Peikert, Tobias

AbstractFibrosing mediastinitis is a rare, often debilitating and potentially lethal disease characterized by an exuberant fibroinflammatory response within the mediastinum. Patients typically present with insidious symptoms related to compression of adjacent structures including the esophagus, heart, airways, and cardiac vessels. Fibrosing mediastinitis is most often triggered by Histoplasmosis infection; however, antifungal and anti‐inflammatory therapies are largely ineffective. While structural interventions aimed at alleviating obstruction can provide significant palliation, surgical interventions are challenging with high mortality and clinical experience with percutaneous interventions is limited. Here, we will review the presentation, natural history, and treatment of fibrosing mediastinitis, placing particular emphasis on catheter‐based therapies.

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.

Abstract Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Consistent with this carcinogenic exposure, cytogenetic analyses have identified multiple recurrent structural chromosomal abnormalities in this malignancy, but more recent high-throughput sequencing evaluations of point mutations suggest that there is a low mutational burden in mesothelioma. Since tumor mutational burden has been correlated with responses to treatment with immune checkpoint inhibitors such as nivolumab, it was not consistent that patients with mesothelioma and low mutation burdens would have similar response rates in clinical trials with immune checkpoint inhibitors as patients with non-small cell lung cancer which is associated with a high mutation burden. In order to reconcile these differences, and given the potential for an improved understanding of the molecular pathogenesis of mesothelioma to improve therapeutic options, we used mate-pair sequencing (MPseq) and RNA sequencing (RNAseq) to understand how structural variants affect the transcriptome. MPseq differs from standard next generation sequencing approaches by tiling the whole genome with larger fragments (2-5kb) to reliably detect structural variants such as insertions, deletions and rearrangements. Amongst 22 mesothelioma specimens there were 1535 chromosomal rearrangements (median 41, range 3-298 per specimen), that resulted in junctions or novel fusions of non-coding DNA or genes. Six-hundred thirty-seven of these rearrangements (median 22, range 5-103 range per specimen) resulted in novel fusions of genes. Many of these inter- or intra-chromosomal rearrangements were consistent with a pattern of chromoanagesis such as chromoplexy or chromothripsis. Chromosomal rearrangements detected by MPseq were used to guide analysis of RNAseq data and revealed that these chromosomal junctions resulted in the expression of 179 novel amino acid sequences (median 5, 0-51 range per specimen). To determine whether transcription of chromosomal rearrangement-related junctions have neoantigenic potential, we used in silico tools to determine whether any of the expressed junctions contained peptides that could be presented by patient-specific HLA molecules. The top candidate rearrangement-related peptides with neoantigenic potential bound patient-specific HLA molecules nearly as well or as well as a positive control in competitive binding assays. Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel therapeutic strategies, the selection of patients to receive immunotherapy, and blood-based treatment monitoring strategies. Citation Format: Aaron S. Mansfield, Tobias Peikert, James B. Smadbeck, Julia B. Udell, Farhad Kosari, Stephen J. Murphy, Hongzheng Ren, Vishnu V. Serla, Janet L. Schaefer Klein, Giannoula Karagouga, Faye R. Harris, Carlos Sosa, Sarah H. Johnson, Wendy Nevala, Svetomir N. Markovic, Aaron O. Bungum, Eric S. Edell, Haidong Dong, John C. Cheville, Marie Christine Aubry, Jin Jen, George Vasmatzis. Rearrangement-related peptides with neoantigenic potential in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5726.

Purpose: Optimal strategies to detect early interstitial lung disease (ILD) are unknown. ILD is frequently subpleural in distribution and affects lung elasticity. Lung ultrasound surface wave elastography (LUSWE) is a noninvasive method of quantifying superficial lung tissue elastic properties. In LUWSE a handheld device applied at the intercostal space vibrates the chest at a set frequency, and the lung surface wave velocity is measured by an ultrasound probe 5 mm away in the same intercostal space. We explored LUWSE’s ability to detect ILD and correlated LUSWE velocity with physiological, quantitative, and visual radiologic features of subjects with known ILD and of healthy controls. Materials and Methods: Seventy-seven subjects with ILD, mostly caused by connective tissue disease, and 19 healthy controls were recruited. LUSWE was performed on all subjects in 3 intercostal lung regions bilaterally. Comparison of LUSWE velocities pulmonary function testing, visual assessment, and quantitative analysis of recent computed tomographic imaging with Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) software. Results: Sonographic velocities were higher in all lung regions for cases, with the greatest difference in the lateral lower lung. Median velocity in m/s was 5.84 versus 4.11 and 5.96 versus 4.27 (P<0.00001) for cases versus controls, left and right lateral lower lung zones, respectively. LUSWE velocity correlated negatively with vital capacity and positively with radiologist and CALIPER-detected interstitial abnormalities. Conclusions: LUSWE is a safe and noninvasive technique that shows high sensitivity to detect ILD and correlated with clinical, physiological, radiologic, and quantitative assessments of ILD. Prospective study in detecting ILD is indicated.

Distinguishing reactive mesothelial proliferation from malignant mesothelioma (MM) can be difficult, particularly on small biopsies. In this scenario, a diagnosis of atypical mesothelial proliferation might be rendered. However, the distinction between a reactive process and MM is important for prognosis and treatment. Recently, loss of BRCA1-associated protein 1 (BAP1) expression and/or homozygous deletion of CDKN2A were identified in some MM, but not in reactive mesothelial proliferations. We studied 34 cases of atypical mesothelial proliferation from our institutional files (1993 to 2016) for BAP1 expression, deletion of CDKN2A, and clinical outcome. Fifteen of 34 patients (44%) were subsequently diagnosed with MM. BAP1 expression was lost in 6 of these 15 (40%) patients. Ten of 15 (67%) patients died of disease within a median time of 18.2 months. BAP1 expression was also lost in 1 case of probable MM. In this case atypical mesothelial proliferation was identified in the pleura during a lobectomy procedure for lung adenocarcinoma. Follow-up of 57.0 months was remarkable for visceral and parietal pleural thickening with continued unilateral effusion identified on imaging studies but no subsequent definitive diagnosis of MM. CDKN2A studies by fluorescence in situ hybridization (performed in 31 cases) found no homozygous deletion of that gene in any case. In conclusion, loss of BAP1 expression in atypical mesothelial proliferation helps to predict MM and is a useful adjunct test in these cases. Homozygous deletion of CDKN2A in mesothelial cell proliferations did not prove to be useful to predict MM in cases of atypical mesothelial proliferation.

Tumor necrosis factor α antagonists are increasingly used to treat inflammatory and autoimmune disorders and are associated with increased risk of active tuberculosis. Diagnosis of active tuberculosis in patients taking tumor necrosis factor α antagonists can be challenging owing to increased incidence of extrapulmonary manifestations and false-negative results on current available diagnostic tests. We present a case of a young woman on infliximab for ulcerative colitis who presented with disseminated tuberculosis. As part of a research study, we performed flow cytometric immune profiling, which has previously not been reported in patients with active tuberculosis taking tumor necrosis α antagonists. The flow cytometry results were within the positive thresholds for tuberculosis infection. Flow cytometric immune profiling may be a valid diagnostic tool for patients taking tumor necrosis factor α antagonists.

Abstract This study assessed the inter-user reproducibility of Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel analytical tool that risk stratifies lung adenocarcinomas (ADCs) according to defined computed tomography (CT) structural characteristics. CANARY detects nine distinct voxel signatures in ADCs based on standard CT imaging, thereby defining nodule characteristics correlating with patient outcomes, and corresponding to invasion or lepidic growth histologically. A software user segments the borders of each ADC prior to voxel analysis, introducing potential variability into the assessment. While CANARY is a promising method, it requires validation of the analytical variability between users and prediction of accuracy in an independent cohort. To evaluate the reproducibility of CANARY analysis, three independent users who are not part of the CANARY development team segmented and analyzed 50 biopsy-confirmed primary lung ADCs from Vanderbilt University Medical Center. The CT scans of ADCs were selected retrospectively based on the following criteria: ADC-histology proven on biopsy, diagnosed between 2009-2015, less than 3cm in greatest diameter, and stages IA-IV. Users followed a standard operating procedure established at the Mayo Clinic, and were blinded to clinical characteristics and patient outcomes. Results: To measure inter-user variability of ADC voxel composition, the intraclass correlation coefficient (ICC) was calculated based upon the percentage of each voxel subtype within the whole ADC. An ICC of 1 reflects high reproducibility between users. Amongst all 50 ADCs, the average ICC for all nine voxel types was 0.828 (95% CI 0.76, 0.895). The ICC of the four voxel types associated with invasive features on CT was 0.865 (95% CI 0.805, 0.924). ICCs were also calculated using a logarithmic transformation for data normalization, generating an ICC of 0.745 (95% CI 0.663, 0.826) for all nine voxel types, and an ICC of 0.995 (95% CI 0.993, 0.997) for the four voxel types associated with invasion. Conclusions: (1) CANARY analysis of lung ADC voxel signatures appears to be reproducible amongst users, making it a reliable tool for the evaluation of ADC voxel density. (2) Correlation of invasive signatures associated with more aggressive ADCs was nearly perfect amongst users. Additional validation metrics for CANARY with larger datasets are being evaluated, including the accuracy of tumor prognostic predictions between users and analysis of ADC datasets from other institutions. Citation Format: Erica C. Nakajima, Michael P. Frankland, Tucker Johnson, Sanja L. Antic, Ronald A. Karwoski, Bennett Landman, Heidi Chen, Ronald C. Walker, Brian J. Bartholmai, Tobias Peikert, Srinivasan Rajagopalan, Pierre P. Massion, Fabien Maldonado. Assessing the reproducibility of computer-aided nodule assessment and risk yield (CANARY) method to characterize lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3723. doi:10.1158/1538-7445.AM2017-3723