Kristopher S. Cunningham

The role of shear stress in the pathogenesis of atherosclerosis

Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis.

Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma.

OBJECTIVE The aim of the study was to determine the impact of tumor-infiltrating lymphocytes on survival in patients with malignant pleural mesothelioma treated with induction chemotherapy followed by extrapleural pneumonectomy. METHODS We performed an immunohistochemical analysis of 32 extrapleural pneumonectomy specimens to assess the distribution of T-cell subtypes (CD3(+), CD4(+), and CD8(+)), regulatory subtypes (CD25(+) and FOXP3(+)), and memory subtype (CD45RO(+)) within the tumor. RESULTS Patients with high levels of CD8(+) tumor-infiltrating lymphocytes demonstrated better survival than those with low levels (3-year survival: 83% vs 28%; P = .06). Moreover, high levels of CD8(+) tumor-infiltrating lymphocytes were associated with a lower incidence of mediastinal node disease (P = .004) and longer progression-free survival (P = .05). Higher levels of CD8(+) tumor-infiltrating lymphocytes were observed in patients treated with cisplatin and pemetrexed than in those treated with cisplatin and vinorelbine (P = .02). Patients presenting high levels of CD4(+) or CD25(+) tumor-infiltrating lymphocytes or low levels of CD45RO(+) also demonstrated a trend toward shorter survival. However, the presence of FOXP3(+) tumor-infiltrating lymphocytes did not affect survival. After multivariate adjustment, high levels of CD8(+) tumor-infiltrating lymphocytes remained an independent prognostic factor associated with delayed recurrence (hazard ratio = 0.38; confidence interval = 0.09-0.87; P = .02) and better survival (hazard ratio = 0.39; confidence interval = 0.09-0.89; P = .02). CONCLUSION The presence of high levels of CD8(+) tumor-infiltrating lymphocytes is associated with better prognosis in patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma. The stimulation of CD8(+) lymphocytes can be a potential therapeutic strategy to improve outcome.

An approach to endomyocardial biopsy interpretation

The endomyocardial biopsy (EMB) remains the gold standard mode of investigation for diagnosing many primary and secondary cardiac conditions. Through a percutaneous and transvenous route, tissue fragments are generally procured from the right ventricular septum, with very few complications. Widespread use of EMB followed the development of heart transplantation as a means to follow allograft rejection. It has since been useful in helping to diagnose conditions affecting the heart, including cardiomyopathies, myocarditis, infiltrative lesions, arrhythmias, and drug toxicities. The procedure has also been used as a research tool to investigate the natural history of disease and the cardiotoxicity of new medications. This review presents an approach to the evaluation of the EMB, which is particularly directed towards those who may be asked to interpret such biopsies, but are not dedicated cardiovascular pathologists. Through a systematic evaluation of the endocardium, myocardium, interstitium, and intramural vessels, in the context of a complete clinical history, enough information can be deduced to diagnose or exclude specific conditions of clinical value.

CD10 is expressed in most epithelioid hemangioendotheliomas: a potential diagnostic pitfall.

CONTEXT -Epithelioid hemangioendothelioma (EHE) is a vascular neoplasm that occasionally is difficult to distinguish from primary/metastatic carcinomas, particularly when EHEs express keratins. We recently encountered an EHE with strong CD10 positivity mimicking renal cell carcinoma. OBJECTIVE -To examine sensitivity and specificity of CD10 in EHE. DESIGN -Nine EHEs were stained with keratins, factor VIII, CD31, CD34, and CD10. Mimics of EHE were also retrieved and stained with CD10. RESULTS -The EHE patients included 5 men and 4 women. Patients ranged in age from 24 to 74 years. Tumors were located in liver (3), skin (2), lung/pleura (2), and sternomastoid and mediastinum (1 each). Two had skin metastases. All EHEs were positive for vascular markers. A total of 7 of 9 primary tumors expressed cytoplasmic and intracytoplasmic luminal CD10. The 2 skin metastases were positive, whereas 2 primary skin EHEs were negative. Of the mimics, CD10 showed staining in 7 of 23 cases: 3 of 3 renal cell carcinomas, 1 of 7 other carcinomas, 2 of 3 epithelioid angiosarcomas, 1 of 3 melanomas, 0 of 3 mesotheliomas, and 0 of 4 epithelioid hemangiomas. CONCLUSIONS -CD10 has a sensitivity of 78% (confidence interval, 63.6%-92.4%) and specificity of 70% (confidence interval, 54%-85.9%) for EHE. There is a growing list of tumors that show expression of CD10. Pathologists should be aware of this diagnostic pitfall.

Pulmonary Bacterial Communities in Surgically Resected Noncystic Fibrosis Bronchiectasis Lungs Are Similar to Those in Cystic Fibrosis

Background. Recurrent bacterial infections play a key role in the pathogenesis of bronchiectasis, but conventional microbiologic methods may fail to identify pathogens in many cases. We characterized and compared the pulmonary bacterial communities of cystic fibrosis (CF) and non-CF bronchiectasis patients using a culture-independent molecular approach. Methods. Bacterial 16S rRNA gene libraries were constructed from lung tissue of 10 non-CF bronchiectasis and 21 CF patients, followed by DNA sequencing of isolates from each library. Community characteristics were analyzed and compared between the two groups. Results. A wide range of bacterial diversity was detected in both groups, with between 1 and 21 bacterial taxa found in each patient. Pseudomonas was the most common genus in both groups, comprising 49% of sequences detected and dominating numerically in 13 patients. Although Pseudomonas appeared to be dominant more often in CF patients than in non-CF patients, analysis of entire bacterial communities did not identify significant differences between these two groups. Conclusions. Our data indicate significant diversity in the pulmonary bacterial community of both CF and non-CF bronchiectasis patients and suggest that this community is similar in surgically resected lungs of CF and non-CF bronchiectasis patients.

Pathology of isolated atrial infarction: case report and review of the literature.

Infarction of the cardiac atria occurs more frequently than is commonly considered. Ischemic damage to the atrial myocardium is usually associated with infarction of cardiac ventricles, but isolated infarction of an atrium can occur and may be of clinical significance. We present an unusual case of an isolated right atrial infarct with an infarction-related endocardial thrombus that mimicked a mass lesion near the inferior vena cava. The presentation and causes of isolated atrial infarction are discussed.

A Bicuspid Pulmonary Valve Associated with Tetralogy of Fallot

Abstract  Congenitally bicuspid pulmonary valves are uncommon. When they occur, it is usually in association with other congenital cardiac lesions, most often a tetralogy of Fallot. We present a rare case of a patient with a congenitally bicuspid pulmonary valve who had pulmonary valve and RVOT reconstruction. The patient did well for 17 years, but needed further reconstruction when the pulmonary valve started getting stenosed and RV pressures went up significantly. The pulmonary valve showed fibroses, thickening, and focal calcification.