Faculty Bibliography

Systemic lupus erythematosus (SLE) is a major cause of nonbacterial thrombotic endocarditis (NBTE) associated with intracardiac sterile vegetations. It is rare for vegetations to present as an atrial tumor. This report describes a 48-year-old female with SLE and antiphospholipid syndrome complicated by recurrent thrombosis on anticoagulation. A large left atrial mass lesion was detected on echocardiography during a work-up for leg burning. Infective endocarditis could not be confirmed, and hence left atrial mass lesion was the most likely diagnosis. The patient was managed surgically and the pathology report revealed fibrin networks in a pattern similar to that of thrombosis, characteristic of NBTE.

AIMS/OBJECTIVE:Atherosclerotic plaques vulnerable to rupture are almost always inflamed, and carry a large lipid core covered by a thin fibrous cap. The other components may include neovascularisation, intraplaque haemorrhage and spotty calcification. In contrast, stable plaques are characterised by a predominance of smooth muscle cells and collagen, and lipid core is usually deep seated or absent. This study is a proof of principle experiment to evaluate the feasibility of multiphoton microscopy (MPM) to identify aforementioned plaque components. METHODS AND RESULTS/RESULTS:MPM is a nonlinear optical technique that allows imaging based on intrinsic tissue signals including autofluorescence and higher-order scattering. In our study, MPM imaging was performed on morphologically diverse aortic and coronary artery plaques obtained during autopsy. Various histologically verified plaque components including macrophages, cholesterol crystals, haemorrhage, collagen and calcification were recognised by MPM. CONCLUSIONS:Recognition of the distinct signatures of various plaque components suggests that MPM has the potential to offer next-generation characterisation of atherosclerotic plaques. The higher lateral resolution (comparable to histology) images generated by MPM for identifying plaque components might complement larger field of view and greater imaging depth currently available with optical coherence tomography imaging. As the next step MPM would need to be evaluated for intact vessel imaging ex vivo and in vivo.

BACKGROUND: Although early reperfusion is the most desirable intervention after ischemic myocardial insult, it may add to damage through oxidative stress. OBJECTIVES: This study investigated the cardioprotective effects of a single intravenous dose of heat shock protein-72 (HSP72) coupled to a single-chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv) in a rabbit ischemia-reperfusion model. The Fv facilitates rapid transport of HSP72 into cells, even with intact membranes. METHODS: A left coronary artery occlusion (40 min) reperfusion (3 h) model was used in 31 rabbits. Of these, 12 rabbits received the fusion protein (Fv-HSP72) intravenously. The remaining 19 control rabbits received a molar equivalent of 3E10Fv alone (n = 6), HSP72 alone (n = 6), or phosphate-buffered saline (n = 7). Serial echocardiographic examinations were performed to assess left ventricular function before and after reperfusion. Micro-single-photon emission computed tomography imaging of 99mTc-labeled annexin-V was performed with micro-computed tomography scanning to characterize apoptotic damage in vivo, followed by gamma counting of the excised myocardial specimens to quantify cell death. Histopathological characterization of the myocardial tissue and sequential cardiac troponin I measurements were also undertaken. RESULTS: Myocardial annexin-V uptake was 43% lower in the area at risk (p = 0.0003) in Fv-HSP72-treated rabbits compared with control animals receiving HSP72 or 3E10Fv alone. During reperfusion, troponin I release was 42% lower and the echocardiographic left ventricular ejection fraction 27% higher in the Fv-HSP72-treated group compared with control animals. Histopathological analyses confirmed penetration of 3E10Fv-containing molecules into cardiomyocytes in vivo, and treatment with Fv-HSP72 showed fewer apoptotic nuclei compared with control rabbits. CONCLUSIONS: Single-dose administration of Fv-HSP72 fusion protein at the time of reperfusion reduced myocardial apoptosis by almost one-half and improved left ventricular functional recovery after myocardial ischemia-reperfusion injury in rabbits. It might have potential to serve as an adjunct to early reperfusion in the management of myocardial infarction.

Distinguishing synchronous and metachronous primary lung adenocarcinomas from adenocarcinomas with intrapulmonary metastasis is essential for optimal patient management. In this study, multiple lung adenocarcinomas occurring in the same patient were evaluated using comprehensive histopathologic evaluation supplemented with molecular analysis. The cohort included 18 patients with a total of 52 lung adenocarcinomas. Eleven patients had a new diagnosis of multiple adenocarcinomas in the same lobe (n=5) or different lobe (n=6). Seven patients had a history of lung cancer and developed multiple new tumors. The final diagnosis was made in resection specimens (n=49), fine needle aspiration (n=2), and biopsy (n=1). Adenocarcinomas were non-mucinous, and histopathologic comparison of tumors was performed. All tumors save for one were subjected to ALK gene rearrangement testing and targeted Next Generation Sequencing (NGS). Using clinical, radiologic, and morphologic features, a confident conclusion favoring synchronous/metachronous or metastatic disease was made in 65% of patients. Cases that proved challenging included ones with more than three tumors showing overlapping growth patterns and lacking a predominant lepidic component. Genomic signatures unique to each tumor were helpful in determining the relationship of multiple carcinomas in 72% of patients. Collectively, morphologic and genomic data proved to be of greater value and achieved a conclusive diagnosis in 94% of patients. Assessment of the genomic profiles of multiple lung adenocarcinomas complements the histological findings, enabling a more comprehensive assessment of synchronous, metachronous, and metastatic lesions in most patients, thereby improving staging accuracy. Targeted NGS can identify genetic alterations with therapeutic implications.

BACKGROUND: Minimally invasive diagnostic procedures such as needle-core biopsy and fine-needle aspiration provide adequate material for molecular analyses. Advances in precision oncology are trending toward the interrogation of limited amounts of genomic material to guide clinical and therapeutic decisions. The aim of this study was to investigate the minimum cellularity needed on cytologic smears for the identification of clinically relevant variants with next-generation sequencing (NGS). METHODS: Thirty cases of cytologically diagnosed, resection-proven primary lung adenocarcinoma were identified. Nineteen of the 30 cases were known to harbor actionable variants. One Diff-Quik (DQ)-stained slide and 1 Papanicolaou (Pap)-stained slide were selected from each case. Cases were categorized as containing fewer than 100 tumor cells, 100 to 500 tumor cells, or more than 500 tumor cells. NGS was performed on the Ion Torrent platform. RESULTS: NGS was successfully performed on all cell blocks and on 90% of the smears. Paired DQ and Pap smears showed similar cellularity, and cases that differed in cellularity were within 1 category of each other. The cases with more than 100 tumor cells had a 93% success rate; this was significantly different from the situation for cases with fewer than 100 tumor cells, which were successfully sequenced only 67% of the time. Overall, NGS was able to provide clinically relevant information for 83% of DQ smears and for 90% of Pap smears tested. CONCLUSIONS: The data show a significantly higher likelihood of successful NGS with cytologic smears with more than 100 tumor cells. There was a trend for a higher NGS success rate with Pap smears versus DQ smears. Cancer Cytopathol 2017;125:398-406. (c) 2017 American Cancer Society.

Vascular calcification is a hallmark of atherosclerosis. The location, density, and confluence of calcification may change portions of the arterial conduit to a noncompliant structure. Calcifications may also seed the cap of a thin cap fibroatheroma, altering tensile forces on the cap and rendering the lesion prone to rupture. Many local and systemic factors participate in this process, including hyperlipidemia, ongoing inflammation, large necrotic cores, and diabetes. Vascular cells can undergo chondrogenic or osteogenic differentiation, causing mineralization of membranous bone and formation of endochondral bone. Calcifying vascular cells are derived from local smooth muscle cells and circulating hematopoietic stem cells (especially in intimal calcification). Matrix vesicles in the extracellular space of the necrotic core serve as a nidus for calcification. Although coronary calcification is a marker of coronary atheroma, dense calcification (>400 HU) is usually associated with stable plaques. Conversely, microcalcification (often also referred to as spotty calcification) is more commonly an accompaniment of vulnerable plaques. Recent studies have suggested that microcalcification in the fibrous cap may increase local tissue stress (depending on the proximity of one microcalcific locus to another, and the orientation of the microcalcification in reference to blood flow), resulting in plaque instability. It has been proposed that positron emission tomography imaging with sodium fluoride may identify early calcific deposits and hence high-risk plaques.