Citations

Interstitial lung disease (ILD) is an inflammatory condition encompassing greater than 200 different chronic disorders that often lead to pulmonary fibrosis and the attendant morbidity and mortality. Distinguishing one ILD from another can be challenging even for experts given similar clinical manifestations. However, firm diagnosis is important for management, counseling, and surveillance. Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER, Mayo Clinic, Rochester, MN, USA), a machine learned image analysis tool for characterizing and quantifying diffused lung diseases on CT, has been shown to correlate with ILD mortality such as for idiopathic pulmonary fibrosis. The CALIPER assessment of ILD is not influenced by confounding conditions such as emphysema or pulmonary hypertension that may affect pulmonary function measurements. Moreover, CALIPER can provide more reproducible results with less inter- and intraobserver variability compared to the conventional subjective visual assessment of CT scans by radiologists. Herein, we aim to provide an overview of ILD and discuss CALIPER evaluation of ILD.

Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.

Abstract The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. Significance: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy. See related commentary by Farrington and Narla, p. 1756

BackgroundThere is no accurate method distinguishing different types of pulmonary nodules.PurposeTo investigate whether multiparametric 3T MRI biomarkers can distinguish malignant from benign pulmonary nodules, differentiate different types of neoplasms, and compare MRI‐derived measurements with values from commonly used noninvasive imaging modalities.Study TypeProspective.SubjectsSixty‐eight adults with pulmonary nodules undergoing resection.SequencesRespiratory triggered diffusion‐weighted imaging (DWI), periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) fat saturated T2‐weighted imaging, T1‐weighted 3D volumetric interpolated breath‐hold examination (VIBE) using CAIPIRINHA (controlled aliasing in parallel imaging results in a higher acceleration).Assessment/StatisticsApparent diffusion coefficient (ADC), T1, T2, T1 and T2 normalized to muscle (T1/M and T2/M), and dynamic contrast enhancement (DCE) values were compared with histology to determine whether they could distinguish malignant from benign nodules and discern primary from secondary malignancies using logistic regression. Predictability of primary neoplasm types was assessed using two‐sample t‐tests. MRI values were compared with positron emission tomography / computed tomography (PET/CT) to examine if they correlated with standardized uptake value (SUV) or CT Hounsfield unit (HU). Intra‐ and interreader agreements were assessed using intraclass correlations.ResultsForty‐nine of 74 nodules were malignant. There was a significant association between ADC and malignancy (odds ratio 4.47, P < 0.05). ADC ≥1.3 μm2/ms predicted malignancy. ADC, T1, and T2 together predicted malignancy (P = 0.003). No MRI parameter distinguished primary from metastatic neoplasms. T2 predicted PET positivity (P = 0.016). T2 and T1/M correlated with SUV (P < 0.05). Of 18 PET‐negative malignant nodules, 12 (67%) had an ADC ≥1.3 μm2/ms. With the exception of T2, all noncontrast MRI parameters distinguished adenocarcinomas from carcinoid tumors (P < 0.05). T1, T2, T1/M, and T2/M correlated with HU and therefore can predict nodule density. Combined with ADC, washout enhancement, arrival time (AT), peak enhancement intensity (PEI), Ktrans, Kep, Ve collectively were predictive of malignancy (P = 0.012). Combined washin, washout, time to peak (TTP), AT, and PEI values predicted malignancy (P = 0.043). There was good observer agreement for most noncontrast MRI biomarkers.Data ConclusionMRI can contribute to pulmonary nodule analysis. Multiparametric MRI might be better than individual MRI biomarkers in pulmonary nodule risk stratification.Level of Evidence: 1Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2018.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Objectives The aim of this study was to evaluate if a high-resolution photon-counting detector computed tomography (PCD-CT) system with a 1024×1024 matrix reconstruction can improve the visualization of fine structures in the lungs compared with conventional high-resolution CT (HRCT). Materials and Methods Twenty-two adult patients referred for clinical chest HRCT (mean CTDI vol, 13.58 mGy) underwent additional dose-matched PCD-CT (mean volume CT dose index, 13.37 mGy) after written informed consent. Computed tomography images were reconstructed at a slice thickness of 1.5 mm and an image increment of 1 mm with our routine HRCT reconstruction kernels (B46 and Bv49) at 512 and 1024 matrix sizes for conventional energy-integrating detector (EID) CT scans. For PCD-CT, routine B46 kernel and an additional sharp kernel (Q65, unavailable for EID) images were reconstructed at 1024 matrix size. Two thoracic radiologists compared images from EID and PCD-CT noting the highest level bronchus clearly identified in each lobe of the right lung, and rating bronchial wall conspicuity of third- and fourth-order bronchi. Lung nodules were also compared with the B46/EID/512 images using a 5-point Likert scale. Statistical analysis was performed using a Wilcoxon signed rank test with a P < 0.05 considered significant. Results Compared with B46/EID/512, readers detected higher-order bronchi using B46/PCD/1024 and Q65/PCD/1024 images for every lung lobe (P < 0.0015), but in only the right middle lobe for B46/EID/1024 (P = 0.007). Readers were able to better identify bronchial walls of the third- and fourth-order bronchi better using the Q65/PCD/1024 images (mean Likert scores of 1.1 and 1.5), which was significantly higher compared with B46/EID/1024 or B46/PCD/1024 images (mean difference, 0.8; P < 0.0001). The Q65/PCD/1024 images had a mean nodule score of 1 ± 1.3 for reader 1, and −0.1 (0.9) for reader 2, with one reader having improved nodule evaluation scores for both PCD kernels (P < 0.001), and the other reader not identifying any increased advantage over B46/EID/1024 (P = 1.0). Conclusions High-resolution lung PCD-CT with 1024 image matrix reconstruction increased radiologists' ability to visualize higher-order bronchi and bronchial walls without compromising nodule evaluation compared with current chest CT, creating an opportunity for radiologists to better evaluate airway pathology.