Microscopic Small Airway Abnormalities Identified in Early Idiopathic Pulmonary Fibrosis In Vivo Using Endobronchial Optical Coherence Tomography.

Rationale: Idiopathic pulmonary fibrosis (IPF) affects the subpleural lung but is considered to spare small airways. Micro-computed tomography (micro-CT) studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. Objectives: In this study, EB-OCT was used to evaluate small airways in early IPF and control subjects in vivo. Methods: EB-OCT was performed in 12 subjects with IPF and 5 control subjects (matched by age, sex, smoking history, height, and body mass index). Subjects with IPF had early disease with mild restriction (FVC: 83.5% predicted), which was diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for usual interstitial pneumonia present) and less affected (some but not all criteria for usual interstitial pneumonia present). Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. Measurements and Main Results: Compared with the number of bronchioles in control subjects (mean = 11.2/cm3; SD = 6.2), there was significant bronchiole reduction in subjects with IPF (42% loss; mean = 6.5/cm3; SD = 3.4; P = 0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; P < 0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; P = 0.024) sites. Stereology metrics showed that IPF-affected small airways were significantly larger, more distorted, and more irregular than in IPF-less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (P = 0.36-1.0). Conclusions: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30% and 50%), even in areas minimally affected by disease, compared with matched control subjects. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

A Pilot Study Using Machine Learning Algorithms and Wearable Technology for the Early Detection of Postoperative Complications After Cardiothoracic Surgery.

OBJECTIVE: To evaluate whether a machine learning algorithm (i.e. the "NightSignal" algorithm) can be used for the detection of postoperative complications prior to symptom onset after cardiothoracic surgery. SUMMARY BACKGROUND DATA: Methods that enable the early detection of postoperative complications after cardiothoracic surgery are needed. METHODS: This was a prospective observational cohort study conducted from July 2021 to February 2023 at a single academic tertiary care hospital. Patients aged 18 years or older scheduled to undergo cardiothoracic surgery were recruited. Study participants wore a Fitbit watch continuously for at least 1 week preoperatively and up to 90-days postoperatively. The ability of the NightSignal algorithm-which was previously developed for the early detection of Covid-19-to detect postoperative complications was evaluated. The primary outcomes were algorithm sensitivity and specificity for postoperative event detection. RESULTS: A total of 56 patients undergoing cardiothoracic surgery met inclusion criteria, of which 24 (42.9%) underwent thoracic operations and 32 (57.1%) underwent cardiac operations. The median age was 62 (IQR: 51-68) years and 30 (53.6%) patients were female. The NightSignal algorithm detected 17 of the 21 postoperative events a median of 2 (IQR: 1-3) days prior to symptom onset, representing a sensitivity of 81%. The specificity, negative predictive value, and positive predictive value of the algorithm for the detection of postoperative events were 75%, 97%, and 28%, respectively. CONCLUSIONS: Machine learning analysis of biometric data collected from wearable devices has the potential to detect postoperative complications-prior to symptom onset-after cardiothoracic surgery.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

BACKGROUND: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. PATIENTS AND METHODS: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. RESULTS: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. CONCLUSION: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Multimodality Management of Thoracic Tumors: Initial Experience With a Multidisciplinary Thoracic Ablation Conference.

BACKGROUND: This study aimed to describe lesion-specific management of thoracic tumors referred for consideration of image-guided thermal ablation (IGTA) at a newly established multidisciplinary ablation conference. METHODS: This retrospective single-center cohort study included consecutive patients with non-small cell lung cancer (NSCLC) or thoracic metastases evaluated from June 2020 to January 2022 in a multidisciplinary conference. Outcomes included the management recommendation, treatments received (IGTA, surgical resection, stereotactic body radiation therapy [SBRT], multimodality management), and number of tumors treated per patient. Pearson's chi-square test was used to assess for a change in management, and Poisson regression was used to compare the number of tumors by treatment received. RESULTS: The study included 172 patients (58 % female; median age, 69 years; 56 % thoracic metastases; 27 % multifocal primary lung cancer; 59 % ECOG 0 [range, 0-3]) assessed in 206 evaluations. For the patients with NSCLC, IGTA was considered the most appropriate local therapy in 12 %, equal to SBRT in 22 %, and equal to lung resection in 3 % of evaluations. For the patients with thoracic metastases, IGTA was considered the most appropriate local therapy in 22 %, equal to SBRT in 12 %, and equal to lung resection in 3 % of evaluations. Although all patients were referred for consideration of IGTA, less than one third of patients with NSCLC or thoracic metastases underwent IGTA (p < 0.001). Multimodality management allowed for treatment of more tumors per patient than single-modality management (p < 0.01). CONCLUSIONS: Multidisciplinary evaluation of patients with thoracic tumors referred for consideration of IGTA significantly changed patient management and facilitated lesion-specific multimodality management.

Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

NCCN Guidelines® Insights: Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

First-in-Human Intrathoracic Implantation of Multidrug-Eluting Microdevices for In Situ Chemotherapeutic Sensitivity Testing as Proof of Concept in Nonsmall Cell Lung Cancer.

OBJECTIVE: To evaluate the safety and feasibility of implantation and retrieval of a novel implantable microdevice (IMD) in NSCLC patients undergoing operative resection. BACKGROUND: Adjuvant therapy has limited impact on postsurgical outcomes in NSCLC due to the inability to predict optimal treatment regimens. METHODS: An IMD measuring 6.5 mm by 0.7 mm, containing micro-reservoirs allowing for high-throughput localized drug delivery, was developed and loaded with 12 chemotherapeutic agents. Five patients with peripheral lung lesions larger than 1.0 cm were enrolled in this phase 1 clinical study. IMDs were inserted into tumors intraoperatively under direct vision, removed with the resected specimen, and retrieved in pathology. Surrounding tissues were sectioned, stained, and analyzed for tissue drug response to the IMD-delivered microdoses of these agents by a variety of pharmacodynamic markers. RESULTS: A total of 14 IMDs were implanted intraoperatively with 13 (93%) successfully retrieved. After technique refinement, IMDs were reliably inserted and retrieved in open, Video-Assisted Thoracoscopic Surgery, and robotic cases. No severe adverse reactions were observed. The one retained IMD has remained in place without movement or any adverse effects. Analysis of patient blood revealed no detection of chemotherapeutic agents. We observed differential sensitivities of patient tumors to the drugs on the IMD. CONCLUSIONS: A multi-drug IMD can be safely inserted and retrieved into lung tumors during a variety of surgical approaches. Future studies will encompass preoperative placement to better examine specific tumor responsiveness to therapeutic agents, allowing clinicians to tailor treatment regimens to the microenvironment of each patient.

NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 2.2023.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Lung-RADS Category 3 and 4 Nodules on Lung Cancer Screening in Clinical Practice.

BACKGROUND. Lung-RADS category 3 and 4 nodules account for most screening-detected lung cancers and are considered actionable nodules with management implications. The cancer frequency among such nodules is estimated in the Lung-RADS recommendations and has been investigated primarily by means of retrospectively assigned Lung-RADS classifications. OBJECTIVE. The purpose of this study was to assess the frequency of cancer among lung nodules assigned Lung-RADS category 3 or 4 at lung cancer screening (LCS) in clinical practice and to evaluate factors that affect the cancer frequency within each category. METHODS. This retrospective study was based on review of clinical radiology reports of 9148 consecutive low-dose CT LCS examinations performed for 4798 patients between June 2014 and January 2021 as part of an established LCS program. Unique nodules assigned Lung-RADS category 3 or 4 (4A, 4B, or 4X) that were clinically categorized as benign or malignant in a multidisciplinary conference that considered histologic analysis and follow-up imaging were selected for further analysis. Benign diagnoses based on stability required at least 12 months of follow-up imaging. Indeterminate nodules were excluded. Cancer frequencies were evaluated. RESULTS. Of the 9148 LCS examinations, 857 (9.4%) were assigned Lung-RADS category 3, and 721 (7.9%) were assigned category 4. The final analysis included 1297 unique nodules in 1139 patients (598 men, 541 women; mean age, 66.0 ± 6.3 years). A total of 1108 of 1297 (85.4%) nodules were deemed benign, and 189 of 1297 (14.6%) were deemed malignant. The frequencies of malignancy of category 3, 4A, 4B, and 4X nodules were 3.9%, 15.5%, 36.3%, and 76.8%. A total of 45 of 46 (97.8%) endobronchial nodules (all category 4A) were deemed benign on the basis of resolution. Cancer frequency was 13.1% for solid, 24.4% for part-solid, and 13.5% for ground-glass nodules. CONCLUSION. In the application of Lung-RADS to LCS clinical practice, the frequency of Lung-RADS category 3 and 4 nodules and the cancer frequency in these categories were higher than the prevalence and cancer risk estimated for category 3 and 4 nodules in the Lung-RADS recommendations and those reported in earlier studies in which category assignments were retrospective. Nearly all endobronchial category 4A nodules were benign. CLINICAL IMPACT. Future Lung-RADS iterations should consider the findings of this study from real-world practice to improve the clinical utility of the system.

Diagnostic Accuracy of Endobronchial Optical Coherence Tomography for the Microscopic Diagnosis of Usual Interstitial Pneumonia.

Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and DlCO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8-100.0%) and 100% (79.6-100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72-1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

Management and outcomes of esophageal perforation.

BACKGROUND: Esophageal perforation is a morbid condition and remains a therapeutic challenge. We report the outcomes of a large institutional experience with esophageal perforation and identify risk factors for morbidity and mortality. METHODS: A retrospective analysis was conducted on 142 patients who presented with a thoracic or gastroesophageal junction esophageal perforation from 1995 to 2020. Baseline characteristics, operative or interventional strategies, and outcomes were analyzed by etiology of the perforation and management approach. Multivariable cox and logistic regression models were constructed to identify predictors of mortality and morbidity. RESULTS: Overall, 109 (77%) patients underwent operative intervention, including 80 primary reinforced repairs and 21 esophagectomies and 33 (23%) underwent esophageal stenting. Stenting was more common in iatrogenic (27%) and malignant (64%) perforations. Patients who presented with a postemetic or iatrogenic perforation had similar 90-day mortality (16% and 16%) and composite morbidity (51% and 45%), whereas patients who presented with a malignant perforation had a 45% 90-day mortality and 45% composite morbidity. Risk factors for mortality included age >65 years (hazard ratio [HR] 1.89 [1.02-3.26], P = 0.044) and a malignant perforation (HR 4.80 [1.31-17.48], P = 0.017). Risk factors for composite morbidity included pleural contamination (odds ratio [OR] 2.06 [1.39-4.43], P = 0.046) and sepsis (OR 3.26 [1.44-7.36], P = 0.005). Of the 33 patients who underwent stent placement, 67% were successfully managed with stenting alone and 30% required stent repositioning. CONCLUSIONS: Risk factors for morbidity and mortality after esophageal perforation include advanced age, pleural contamination, septic physiology, and malignant perforation. Primary reinforced repair remains a reasonable strategy for patients with an esophageal perforation from a benign etiology.

Longitudinal CT and MRI Characteristics of Unilocular Thymic Cysts.

Background Isoattenuating and hyperattenuating thymic cysts at CT are often misinterpreted as lymphadenopathy or thymic epithelial neoplasms. Purpose To evaluate the longitudinal change in thymic cyst appearance at CT and MRI. Materials and Methods All chest MRI studies showing thymic cysts between July 2008 and December 2019, identified from a retrospective search of a quality assurance database, were included in this study if initial CT depicted a thymic lesion, the patient was referred for follow-up MRI for characterization, and the baseline (ie, index) MRI indicated a cystic lesion. Follow-up CT scans and/or MRI scans were identified through July 2020. Thymic cyst characteristics, such as size, location, and morphologic features, as well as CT and MRI characteristics, were recorded. Change in size, attenuation, and T1-weighted MRI signal was assessed longitudinally. Descriptive statistics of longitudinal change were tabulated. Results A total of 244 chest MRI studies in 140 patients with 142 unique cysts and 392 CT examinations (636 total examinations and 645 thymic cysts-nine examinations with two cysts each) were evaluated. The median follow-up duration was 2.2 years. Thirty-three patients with 34 unique cysts (34 of 142 cysts [24%]) underwent imaging follow-up for more than 5 years. Thymic cysts followed up for more than 5 years were most commonly saccular (189 of 274 cysts [69% axially]) and retrosternal (14 of 34 cysts [41%]). Craniocaudal dimension was larger than transverse and anteroposterior dimensions in 223 of 274 cysts (81%). Mean thymic cyst attenuation was 25 HU (range, 15-100 HU). Five of 31 cysts (16%) exhibited wall calcification. The median cyst wall thickness was 2.0 mm (range, 0.9-3.0 mm). Most thymic cysts changed in volume (31 of 34 cysts [91%]), CT attenuation (15 of 35 cysts [43%]), and T1-weighted MRI signal (12 of 18 cysts [67%]) over time. None developed mural irregularity, nodularity, or septations. Conclusion Unilocular thymic cysts, defined at index MRI, never developed irregular wall thickening, mural nodularity, or septations that would raise concern for malignant transformation. However, these cysts showed mural calcification and change in size, CT attenuation, and MRI signal over more than 5 years of follow-up. © RSNA, 2021 Online supplemental material is available for this article.

Outcomes Following Percutaneous Microwave and Cryoablation of Lung Metastases from Adenoid Cystic Carcinoma of the Head and Neck: A Bi-Institutional Retrospective Cohort Study.

OBECTIVE: The aim of this study was to report outcomes following percutaneous microwave and cryoablation of lung metastases from adenoid cystic carcinoma (ACC) of the head and neck. MATERIAL AND METHODS: This bi-institutional retrospective cohort study included 10 patients (6 females, median age 59 years [range 28-81]) who underwent 32 percutaneous ablation sessions (21 cryoablation, 11 microwave) of 60 lung metastases (median 3.5 tumors per patient [range 1-16]) from 2007 to 2019. Median tumor diameter was 16 mm [range 7-40], significantly larger for cryoablation (22 mm, p = 0.002). A median of two tumors were treated per session [range 1-7]. Technical success, local control, complications, and overall survival were assessed. RESULTS: Primary technical success was achieved for 55/60 tumors (91.7%). Median follow-up was 40.6 months (clinical) and 32.5 months (imaging, per tumor). Local control at 1, 2, and 3 years was 94.7%, 80.8%, and 76.4%, respectively, and did not differ between ablation modalities. Five of fifteen recurrent tumors underwent repeat ablation, and secondary technical success was achieved in four (80%). Assisted local tumor control at 1, 2, and 3 years was 96.2%, 89.8%, and 84.9%, respectively. Complications occurred following 24/32 sessions (75.0%) and 57.2% Common Terminology Criteria for Adverse Events (CTCAE) lower than grade 3. Of 13 pneumothoraces, 7 required chest tube placements. Hemoptysis occurred after 7/21 cryoablation sessions, and bronchopleural fistula developed more frequently with microwave (p = 0.037). Median length of hospital stay was 1 day [range 0-10], and median overall survival was 81.5 months (IQR 40.4-93.1). CONCLUSION: Percutaneous computed tomography-guided microwave and cryoablation can treat lung metastases from ACC of the head and neck. Complications are common but manageable, with full recovery expected.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

Treatment of pulmonary hypertension in patients with Hereditary Hemorrhagic Telangiectasia - A case series and systematic review.

RATIONALE: Pulmonary Arterial Hypertension (PAH), a rare complication of HHT is associated with poor outcome. There are no trials to date that have investigated whether pulmonary vasodilator therapy improves hemodynamics or survival in this disease. OBJECTIVE: To determine whether pulmonary vasodilator therapy improves survival, exercise capacity, or hemodynamics in HHT patients with pre-capillary PH. METHODS: We performed a before-and-after observational study on a multicenter cohort of subjects with HHT-PAH who received intravenous prostanoid therapy. We then conducted a systematic review, searching Medline and EMBASE through December 2019. Studies that enrolled HHT-PAH subjects and reported treatment outcomes were selected. PROSPERO #158179. RESULTS: Twenty-one articles were selected. Studies were before-and-after observational studies, case reports, and case series. Among all subjects with HHT-PAH, both mPAP (65 ± 19 pre-treatment vs 51 ± 16 mmHg post-treatment p = 0.04) and PVR (12 ± 6 pre-treatment vs 8 ± 4 WU post-treatment p = 0.01) improved with treatment. The mPAP improved with either oral (57 ± 17 pre-treatment versus 44 ± 13 mmHg post-treatment, p = 0.03) or intravenous (80 ± 15 pre-treatment versus 64 ± 16 mmHg post-treatment, p = 0.017) therapy. PVR also improved with either oral (10 ± 4 pre-treatment versus 6 ± 3 WU post-treatment, p = 0.004) or intravenous (17 ± 5 pre-treatment versus 10 ± 4 WU post-treatment, p = 0.04) therapy. Survival among HHT-PAH patients who received oral or intravenous therapy was not different (p = 0.2). Unadjusted survival among HHT-PAH patients was longer than that of IPAH patients (p = 0.008). There was no difference in side effects among HHT-PAH patient who received oral or intravenous therapy (p = 0.1). CONCLUSION: Pulmonary vasodilator therapy is effective in improving hemodynamics of subjects with HHT-PAH and was not associated with increased risk of side effects.

Clinicopathologic and Longitudinal Imaging Features of Lung Cancer Associated With Cystic Airspaces: A Systematic Review and Meta-Analysis.

BACKGROUND. Lung cancer (LC) associated with cystic airspaces is an uncommon presentation that is underrecognized on imaging. Additionally, understanding of its underlying pathology and risk factors is limited, which can contribute to delays in diagnosis. OBJECTIVE. The purpose of this analysis was to systematically review, analyze, and synthesize the medical literature to determine the imaging features of LC associated with cystic airspaces. EVIDENCE ACQUISITION. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included published research reporting the clinical, pathologic, and imaging features of LC associated with cystic airspaces. We then performed a pooled analysis of continuous and categoric data with respect to patient clinical characteristics, tumor pathologic features, underlying driver mutation, CT features, and evolution of these features over time. EVIDENCE SYNTHESIS. The analysis included eight original observational studies with a combined total of 341 patients with LC associated with cystic airspaces (weighted mean age, 61.8 years; range, 30-87 years; 135 women and 206 men). Most patients were current or previous smokers (127/192 [66.1%]). The most common histologic finding was adenocarcinoma (289/328 [88.1%]) followed by squamous cell carcinoma (30/328 [9.1%]). The most common driver mutations were EGFR (46/122 [37.7%]) and KRAS (21/122 [17.2%]). The cysts in LC associated with cystic airspaces commonly had nonuniform (104/114 [91.2%]) and thick (83/222 [37.4%]) walls, irregular margins (53/142 [37.3%]), and were unilocular (173/272 [63.6%]). Most cysts had a nodular component (210/328 [64.0%]). Over time, most cysts showed development or enlargement of the nodular component (61/89 [68.5%]), approximately half showed wall thickening (43/89 [48.3%]), and a minority evolved into completely solid lesions (11/89 [12.4%]). The size of the cystic component increased in 36 of 89 patients (40.4%), decreased in 28 (31.5%), and remained stable in 24 (27.0%). CONCLUSION. LC associated with cystic airspaces occurs most commonly as adeno-carcinoma and is seen in both smokers and nonsmokers. The cysts associated with LC show wall thickening and mural nodularity, which may evolve over time. LC associated with cystic airspaces can be indolent, and long-term surveillance with imaging should be considered if cysts are not resected. CLINICAL IMPACT. Familiarity with the imaging features and temporal evolution of LC associated with cystic airspaces can minimize delays in LC diagnosis. Future management guidelines should include protocols for follow-up and management of cystic lung lesions identified during diagnostic and LC screening CT.

Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Approximately 25% of all patients with non-small-cell lung cancer present with resectable stage IB-IIIA disease, and although perioperative chemotherapy is the standard of care, this treatment strategy provides only modest survival benefits. On the basis of the activity of immune checkpoint inhibitors in metastatic non-small-cell lung cancer, we designed a trial to test the activity of the PD-L1 inhibitor, atezolizumab, with carboplatin and nab-paclitaxel given as neoadjuvant treatment before surgical resection. METHODS: This open-label, multicentre, single-arm, phase 2 trial was done at three hospitals in the USA. Eligible patients were aged 18 years or older and had resectable American Joint Committee on Cancer-defined stage IB-IIIA non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1, and a history of smoking exposure. Patients received neoadjuvant treatment with intravenous atezolizumab (1200 mg) on day 1, nab-paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1, of each 21-day cycle. Patients without disease progression after two cycles proceeded to receive two further cycles, which were then followed by surgical resection. The primary endpoint was major pathological response, defined as the presence of 10% or less residual viable tumour at the time of surgery. All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT02716038, and is ongoing but no longer recruiting participants. FINDINGS: Between May 26, 2016, and March 1, 2019, we assessed 39 patients for eligibility, of whom 30 patients were enrolled. 23 (77%) of these patients had stage IIIA disease. 29 (97%) patients were taken into the operating theatre, and 26 (87%) underwent successful R0 resection. At the data cutoff (Aug 7, 2019), the median follow-up period was 12·9 months (IQR 6·2-22·9). 17 (57%; 95% CI 37-75) of 30 patients had a major pathological response. The most common treatment-related grade 3-4 adverse events were neutropenia (15 [50%] of 30 patients), increased alanine aminotransferase concentrations (two [7%] patients), increased aspartate aminotransferase concentration (two [7%] patients), and thrombocytopenia (two [7%] patients). Serious treatment-related adverse events included one (3%) patient with grade 3 febrile neutropenia, one (3%) patient with grade 4 hyperglycaemia, and one (3%) patient with grade 2 bronchopulmonary haemorrhage. There were no treatment-related deaths. INTERPRETATION: Atezolizumab plus carboplatin and nab-paclitaxel could be a potential neoadjuvant regimen for resectable non-small-cell lung cancer, with a high proportion of patients achieving a major pathological response, and manageable treatment-related toxic effects, which did not compromise surgical resection. FUNDING: Genentech and Celgene.

The farnesoid X receptor agonist EDP-305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction.

Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance of hepatic steatosis, inflammation, and fibrosis. However, the role of FXR in renal fibrosis remains to be established. Here, we investigate the effects of the FXR agonist EDP-305 in a mouse model of tubulointerstitial fibrosis via unilateral ureteral obstruction (UUO). Male C57Bl/6 mice received a UUO on their left kidney. On postoperative d 4, mice received daily treatment by oral gavage with either vehicle control (0.5% methylcellulose) or 10 or 30 mg/kg EDP-305. All animals were euthanized on postoperative d 12. EDP-305 dose-dependently decreased macrophage infiltration as measured by the F4/80 staining area and proinflammatory cytokine gene expression. EDP-305 also dose-dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen proportional area and kidney hydroxyproline levels. Finally, yes-associated protein (YAP) activation, a major driver of fibrosis, increased after UUO injury and was diminished by EDP-305 treatment. Consistently, EDP-305 decreased TGF-ß1-induced YAP nuclear localization in human kidney 2 cells by increasing inhibitory YAP phosphorylation. YAP inhibition may be a novel antifibrotic mechanism of FXR agonism, and EDP-305 could be used to treat renal fibrosis.-Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., Ferriera, D. S., Li, Y., Wang, G., Lanuti, M., Caravan, P., Or, Y. S., Jiang, L.-J., Tanabe, K. K., Fuchs, B. C. The farnesoid X receptor agonist EDP-305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction.