Citations

Abstract Lung transplant recipients are at higher risk of developing COVID-19 infection compared to other solid organ transplants. The risk further increases in the unvaccinated patients. We present a case of a 43-year-old male who underwent bilateral sequential lung transplantation for pulmonary alveolar microlithiasis (PAM) and had an uneventful recovery. However, two years post-transplantation, the patient developed chronic lung allograft dysfunction (CLAD) with bronchiolitis obliterans syndrome and two episodes of COVID-19 infection. During the second episode of COVID-19 infection, the patient developed sepsis and multi-organ dysfunction ultimately resulting in death. Our case report highlights the increased susceptibility of PAM patients’ post-lung transplant to COVID-19 infection. Continuous follow-up of PAM patients’ post-lung transplantation is necessary to prevent unfavorable outcomes.

Interstitial lung disease (ILD) is a common and serious complication of systemic autoimmune rheumatic diseases (SARD). The prevalence and prognosis of ILD vary depending on the type and severity of the underlying SARD. Recently, two drugs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ILD in SARD, and the American College of Rheumatology (ACR) has issued guidelines for the screening and monitoring of these patients. Therefore, it is essential to detect and manage ILD in SARDs as early as possible. High-resolution CT of the chest is the current gold standard test for diagnosis of ILD, yet, it is not uniformly performed as an initial diagnostic test. This review discusses the latest advances in imaging techniques for the diagnosis, assessment, and follow-up of SARD-ILDs.

Abstract The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

ABSTRACT Introduction Endurance exercise at altitude can increase cardiac output and pulmonary vascular pressure to levels that may exceed the stress tolerability of the alveolar–capillary unit. This study examined the effect of ultramarathon trail racing at different altitudes (ranging from <1000 m to between 1500 and 2700 m) on alveolar–capillary recruitment and lung diffusion. Methods Cardiac and lung function were examined before and after an ultramarathon in 67 runners (age: 41 ± 9 yr, body mass index: 23 ± 2 kg·m −2 , 10 females), and following 12–24 h of recovery in a subset ( n = 27). Cardiac biomarkers (cTnI and BNP) were assessed from whole blood, whereas lung fluid accumulation (comet tails), stroke volume (SV), and cardiac output ( Q ) were quantified via echocardiography. Lung diffusing capacity for carbon monoxide (DLco) and its components, alveolar membrane conductance (Dm) and capillary blood volume (Vc), were determined via a single-breath method at rest and during three stages of submaximal semirecumbent cycling (20, 30, and 40 W). Results Average race time was 25 ± 12 h. From pre- to post-race, there was an increase in cardiac biomarkers (cTnI: 0.04 ± 0.02 vs 0.13 ± 0.03 ng·mL −1 , BNP: 20 ± 2 vs 112 ± 21 pg·mL −1 ; P < 0.01) and lung comet tails (2 ± 1 vs 7 ± 6, P < 0.01), a decrease in resting and exercise SV (76 ± 2 vs 69 ± 2 mL, 40 W: 93 ± 2 vs 88 ± 2 mL; P < 0.01), and an elevation in Q at rest (4.1 ± 0.1 vs 4.6 ± 0.2 L·min −1 , P < 0.01; 40 W: 7.3 ± 0.2 vs 7.4 ± 0.3 L·min −1 , P = 0.899). Resting DLco and Vc decreased after the race ( P < 0.01), whereas Dm was unchanged ( P = 0.465); however, during the three stages of exercise, DLco, Vc, and Dm were all reduced from pre- to post-race (40 W: 36.3 ± 0.9 vs 33.0 ± 0.8 mL·min −1 ·mm Hg −1 , 83 ± 3 vs 73 ± 2 mL, 186 ± 6 vs 170 ± 7 mL·min −1 ·mm Hg −1 , respectively; P < 0.01). When corrected for alveolar volume and Q , DLco decreased from pre- to post-race ( P < 0.01), and changes in DLco were similar for all ultramarathon events ( P > 0.05). Conclusions Competing in an ultramarathon leads to a transient increase in cardiac injury biomarkers, mild lung-fluid accumulation, and impairments in lung diffusion. Reductions in DLco are predominantly caused by a reduced Vc and possible pulmonary capillary de-recruitment at rest. However, impairments in alveolar–capillary recruitment and Dm both contribute to a fall in exertional DLco following an ultramarathon. Perturbations in lung diffusion were evident across a range of event distances and varying environmental exposures.

Abstract Background Rescanning is a common technique used in proton pencil beam scanning to mitigate the interplay effect. Advances in machine operating parameters across different generations of particle therapy systems have led to improvements in beam delivery time (BDT). However, the potential impact of these improvements on the effectiveness of rescanning remains an underexplored area in the existing research. Methods We systematically investigated the impact of proton machine operating parameters on the effectiveness of layer rescanning in mitigating interplay effect during lung SBRT treatment, using the CIRS phantom. Focused on the Hitachi synchrotron particle therapy system, we explored machine operating parameters from our institution's current (2015) and upcoming systems (2025A and 2025B). Accumulated dynamic 4D dose were reconstructed to assess the interplay effect and layer rescanning effectiveness. Results Achieving target coverage and dose homogeneity within 2% deviation required 6, 6, and 20 times layer rescanning for the 2015, 2025A, and 2025B machine parameters, respectively. Beyond this point, further increasing the number of layer rescanning did not further improve the dose distribution. BDTs without rescanning were 50.4, 24.4, and 11.4 s for 2015, 2025A, and 2025B, respectively. However, after incorporating proper number of layer rescanning (six for 2015 and 2025A, 20 for 2025B), BDTs increased to 67.0, 39.6, and 42.3 s for 2015, 2025A, and 2025B machine parameters. Our data also demonstrated the potential problem of false negative and false positive if the randomness of the respiratory phase at which the beam is initiated is not considered in the evaluation of interplay effect. Conclusion The effectiveness of layer rescanning for mitigating interplay effect is affected by machine operating parameters. Therefore, past clinical experiences may not be applicable to modern machines.

PURPOSE KRAS is the most commonly mutated driver oncogene in non–small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS G12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRAS G12C -mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS G12C -mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS G12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Abstract Rationale It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between −600 and −250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97–6.0; and RR per 4 μg ⋅ m−3 PM2.5, 1.43; 95% CI, 0.93–2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0–2.7). Conclusions Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene–environment interactions may influence prevalence of interstitial lung features in COPD.

ABSTRACT During deployment, a 52-year-old male developed acute behavioral changes. Though initially considered to have PTSD and related agitation and confusional state, his evaluation was consistent with acute encephalopathy. Magnetic resonance imaging of the brain showed T2 hyperintensities, and CSF analysis was positive for anti-N-methyl-D-aspartate receptor antibody. A nuclear protein in testis carcinoma midline carcinoma was discovered in the lung. Immunotherapy and surgical resection led to steady improvement prior to adjuvant chemotherapy. Autoimmune encephalitis due to anti-N-methyl-D-aspartate receptor antibodies is increasingly being recognized as causal of acute behavioral change.

This novel study deciphered the expression and function of protein phosphatase 2Aα (PP2Aα) in airway smooth muscle (ASM) during asthma and/or inflammation. We showed robust expression of PP2Aα in human ASM while its downregulation in asthmatic ASM. Similarly, we demonstrated reduced PP2Aα expression in ASM exposed to proinflammatory cytokines. PP2Aα activation inhibited bronchoconstriction of isolated mouse bronchi. In addition, we unveiled that PP2Aα activation inhibits the intracellular calcium release and myosin light chain phosphorylation in human ASM.