Development of a Novel Circulating Autoantibody Biomarker Panel for the Identification of Patients with 'Actionable' Pulmonary Nodules.

Due to poor compliance and uptake of LDCT screening among high-risk populations, lung cancer is often diagnosed in advanced stages where treatment is rarely curative. Based upon the American College of Radiology's Lung Imaging and Reporting Data System (Lung-RADS) 80-90% of patients screened will have clinically "non-actionable" nodules (Lung-RADS 1 or 2), and those harboring larger, clinically "actionable" nodules (Lung-RADS 3 or 4) have a significantly greater risk of lung cancer. The development of a companion diagnostic method capable of identifying patients likely to have a clinically actionable nodule identified during LDCT is anticipated to improve accessibility and uptake of the paradigm and improve early detection rates. Using protein microarrays, we identified 501 circulating targets with differential immunoreactivities against cohorts characterized as possessing either actionable (n = 42) or non-actionable (n = 20) solid pulmonary nodules, per Lung-RADS guidelines. Quantitative assays were assembled on the Luminex platform for the 26 most promising targets. These assays were used to measure serum autoantibody levels in 841 patients, consisting of benign (BN; n = 101), early-stage non-small cell lung cancer (NSCLC; n = 245), other early-stage malignancies within the lung (n = 29), and individuals meeting United States Preventative Screening Task Force (USPSTF) screening inclusion criteria with both actionable (n = 87) and non-actionable radiologic findings (n = 379). These 841 patients were randomly split into three cohorts: Training, Validation 1, and Validation 2. Of the 26 candidate biomarkers tested, 17 differentiated patients with actionable nodules from those with non-actionable nodules. A random forest model consisting of six autoantibody (Annexin 2, DCD, MID1IP1, PNMA1, TAF10, ZNF696) biomarkers was developed to optimize our classification performance; it possessed a positive predictive value (PPV) of 61.4%/61.0% and negative predictive value (NPV) of 95.7%/83.9% against Validation cohorts 1 and 2, respectively. This panel may improve patient selection methods for lung cancer screening, serving to greatly reduce the futile screening rate while also improving accessibility to the paradigm for underserved populations.

Respiratory Musculature Evaluated by Computed Tomography in the Setting of Prolonged Mechanical Ventilation.

BACKGROUND: Diaphragm atrophy has been observed in subjects who undergo invasive mechanical ventilation. We propose a new method to assess for respiratory muscle (RM) changes in subjects who undergo invasive mechanical ventilation by assessing for changes in respiratory muscles through computed tomography (CT). METHODS: A retrospective case series study was conducted on subjects who underwent invasive mechanical ventilation and received at least 2 chest CT scans during admission. Exclusion criteria included history of chronic mechanical ventilation dependence and neuromuscular disease. Respiratory muscle cross-sectional area (CSA) was measured at the T6 vertebrae. RESULTS: Fourteen subjects were included: mean (± SD) age, BMI, and admission APACHE II scores were 54.0 y (± 14.9), 32.6 kg/m2 (± 10.9), and 23.5 (± 6.0), respectively. Ten (71%) subjects were male. Mean length of time between CT chest scans was 7.5 d (± 3.3). Mean duration of invasive mechanical ventilation was 4.5 d (± 3.4). The percentage change in TM CSA among those who underwent invasive mechanical ventilation was 10.5% (± 6.1). CONCLUSIONS: We demonstrated that serial analysis of respiratory muscle CSA through CT chest scans can be a method to assess for respiratory muscle atrophy in subjects undergoing mechanical ventilation. Future prospective studies involving larger populations are needed to better understand how this method can be used to predict outcomes in mechanically ventilated patients.

The association between thoracic sarcopenia and survival is gender specific in early-stage lung cancer.

Background: Sarcopenia, as measured at the 3rd lumbar (L3) level, has been shown to prognosticate survival in cancer patients. However, many patients with early-stage non-small cell lung cancer (NSCLC) do not undergo abdominal imaging. We hypothesized that preoperative thoracic sarcopenia is associated with survival in patients undergoing lung resection for early-stage NSCLC. Methods: Patients who underwent anatomic resection for NSCLC between 2010-2019 were retrospectively identified. Exclusion criteria included induction therapy, less than 90 days of follow-up, and absence of computed tomography (CT) imaging. Cross sectional skeletal muscle area was calculated at the fifth thoracic vertebra (T5), twelfth thoracic vertebra (T12), and L3 level. Gender-specific lowest quartile values and previously defined values were used to define sarcopenia. Overall survival and disease-free survival were assessed using the Kaplan-Meier method. Results: Overall, 221 patients met inclusion criteria with a median body mass index (BMI) of 26.5 kg/m2 [interquartile range (IQR), 23.3-29.9 kg/m2], age of 69 years (IQR, 62.4-74.9 years), and follow-up of 46.9 months (IQR, 25.0-70.7 months). At the T5 level, sarcopenic males demonstrated worse overall survival [median 41.0 (IQR, 13.8-53.7) vs. 42.0 (IQR, 23.1-55.1) months, P=0.023] and disease-free survival [median 15.8 (IQR, 8.4-30.78) vs. 34.8 (IQR, 20.1-50.5) months, P=0.007] when compared to non-sarcopenic males. There was no difference in survival between sarcopenic and non-sarcopenic females when assessed at T5. Sarcopenia at T12 or L3 was associated with worse overall survival (P<0.05). Conclusions: Sarcopenia at T5 is associated with worse survival in males, but not females. When using upper thoracic vertebral levels to assess for sarcopenia, it is necessary to account for gender.

Validation of skeletal muscle and adipose tissue measurements using a fully automated body composition analysis neural network versus a semi-automatic reference program with human correction in patients with lung cancer.

Rationale and objectives: To validate skeletal muscle and adipose tissues cross sectional area (CSA) and densities between a fully automated neural network (test program) and a semi-automated program requiring human correction (reference program) for lumbar 1 (L1) and lumbar 2 (L2) CT scans in patients with lung cancer. Materials and methods: Agreement between the reference and test programs was measured using Dice-similarity coefficient (DSC) and Bland-Altman plots with limits of agreement within 1.96 standard deviation. Results: A total of 49 L1 and 47 L2 images were analyzed from patients with lung cancer (mean age = 70.51 ± 9.48 years; mean BMI = 27.45 ± 6.06 kg/m2; 71% female, 55% self-identified as Black and 96% as non-Hispanic ethnicity). The DSC indicates excellent overlap (>0.944) or agreement between the two measurement methods for muscle, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) CSA and all tissue densities at L1 and L2. The DSC was lowest for intermuscular adipose tissue (IMAT) CSA at L1 (0.889) and L2 (0.919). Conclusion: The use of a fully automated neural network to analyze body composition at L1 and L2 in patients with lung cancer is valid for measuring skeletal muscle and adipose tissue CSA and densities when compared to a reference program. Further validation in a more diverse sample and in different disease and health states is warranted to increase the generalizability of the test program at L1 and L2.

Novel application of respiratory muscle index obtained from chest computed tomography to predict postoperative respiratory failure after major non-cardiothoracic surgery.

BACKGROUND: Postoperative respiratory failure (PRF) is a serious complication associated with significant morbidity and mortality. We propose a new method to predict PRF by utilizing computed tomography (CT) of the chest to assess degree of respiratory muscle wasting prior to surgery. METHODS: Patients who received a chest CT and required invasive mechanical ventilation (MV) after major non-cardiothoracic surgery were included. Exclusion criteria included cardiothoracic surgery. Respiratory muscle index (RMI) was calculated at the T6 vertebra measured on Slice-O-Matic® software. RESULTS: Thirty three patients met inclusion with a mean (±SD) age, BMI, and APACHE II score of 62.2 years (±12.1), 28.1 kg/m2 (±7.8), and 14.1 (±4.7). Most patients were female (n = 22 [67%]). Eleven patients (33%) developed PRF with a mean of 6.0 (±10.7) initial ventilation days. There was no difference in baseline demographics between groups. RMI values for the PRF group were significantly lower when compared to the non-PRF group: 22.7 cm2/m2 (±5.3) vs. 28.5 cm2/m2 (±5.9) (p = 0.008). CONCLUSION: Presence of respiratory muscle wasting prior to surgery was found to be associated with postoperative respiratory failure.

Case 287: Intrathoracic Migration of a Breast Implant after Video-assisted Thoracoscopic Surgery for Right Upper Lobectomy.

History A 60-year-old woman was diagnosed with a new right upper lobe stage I lung adenocarcinoma and underwent video-assisted thoracoscopic surgery (VATS) for right upper lobectomy. Her postoperative course was complicated by a large pneumothorax after chest tube removal on postoperative day 3. This was managed with repeat right-sided chest tube placement on the same day. The second chest tube was removed on postoperative day 8 without complications. A 2-week postoperative clinic visit was unremarkable. Postoperative chest radiographs on postoperative days 1, 3, and 8 are provided. Subsequently, chest CT scanning was performed as part of routine 6-month postsurgical lung cancer surveillance follow-up. The patient had no clinical complaints at routine follow-up. Physical examination revealed well-healed VATS scars in the chest wall. Laboratory results were within normal limits, including a normal white blood cell count of 6400/mL. Her surgical history included prior left upper lobectomy for remote left upper lobe stage IIIA adenocarcinoma and prior bilateral breast implantation for cosmesis. On the basis of chest CT findings, the patient was transferred from an outside institution.

Imaging Adult ECMO.

Adult extracorporal membrane oxygenation utilization in the ICU has rapidly increased. Newer technology and cannulation strategies and the complex hemodynamics make imaging interpretation challenging. There is also a high rate of complications. This review details the common indications, cannulation strategies, relevant hemodynamics and complications which impact imaging interpretation. Recommendations for modifying computed tomography protocols and techniques to obtain diagnostic images and some of the imaging pitfalls are also discussed.

Case 287.

History A 60-year-old woman was diagnosed with a new right upper lobe stage I lung adenocarcinoma and underwent video-assisted thoracoscopic surgery (VATS) for right upper lobectomy. Her postoperative course was complicated by a large pneumothorax after chest tube removal on postoperative day 3. This was managed with repeat right-sided chest tube placement on the same day. The second chest tube was removed on postoperative day 8 without complications. A 2-week postoperative clinic visit was unremarkable. Postoperative chest radiographs on postoperative days 1, 3, and 8 (Fig 1a-1c) are provided. Subsequently, chest CT scanning was performed as part of routine 6-month postsurgical lung cancer surveillance follow-up (Figs 2, 3). The patient had no clinical complaints at routine follow-up. Physical examination revealed well-healed VATS scars in the chest wall. Laboratory results were within normal limits, including a normal white blood cell count of 6400/µL. Her surgical history included prior left upper lobectomy for remote left upper lobe stage IIIA adenocarcinoma and prior bilateral breast implantation for cosmesis. On the basis of chest CT findings, the patient was transferred from an outside institution.

A 59-Year-Old Man With Chronic Kidney Disease After Kidney Transplantation Presents With Chronic Dyspnea.

CASE PRESENTATION: A 59-year-old man presented to the ED with a chief complaint of shortness of breath. His past medical history was significant for end-stage renal disease secondary to lithium toxicity, immunosuppression subsequent to cadaveric renal transplantation, bipolar disorder, and hypertension. His shortness of breath had begun 6 months previously and was initially intermittent; it then progressed to constant shortness of breath over the few weeks before presentation. He had no fever, hemoptysis, or chest pain. The patient was admitted to hospital for further evaluation.

Crowdsourcing pneumothorax annotations using machine learning annotations on the NIH chest X-ray dataset.

Pneumothorax is a potentially life-threatening condition that requires prompt recognition and often urgent intervention. In the ICU setting, large numbers of chest radiographs are performed and must be interpreted on a daily basis which may delay diagnosis of this entity. Development of artificial intelligence (AI) techniques to detect pneumothorax could help expedite detection as well as localize and potentially quantify pneumothorax. Open image analysis competitions are useful in advancing state-of-the art AI algorithms but generally require large expert annotated datasets. We have annotated and adjudicated a large dataset of chest radiographs to be made public with the goal of sparking innovation in this space. Because of the cumbersome and time-consuming nature of image labeling, we explored the value of using AI models to generate annotations for review. Utilization of this machine learning annotation (MLA) technique appeared to expedite our annotation process with relatively high sensitivity at the expense of specificity. Further research is required to confirm and better characterize the value of MLAs. Our adjudicated dataset is now available for public consumption in the form of a challenge.

Theoretical and Practical Implications of Treating Cachexia in Advanced Lung Cancer Patients.

Lung cancer continues to be a major worldwide health issue, with more than 50% of patients having incurable metastatic disease at diagnosis. Fortunately, the advanced lung cancer treatment landscape is changing rapidly as a result of the positive impact of effective inhibitors of tumor driver mutations, and the more recent discovery that immune modulation with anti-PD-1/PD-L1 monoclonal antibodies results in tumor regression and prolonged survival. While a relatively small subset of lung cancer patients are candidates for inhibitors of driver mutations, the majority of advanced lung cancer patients are candidates for an immunotherapy regimen. Many of these patients have cachexia, which is associated with increased cancer therapy toxicity and possibly reduced responsiveness to immunotherapy. Two ongoing cachexia trials, one testing a ghrelin analogue and the other testing a multimodal strategy, have endpoints which assess clinical benefit-weight gain and relief of anorexia/cachexia symptoms. Provided that the trial objectives are achieved, these treatment strategies will provide a way to relieve suffering and distress for cachectic cancer patients. While awaiting the results of these trials, it would be reasonable to consider designing studies testing cachexia treatments combined with first-line immunotherapy and chemotherapy-immunotherapy in stage IV lung cancer patients, with enhanced overall survival being one of the endpoints.

Improved False-Positive Rates and the Overestimation of Unintended Harm from Lung Cancer Screening.

BACKGROUND: Concern over high false-positive rates and the potential for unintended harm to patients is a critical component of the lack of widespread adoption of lung cancer screening. METHODS: An institutional database was used to identify patients who underwent lung cancer screening between 2/2015 and 2/2018 at Rush University Medical Center and Rush Oak Park Hospital. Reads were executed by dedicated thoracic radiologists and communicated using the Lung Imaging Reporting and Data System (Lung-RADS V.1). RESULTS: Six hundred and four patients were screened over the study period. We identified 21 primary lung cancers and 8 incidental cancers. We identified a false-positive rate of 17.5%. Only 9 patients underwent further investigative workup for benign disease (5.3%); however, only 4 (2.9%) of those patients were found to have inflammatory or infectious lesions, which are common mimickers of lung cancer. Excluding Lung-RADS category 3 for the purpose of quantifying risk of unintended harm from unnecessary procedures, we found a 6.9% false-positive rate, while diagnosing 25% of all Lung-RADS category 4 patients with primary lung cancer. CONCLUSION: False-positive rates in lung cancer screening programs continue to decline with improved radiologic expertise. Additionally, false-positive reporting overestimates the risk of unintended harm from further investigative procedures as only a percentage of positive findings are generally considered for tissue diagnosis (i.e., Lung-RADS category 4).

Evaluation of the impact of cachexia on clinical outcomes in aggressive lymphoma.

Cancer cachexia is a state of involuntary weight loss and altered body composition triggered by an underlying malignancy. We sought to correlate measures of cachexia with clinical outcomes in aggressive lymphomas and to identify biological pathways involved in the cachexia phenotype for possible druggable targets. Radiographic measures of cachexia were collected in a retrospective cohort of 109 patients with aggressive B-cell lymphoma and followed for clinical outcome. We found males with sarcopenia had reduced progression-free survival (5·4 vs. 72·3 months, P < 0·0005) and overall survival (OS; 30·2 months vs. not reached, NR, P = 0·02); males with adipopenia also had decreased OS (21·6 months vs. NR, P = 0·04). A trend for increased OS was observed in female sarcopenics only (32·8 months vs. NR, P = 0·08). Additionally, we analysed a prospective cohort of 14 patients for differences in circulating molecular targets involved in various biological pathways. There was a significant correlation with cachexia for reduced serum levels of mediators within the glucose utilization [insulin -like growth factor (IGF)-binding protein 6, P = 0·04; IGF-1, P = 0·02], inflammation (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells; LIGHT, P = 0·005), and energy intake/expenditure (leptin, P = 0·004). We conclude that cachexia in patients with aggressive lymphomas has sex-specific prognostic utility and correlates with measurable changes in metabolism and immune function.

Augmenting the National Institutes of Health Chest Radiograph Dataset with Expert Annotations of Possible Pneumonia.

This dataset is intended to be used for machine learning and is composed of annotations with bounding boxes for pulmonary opacity on chest radiographs which may represent pneumonia in the appropriate clinical setting.

Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Primer for Radiologists.

The past 2 decades have seen a rapid growth in use of stereotactic body radiation therapy (SBRT) for the management of non-small cell lung cancer (NSCLC). Not only is SBRT the reference standard for treatment of early-stage node-negative NSCLC in medically inoperable patients, it is also currently challenging the role of surgery for early-stage operable disease. SBRT is also used to treat recurrent disease and has a role in the management of multiple synchronous lung cancers. Imaging changes after SBRT differ from the changes after conventional radiation therapy in many ways, the knowledge of which is pertinent for accurate image interpretation. Posttreatment response assessment and detection of recurrent disease are heavily reliant on radiologic assessment, and often the decision to treat recurrent disease is based on the imaging findings themselves. This article provides a comprehensive review of the concepts of SBRT and the current indications for its use in the treatment of early-stage NSCLC, as well as a discussion of the CT findings seen after SBRT compared with the changes after conventional radiation therapy. Radiologic findings that are suggestive of recurrent disease and the imaging pitfalls are also highlighted. Finally, the rare complications after SBRT are described. SBRT is a major component of the changing treatment paradigms for early- and late-stage NSCLC. The imaging findings after SBRT often determine the next steps in a patient's clinical management. Therefore, radiologists must be familiar with the uses of this therapy and its radiologic appearance to be able to effectively contribute to the care of patients with NSCLC. ©RSNA, 2018.

Impact of cachexia on outcomes in aggressive lymphomas.

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87-93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into "non-cachectic" (CXI ≥49.8, n = 41) and "cachectic" (CXI <49.8, n = 40) groups. Cachectic patients had significantly worse PFS (HR 2.18, p = 0.044) and OS (HR = 4.05, p = 0.004) than non-cachectic patients. Cachexia as defined by the CXI is prognostic in aggressive lymphomas and implies that novel therapeutic strategies directed at reversing cachexia may improve survival in this population.