patients with brain metastases (BM). Methods: BM patients treated with SRS from 2003 to 2015 were retrospectively identified. NLR was calculated from the most recent full blood counts post-SRS. Overall survival (OS) and intracranial outcomes were calculated using the Kaplan–Meier method and cumulative incidence with competing risk for death, respectively. Results: 188 patients with 328 BM treated with SRS had calculable post-treatment NLR values. Of these, 51 (27.1%) had a NLR > 6. The overall median imaging follow-up was 13.2 (14.0 vs. 8.7 for NLR ≤ 6.0 vs. > 6.0) months. Baseline patient and treatment characteristics were well balanced, except for lower rate of ECOG performance status 0 in the NLR > 6 cohort (33.3 vs. 44.2%, p = 0.026). NLR > 6 was associated with worse 1- and 2-year OS: 59.9 vs. 72.9% and 24.6 vs. 43.8%, (p = 0.028). On multivariable analysis, NLR > 6 (HR: 1.53; 95% CI 1.03–2.26, p = 0.036) and presence of extracranial metastases (HR: 1.90; 95% CI 1.30–2.78; p < 0.001) were significant predictors for worse OS. No association was seen with NLR and intracranial outcomes. Conclusion: Post-treatment NLR, a potential marker for post-SRS inflammatory response, is inversely associated with OS in patients with BM. If prospectively validated, NLR is a simple, systemic marker that can be easily used to guide subsequent management.

Background: Lung cancer patients with KRAS mutation(s) have a poor prognosis due in part to the development of resistance to currently available therapeutic interventions. Development of a new class of anticancer agents that directly targets KRAS may provide a more attractive option for the treatment of KRAS-mutant lung cancer. Results: Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS. In vitro GDP/GTP exchange assay reveals that KRA-533 activates KRAS by preventing the cleavage of GTP into GDP, leading to the accumulation of GTP-KRAS, an active form of KRAS. Treatment of human lung cancer cells with KRA-533 resulted in increased KRAS activity and suppression of cell growth. Lung cancer cell lines with KRAS mutation were relatively more sensitive to KRA-533 than cell lines without KRAS mutation. Mutating one of the hydrogen-bonds among the KRA-533 binding amino acids in KRAS (mutant K117A) resulted in failure of KRAS to bind KRA-533. KRA-533 had no effect on the activity of K117A mutant KRAS, suggesting that KRA-533 binding to K117 is required for KRA-533 to enhance KRAS activity. Intriguingly, KRA-533-mediated KRAS activation not only promoted apoptosis but also autophagic cell death. In mutant KRAS lung cancer xenografts and genetically engineered mutant KRAS-driven lung cancer models, KRA-533 suppressed malignant growth without significant toxicity to normal tissues. Conclusions: The development of this KRAS agonist as a new class of anticancer drug offers a potentially effective strategy for the treatment of lung cancer with KRAS mutation and/or mutant KRAS-driven lung cancer.

Purpose: To assess how accrual to clinical trials is related to U.S. minority population density relative to clinical trial site location and distance traveled to Radiation Therapy Oncology Group (RTOG) clinical trials sites. Methods: Data included member site address and zip codes, patient accrual, and patient race/ethnicity and zip code. Geographic Information System (GIS) maps were developed for overall, Latino and African American accrual to trials by population density. The Kruskal-Wallis test was used to assess differences in distance traveled by site, type of trial and race/ethnicity. Results: From 2006–2009, 6168 patients enrolled on RTOG trials. RTOG U.S. site distribution is generally concordant with overall population density. Sites with highest accrual are located throughout the U.S. and parts of Canada and do not cluster, nor does highest minority accrual cluster in areas of highest U.S. minority population density. Of the 4913 U.S. patients with complete data, patients traveled a median of 11.6 miles to participate in clinical trials. Whites traveled statistically longer distances (12.9 miles; p<0.0001) to participate followed by Latinos (8.22 miles), and African Americans (5.85 miles). Patients were willing to drive longer distances to academic sites than community sites and there was a trend toward significantly longer median travel for therapeutic vs cancer control or metastatic trials. Conclusions: Location matters, but only to a degree, for minority compared to non-minority participation in clinical trials. GIS tools help identify gaps in geographic access and travel burden for clinical trials participation. Strategies that emerged using these tools are discussed.