Improved pulmonary function and exercise tolerance despite persistent pulmonary fibrosis over 1 year after severe COVID-19 infection.

We conducted a prospective single-centre cohort study of 104 multi-ethnic severe COVID-19 survivors from the first wave of the pandemic 15 months after hospitalisation. Of those who were assessed at 4 and 15 months, improvement of ground glass opacities correlated with worsened fibrotic reticulations. Despite a high prevalence of fibrotic patterns (64%), pulmonary function, grip strength, 6 min walk distance and frailty normalised. Overall, dyspnoea, cough and exhaustion did not improve and were not correlated with pulmonary function or radiographic fibrosis at 15 months, suggesting non-respiratory aetiologies. Monitoring persistent, and often subclinical, fibrotic interstitial abnormalities will be needed to determine their potential for future progression.

TGF-ß signaling: critical nexus of fibrogenesis and cancer.

The transforming growth factor-beta (TGF-ß) signaling pathway is a vital regulator of cell proliferation, differentiation, apoptosis, and extracellular matrix production. It functions through canonical SMAD-mediated processes and noncanonical pathways involving MAPK cascades, PI3K/AKT, Rho-like GTPases, and NF-κB signaling. This intricate signaling system is finely tuned by interactions between canonical and noncanonical pathways and plays key roles in both physiologic and pathologic conditions including tissue homeostasis, fibrosis, and cancer progression. TGF-ß signaling is known to have paradoxical actions. Under normal physiologic conditions, TGF-ß signaling promotes cell quiescence and apoptosis, acting as a tumor suppressor. In contrast, in pathological states such as inflammation and cancer, it triggers processes that facilitate cancer progression and tissue remodeling, thus promoting tumor development and fibrosis. Here, we detail the role that TGF-ß plays in cancer and fibrosis and highlight the potential for future theranostics targeting this pathway.

Combined expert-in-the-loop-random forest multiclass segmentation U-net based artificial intelligence model: evaluation of non-small cell lung cancer in fibrotic and non-fibrotic microenvironments.

BACKGROUND: The tumor microenvironment (TME) plays a key role in lung cancer initiation, proliferation, invasion, and metastasis. Artificial intelligence (AI) methods could potentially accelerate TME analysis. The aims of this study were to (1) assess the feasibility of using hematoxylin and eosin (H&E)-stained whole slide images (WSI) to develop an AI model for evaluating the TME and (2) to characterize the TME of adenocarcinoma (ADCA) and squamous cell carcinoma (SCCA) in fibrotic and non-fibrotic lung. METHODS: The cohort was derived from chest CT scans of patients presenting with lung neoplasms, with and without background fibrosis. WSI images were generated from slides of all 76 available pathology cases with ADCA (n = 53) or SCCA (n = 23) in fibrotic (n = 47) or non-fibrotic (n = 29) lung. Detailed ground-truth annotations, including of stroma (i.e., fibrosis, vessels, inflammation), necrosis and background, were performed on WSI and optimized via an expert-in-the-loop (EITL) iterative procedure using a lightweight [random forest (RF)] classifier. A convolution neural network (CNN)-based model was used to achieve tissue-level multiclass segmentation. The model was trained on 25 annotated WSI from 13 cases of ADCA and SCCA within and without fibrosis and then applied to the 76-case cohort. The TME analysis included tumor stroma ratio (TSR), tumor fibrosis ratio (TFR), tumor inflammation ratio (TIR), tumor vessel ratio (TVR), tumor necrosis ratio (TNR), and tumor background ratio (TBR). RESULTS: The model's overall classification for precision, sensitivity, and F1-score were 94%, 90%, and 91%, respectively. Statistically significant differences were noted in TSR (p = 0.041) and TFR (p = 0.001) between fibrotic and non-fibrotic ADCA. Within fibrotic lung, statistically significant differences were present in TFR (p = 0.039), TIR (p = 0.003), TVR (p = 0.041), TNR (p = 0.0003), and TBR (p = 0.020) between ADCA and SCCA. CONCLUSION: The combined EITL-RF CNN model using only H&E WSI can facilitate multiclass evaluation and quantification of the TME. There are significant differences in the TME of ADCA and SCCA present within or without background fibrosis. Future studies are needed to determine the significance of TME on prognosis and treatment.

Lung nodule malignancy classification with associated pulmonary fibrosis using 3D attention-gated convolutional network with CT scans.

BACKGROUND: Chest Computed tomography (CT) scans detect lung nodules and assess pulmonary fibrosis. While pulmonary fibrosis indicates increased lung cancer risk, current clinical practice characterizes nodule risk of malignancy based on nodule size and smoking history; little consideration is given to the fibrotic microenvironment. PURPOSE: To evaluate the effect of incorporating fibrotic microenvironment into classifying malignancy of lung nodules in chest CT images using deep learning techniques. MATERIALS AND METHODS: We developed a visualizable 3D classification model trained with in-house CT dataset for the nodule malignancy classification task. Three slightly-modified datasets were created: (1) nodule alone (microenvironment removed); (2) nodule with surrounding lung microenvironment; and (3) nodule in microenvironment with semantic fibrosis metadata. For each of the models, tenfold cross-validation was performed. Results were evaluated using quantitative measures, such as accuracy, sensitivity, specificity, and area-under-curve (AUC), as well as qualitative assessments, such as attention maps and class activation maps (CAM). RESULTS: The classification model trained with nodule alone achieved 75.61% accuracy, 50.00% sensitivity, 88.46% specificity, and 0.78 AUC; the model trained with nodule and microenvironment achieved 79.03% accuracy, 65.46% sensitivity, 85.86% specificity, and 0.84 AUC. The model trained with additional semantic fibrosis metadata achieved 80.84% accuracy, 74.67% sensitivity, 84.95% specificity, and 0.89 AUC. Our visual evaluation of attention maps and CAM suggested that both the nodules and the microenvironment contributed to the task. CONCLUSION: The nodule malignancy classification performance was found to be improving with microenvironment data. Further improvement was found when incorporating semantic fibrosis information.

Comparison of lung cancer occurring in fibrotic versus non-fibrotic lung on chest CT.

PURPOSE: Evaluate the behavior of lung nodules occurring in areas of pulmonary fibrosis and compare them to pulmonary nodules occurring in the non-fibrotic lung parenchyma. METHODS: This retrospective review of chest CT scans and electronic medical records received expedited IRB approval and a waiver of informed consent. 4500 consecutive patients with a chest CT scan report containing the word fibrosis or a specific type of fibrosis were identified using the system M*Model Catalyst (Maplewood, Minnesota, U.S.). The largest nodule was measured in the longest dimension and re-evaluated, in the same way, on the follow-up exam if multiple time points were available. The nodule doubling time was calculated. If the patient developed cancer, the histologic diagnosis was documented. RESULTS: Six hundred and nine patients were found to have at least one pulmonary nodule on either the first or the second CT scan. 274 of the largest pulmonary nodules were in the fibrotic tissue and 335 were in the non-fibrotic lung parenchyma. Pathology proven cancer was more common in nodules occurring in areas of pulmonary fibrosis compared to nodules occurring in areas of non-fibrotic lung (34% vs 15%, p < 0.01). Adenocarcinoma was the most common cell type in both groups but more frequent in cancers occurring in non-fibrotic tissue. In the non-fibrotic lung, 1 of 126 (0.8%) of nodules measuring 1 to 6 mm were cancer. In contrast, 5 of 49 (10.2%) of nodules in fibrosis measuring 1 to 6 mm represented biopsy-proven cancer (p < 0.01). The doubling time for squamous cell cancer was shorter in the fibrotic lung compared to non-fibrotic lung, however, the difference was not statistically significant (p = 0.24). 15 incident lung nodules on second CT obtained ≤ 18 months after first CT scan was found in fibrotic lung and eight (53%) were diagnosed as cancer. CONCLUSIONS: Nodules occurring in fibrotic lung tissue are more likely to be cancer than nodules in the nonfibrotic lung. Incident pulmonary nodules in pulmonary fibrosis have a high likelihood of being cancer.

Radiology of fibrosis. Part I: Thoracic organs.

Sustained injury from factors such as hypoxia, infection, or physical damage may provoke improper tissue repair and the anomalous deposition of connective tissue that causes fibrosis. This phenomenon may take place in any organ, ultimately leading to their dysfunction and eventual failure. Tissue fibrosis has also been found to be central in both the process of carcinogenesis and cancer progression. Thus, its prompt diagnosis and regular monitoring is necessary for implementing effective disease-modifying interventions aiming to reduce mortality and improve overall quality of life. While significant research has been conducted on these subjects, a comprehensive understanding of how their relationship manifests through modern imaging techniques remains to be established. This work intends to provide a comprehensive overview of imaging technologies relevant to the detection of fibrosis affecting thoracic organs as well as to explore potential future advancements in this field.

Radiology of fibrosis part II: abdominal organs.

Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.

Radiology of fibrosis part III: genitourinary system.

Fibrosis is a pathological process involving the abnormal deposition of connective tissue, resulting from improper tissue repair in response to sustained injury caused by hypoxia, infection, or physical damage. It can impact any organ, leading to their dysfunction and eventual failure. Additionally, tissue fibrosis plays an important role in carcinogenesis and the progression of cancer.Early and accurate diagnosis of organ fibrosis, coupled with regular surveillance, is essential for timely disease-modifying interventions, ultimately reducing mortality and enhancing quality of life. While extensive research has already been carried out on the topics of aberrant wound healing and fibrogenesis, we lack a thorough understanding of how their relationship reveals itself through modern imaging techniques.This paper focuses on fibrosis of the genito-urinary system, detailing relevant imaging technologies used for its detection and exploring future directions.

Incidence of Interstitial Lung Abnormalities: The MESA Lung Study.

The incidence of newly developed interstitial lung abnormalities (ILA) and fibrotic ILA have not been previously reported.Trained thoracic radiologists evaluated 13 944 cardiac CT scans for the presence of ILA in 6197 Multi-Ethnic Study of Atherosclerosis longitudinal cohort study participants >45 years of age from 2000 to 2012. 5% of the scans were re-read by the same or a different observer in a blinded fashion. After exclusion of participants with ILA at baseline, incidence rates and incidence rate ratios for ILA and fibrotic ILA were calculated.The intra-reader agreement of ILA was 92.0% (Gwet AC1=0.912, ICC=0.982) and the inter-reader agreement of ILA was 83.5% (Gwet AC1=0.814; ICC=0.969). Incidence of ILA and fibrotic ILA was estimated to be 13.1 cases/1000 person-years and 3.5/1000 person-years, respectively. In multivariable analyses, age (HR 1.06 (1.05, 1.08), p <0.001; HR 1.08 (1.06, 1.11), p <0.001), high attenuation area (HAA) at baseline (HR 1.05 (1.03, 1.07), p <0.001; HR 1.06 (1.02, 1.10), p=0.002), and the MUC5B promoter SNP (HR 1.73 (1.17, 2.56) p=0.01; HR 4.96 (2.68, 9.15), p <0.001) were associated with incident ILA and fibrotic ILA, respectively. Ever smoking (HR 2.31 (1.34, 3.96), p= 0.002) and an IPF polygenic risk score (HR 2.09 (1.61-2.71), p<0.001) were associated only with incident fibrotic ILA.Incident ILA and fibrotic ILA were estimated by review of cardiac imaging studies. These findings may lead to wider application of a screening tool for atherosclerosis to identify preclinical lung disease.

Fibrotic-Like Pulmonary Radiographic Patterns Are Not Associated With Adverse Outcomes in COVID-19 Chronic Critical Illness.

OBJECTIVES: Pulmonary fibrosis is a feared complication of COVID-19. To characterize the risks and outcomes associated with fibrotic-like radiographic abnormalities in patients with COVID-19-related acute respiratory distress syndrome (ARDS) and chronic critical illness. DESIGN: Single-center prospective cohort study. SETTING: We examined chest CT scans performed between ICU discharge and 30 days after hospital discharge using established methods to quantify nonfibrotic and fibrotic-like patterns. PATIENTS: Adults hospitalized with COVID-19-related ARDS and chronic critical illness (> 21 d of mechanical ventilation, tracheostomy, and survival to ICU discharge) between March 2020 and May 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We tested associations of fibrotic-like patterns with clinical characteristics and biomarkers, and with time to mechanical ventilator liberation and 6-month survival, controlling for demographics, comorbidities, and COVID-19 therapies. A total of 141 of 616 adults (23%) with COVID-19-related ARDS developed chronic critical illness, and 64 of 141 (46%) had a chest CT a median (interquartile range) 66 days (42-82 d) after intubation. Fifty-five percent had fibrotic-like patterns characterized by reticulations and/or traction bronchiectasis. In adjusted analyses, interleukin-6 level on the day of intubation was associated with fibrotic-like patterns (odds ratio, 4.40 per quartile change; 95% CI, 1.90-10.1 per quartile change). Other inflammatory biomarkers, Sequential Organ Failure Assessment score, age, tidal volume, driving pressure, and ventilator days were not. Fibrotic-like patterns were not associated with longer time to mechanical ventilator liberation or worse 6-month survival. CONCLUSIONS: Approximately half of adults with COVID-19-associated chronic critical illness have fibrotic-like patterns that are associated with higher interleukin-6 levels at intubation. Fibrotic-like patterns are not associated with longer time to liberation from mechanical ventilation or worse 6-month survival.

Analogies between the periphery of cancer and the leading edge of pulmonary fibrosis.

The periphery of malignant tumors and the leading edge of fibrotic tissue have analogous metabolic pathways. Both use glycolysis as the primary source of energy to produce biomass with consequential acidification of the microenvironment. A low PH has been shown to increase the ability of cancer cells to invade the surrounding tissue in both in vitro and in vivo studies. The pH-dependent activation of TGF-B leading to myofibroblast activation is an important step in the initiation and progression of fibrosis. Markers of accelerated cell proliferation have also been reported in the periphery of malignant tumors and the leading edge of fibrosis. Understanding the shared molecular and metabolic characteristics of these conditions may explain the increased prevalence of cancer among patients with fibrosis.

Breast stiffness, a risk factor for cancer and the role of radiology for diagnosis.

Over the last five decades, breast density has been associated with increased risk of developing breast cancer. Mammographically dense breasts are considered those belonging to the heterogeneously dense breasts, and extremely dense breasts subgroups according to the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). There is a statistically significant correlation between the increased mammographic density and the presence of more glandular tissue alone. However, the strength of this correlation is weak. Although the mechanisms driving breast density-related tumor initiation and progression are still unknown, there is evidence suggesting that certain molecular pathways participating in epithelial-stromal interactions may play a pivotal role in the deposition of fibrillar collagen, increased matrix stiffness, and cell migration that favor breast density and carcinogenesis. This article describes these molecular mechanisms as potential "landscapers" for breast density-related cancer. We also introduce the term "Breast Compactness" to reflect collagen density of breast tissue on chest CT scan and the use of breast stiffness measurements as imaging biomarkers for breast cancer screening and risk stratification.

Using Informatics to Build a Digital Health Footprint of Patients Living With Inherited Metabolic Disorders Identified by Newborn Screening.

Newborn screening is a process identifying people with inherited metabolic disorders (IMDs) at birth, but these patients are often lost to follow-up, and limited data on their long-term needs are available to advocate for policies that will help this vulnerable community. Using informatics best practices, the Medical Nutrition Therapy for Prevention (MNT4P) program and the Public Health Informatics Institute successfully deployed a minimally viable product-that is, the most basic working version that is scalable-allowing for lifelong patient follow-up and outcome and needs tracking, and that can address national data gaps. The new system offers a HIPAA-compliant, efficient record-keeping system that allows data standardization and harmonization. MNT4P staff have transitioned completely away from former manual processes and are relying on this system to log and track patient information. Other programs serving patient populations burdened with rare, marginalized diseases also may benefit from this work.

Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.

The risk factors for development of fibrotic-like radiographic abnormalities after severe COVID-19 are incompletely described and the extent to which CT findings correlate with symptoms and physical function after hospitalisation remains unclear. At 4 months after hospitalisation, fibrotic-like patterns were more common in those who underwent mechanical ventilation (72%) than in those who did not (20%). We demonstrate that severity of initial illness, duration of mechanical ventilation, lactate dehydrogenase on admission and leucocyte telomere length are independent risk factors for fibrotic-like radiographic abnormalities. These fibrotic-like changes correlate with lung function, cough and measures of frailty, but not with dyspnoea.

The role of initial chest X-ray in triaging patients with suspected COVID-19 during the pandemic.

PURPOSE: The purpose of our research is to evaluate the usefulness of chest X-ray for triaging patients with suspected COVID-19 infection. METHODS: IRB approval was obtained to allow a retrospective review of adult patients who presented to the Emergency Department with a complaint of fever, cough, dyspnea or hypoxia and had a chest X-ray between 12 March 2020 and 26 March 2020. The initial chest X-ray was graded on a scale of 0-3 with grade 0 representing no alveolar opacities, grade 1: < 1/3 alveolar opacities of the lung, Grade 2: 1/3 to 2/3 lung with alveolar opacities and grade 3: > 2/3 alveolar opacities of the lung. Past medical history of diabetes and hypertension, initial oxygen saturation, COVID-19 testing results, intubation, and outcome were also collected. RESULTS: Four hundred ten patient chest X-rays were reviewed. Oxygen saturation and X-ray grade were both significantly associated with the length of stay in hospital, the hazard ratio (HR) of discharge was 1.05 (95% CI [1.01, 1.09], p = 0.017) and 0.61 (95% CI [0.51, 0.73], p < 0.001), respectively. In addition, oxygen saturation and X-ray grade were significant predictors of intubation (odds ratio (OR) of intubation is 0.88 (95% CI [0.81, 0.96], p = 0.004) and 3.69 (95% CI [2.25, 6.07], p < 0.001). CONCLUSIONS: Initial chest X-ray is a useful tool for triaging those subjects who might have poor outcomes with suspected COVID-19 infection and benefit most from hospitalization.

Baseline and annual repeat rounds of screening: implications for optimal regimens of screening.

OBJECTIVES: Differences in results of baseline and subsequent annual repeat rounds provide important information for optimising the regimen of screening. METHODS: A prospective cohort study of 65,374 was reviewed to examine the frequency/percentages of the largest noncalcified nodule (NCN), lung cancer cell types and Kaplan-Meier (K-M) survival rates, separately for baseline and annual rounds. RESULTS: Of 65,374 baseline screenings, NCNs were identified in 28,279 (43.3%); lung cancer in 737 (1.1%). Of 74,482 annual repeat screenings, new NCNs were identified in 4959 (7%); lung cancer in 179 (0.24%). Only adenocarcinoma was diagnosed in subsolid NCNs. Percentages of lung cancers by cell type were significantly different (p < 0.0001) in the baseline round compared with annual rounds, reflecting length bias, as were the ratios, reflecting lead times. Long-term K-M survival rate was 100% for typical carcinoids and for adenocarcinomas manifesting as subsolid NCNs; 85% (95% CI 81-89%) for adenocarcinoma, 74% (95% CI 63-85%) for squamous cell, 48% (95% CI 34-62%) for small cell. The rank ordering by lead time was the same as the rank ordering by survival rates. CONCLUSIONS: The significant differences in the frequency of NCNs and frequency and aggressiveness of diagnosed cancers in baseline and annual repeat need to be recognised for an optimal regimen of screening. KEY POINTS: • Lung cancer aggressiveness varies considerably by cell type and nodule consistency. • Kaplan-Meier survival rates varied by cell type between 100% and 48%. • The percentages of lung cancers by cell type in screening rounds reflect screening biases. • Rank ordering by cell type survival is consistent with that by lead times. • Empirical evidence provides critical information for the regimen of screening.

Correction to: Baseline and annual repeat rounds of screening: implications for optimal regimens of screening.

The original version of this article unfortunately contained a mistake. The conflict of interest was incorrect.

Incremental Role of Mammography in the Evaluation of Gynecomastia in Men Who Have Undergone Chest CT.

OBJECTIVE: The purpose of this study was to determine whether additional breast imaging is clinically valuable in the evaluation of patients with gynecomastia incidentally observed on CT of the chest. MATERIALS AND METHODS: In a retrospective analysis, 62 men were identified who had a mammographic diagnosis of gynecomastia and had also undergone CT within 8 months (median, 2 months). We compared the imaging findings of both modalities and correlated them with the clinical outcome. RESULTS: Gynecomastia was statistically significantly larger on mammograms than on CT images; however, there was a high level of concordance in morphologic features and distribution of gynecomastia between mammography and CT. In only one case was gynecomastia evident on mammographic but not CT images, owing to cachexia. Two of the 62 men had ductal carcinoma, which was obscured by gynecomastia. Both of these patients had symptoms suggesting malignancy. CONCLUSION: The appearance of gynecomastia on CT scans and mammograms was highly correlated. Mammography performed within 8 months of CT is unlikely to reveal cancer unless there is a suspicious clinical finding or a breast mass eccentric to the nipple. Men with clinical symptoms of gynecomastia do not need additional imaging with mammography to confirm the diagnosis if they have undergone recent cross-sectional imaging.