CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors.

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial3. Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8+ cytotoxic T cells, but relative sparing of CD4+ effector subsets. Dual ICB potently engaged CD4+ effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4+ and CD8+ T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Spectrum of Coronary Artery Aneurysms: From the Radiologic Pathology Archives.

Advances in medical diagnosis reveal that coronary artery aneurysms (CAAs) may develop in several clinical scenarios and manifest variable symptoms, imaging appearances, and outcomes. Aneurysms are pathologically classified into three groups: atherosclerotic, inflammatory, and noninflammatory. The last category is associated with congenital, inherited, and connective tissue disorders. Overlap exists among the groups, because secondary atherosclerotic change may be present in an aneurysm of any cause. Atherosclerosis is the most common cause of CAAs in adults, and inflammation is considered the underlying mechanism. In children, Kawasaki disease is the most likely cause of CAAs. In both conditions, the aneurysms are usually multiple and affect more than one coronary artery. Mycotic (infectious), iatrogenic, and cocaine-induced CAAs are also well documented. Most CAAs are discovered incidentally, but potential cardiovascular complications include thrombosis, occlusion, fistula formation, rupture, myocardial infarction, and cardiac tamponade. Imaging modalities to evaluate a suspected CAA include transthoracic echocardiography, angiographic cardiac catheterization, electrocardiographically gated computed tomographic angiography, cardiac magnetic resonance (MR) imaging, and MR angiography. Management is usually individualized, and options include surveillance, anticoagulant therapy, percutaneous stent or coil placement, surgical resection, and coronary artery bypass grafting.

Standardizing the Reporting of Incidental, Non-Lung Cancer (Category S) Findings Identified on Lung Cancer Screening Low-Dose CT Imaging.

Lung cancer screening is slowly but steadily entering the realm of preventive health maintenance. Standardization of reporting of positive findings identified on screening low-dose CT (LDCT) scans, specifically lung nodules, is a key element of high-quality lung cancer screening. The American College of Radiology developed the Lung CT Screening Reporting and Data System (Lung-RADS) system for this purpose. In addition to detailed categorization of lung nodules, Lung-RADS identifies category S for other incidental findings identified on screening LDCT scans. In contrast to the highly structured reporting for nodules, category S findings are reported at the discretion of individual readers, with the potential for high variability of reporting. Incidental findings on lung cancer screening studies are common, may trigger unwarranted evaluation with potential harm and cost, and may precipitate patient distress. In response to these concerns, our multidisciplinary lung cancer screening program developed a structured system for standardized reporting of category S findings based on recommendations of the American College of Radiology and relevant specialty societies.

A 34-Year-Old Man With Lightheadedness and Dyspnea.

CASE PRESENTATION: A 34-year-old man presented to our institution with lightheadedness and dyspnea on exertion. His medical history included chronic pancreatitis, juvenile rheumatoid arthritis (JRA), gastroesophageal reflux disease, hypertension, lumbar degenerative disc disease, seizure disorder, anterior uveitis, and multiple vertebral fractures. In addition, he was a cigarette smoker with a 10-pack-year smoking history.

Comparison of Transbronchial and Cryobiopsies in Evaluation of Diffuse Parenchymal Lung Disease.

BACKGROUND: Diffuse parenchymal lung diseases (DPLDs) are common. An accurate diagnosis is essential due to differences in etiology, clinicopathologic features, therapeutic options, and prognosis. Transbronchial lung biopsies (TBLBs) are often limited by small specimen size, crush artifact, and other factors. Transbronchial lung cryobiopsies (TBLCs) are under investigation to overcome these limitations. METHODS: We conducted a retrospective study of 56 patients in a single, tertiary-care academic center to compare the yield of both techniques when performed in the same patient. Patients underwent flexible bronchoscopy using moderate sedation with TBLB followed by TBLC in the most radiographically abnormal areas. Clinical data and postprocedural outcomes were reviewed, with a final diagnosis made utilizing a multidisciplinary approach. RESULTS: The mean age of patients was 60 years and 54% were male. Comorbidities included COPD (14%) and prior malignancy (48%). The number of TBLB specimens ranged from 1 to 10 per patient (mean 4) and size varied from 0.1 to 0.8 cm. The number of TBLC specimens ranged from 1 to 4 per patient (mean 2) and size ranged from 0.4 to 2.6 cm. Both techniques provided the same diagnosis in 26 patients (46%). An additional 11 (20%) patients had a diagnosis established by adding TBLC to TBLB. Compared with TBLB, TBLC had a higher diagnostic yield in patients with hypersensitivity pneumonitis and interstitial lung disease. Only 2 patients required video-assisted thoracoscopic surgery to establish a diagnosis. Complications included pneumothorax (20%) and massive hemoptysis (2%). CONCLUSION: TBLC used with TBLB can improve the diagnostic yield of flexible bronchoscopy in patients with DPLD.

Genetic, host, and environmental interactions in a 19 year old with severe chronic obstructive lung disease; observations regarding the pathophysiology of airflow obstruction.

A case of a 19-year-old with severe chronic obstructive pulmonary disease is presented. This case illustrates genetic (severe alpha-1 antitrypsin deficiency) and host factors (such as developmental diaphragmatic hernia and the innate response to injury), and environmental (high oxidative stress and lung injury) interactions that lead to severe chronic obstructive lung disease. The development of chronic lung disease was caused by lung injury under high oxidative and inflammatory conditions in the setting of a diaphragmatic hernia. In the absence of normal alpha-1 antitrypsin levels, a pro-elastolytic environment in the early period of lung growth enhanced the development of severe hyperinflation and precocious airflow obstruction.

FDG PET Appearance of "Cannonball" Pulmonary Metastases.

We present the case of a 67-year-old woman with a recent tissue diagnosis of endometrial cancer whose FDG PET scan exhibited multiple hypermetabolic foci through out both the lungs. Contemporaneously acquired conventional radiolographs showed parenchymal nodules that demonstrated the classic "cannon ball" appearance of pulmonary metastases. Pulmonary metastasis from an endometrial primary is a rare event, as are the presence of pulmonary findings at the time of initial staging. Thus, this case demonstrates rare, and yet, distinctive aspects of the disease presentation and image correlation across the various imaging modalities.