Richard Fraser

Human papillomavirus-11 DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous-cell carcinoma of the lung

LARYNGEAL papillomas are benign epithelial tumors that primarily involve the larynx and epiglottis but may extend into the trachea and the bronchi. The development of invasive squamous-cell carcinoma in association with laryngeal papillomatosis is rare and occurs almost exclusively in patients who have had radiation therapy.1 , 2 Laryngeal papillomas are caused by specific human papillomaviruses (HPVs), which have a specific tropism for squamous epithelial cells and which can induce cellular proliferation or dysplasia. More than 46 distinct types of HPVs have been identified, and two of them have been specifically associated with laryngeal papillomas. These are HPV-11, which was originally detected .xa0.xa0.

Primary pulmonary adenocarcinoma with enteric differentiation.

A pulmonary neoplasm with cytologic characteristics typical of differentiated small intestinal epithelium is reported. Individual cells showed features suggesting columnar absorptive, goblet, Paneth, and neuroendocrine cell differentiation. Thorough investigation and follow‐up for 4 years did not identify a primary tumor other than in the lung. The occurrence of such a neoplasm at this site is evidence for the existence of a common stem cell in the lower respiratory and gastrointestinal tract mucosa.

The development of 3-D, in vitro, endothelial culture models for the study of coronary artery disease

The response of the vascular endothelium to wall shear stress plays a central role in the development and progression of atherosclerosis. Current studies have investigated endothelial response using idealized in vitro flow chambers. Such cell culture models are unable to accurately replicate the complex in vivo wall shear stress patterns arising from anatomical geometries. To better understand this implication, we have created both simplified/tubular and anatomically realistic in vitro endothelial flow models of the human right coronary artery. A post-mortem vascular cast of the human left ventricular outflow tract was used to create geometrically accurate silicone elastomer models. Straight, tubular models were created using a custom made mold. Following the culture of human abdominal aortic endothelial cells within the inner lumen, cells were exposed to steady flow (Re = 233) for varying time periods. The resulting cell morphology was analyzed in terms of shape index and angle of orientation relative to the flow direction. In both models a progressive elongation and alignment of the endothelium in the flow direction was observed following 8, 12, and 24 hours. This change, however, was significantly less pronounced in the anatomical model (as observed from morphological variations indicative of localized flow features). Differences were also observed between the inner and outer walls at the disease-prone proximal region. Since morphological adaptation is a visual indication of endothelial shear stress activation, the use of anatomical models in endothelial genetic and biochemical studies may offer better insight into the disease process.

The levels and biologic action of the human neutrophil granule peptide HP-1 in lung tumors

HP-1 is the most abundant human representative of a recently discovered class of neutrophil cystine- and arginine-rich peptides. These peptides have many potentially regulatory activities expressed at nanomolar concentrations. To establish the levels of HP-1 that can accumulate in human lung tumors and nondiseased lung fragments, tissues were extracted for their peptide content. The extracts were purified on reverse phase HPLC, and HP-1 and related peptides were identified by sequence analysis and their concentrations in the tissue quantitated by amino acid analysis. Immunohistochemistry was performed and strongly suggests that HP-1 is confined to granulocytes under most circumstances, and indicates that the levels of HP-1 measured in the tumors reflect the levels obtained when solid tissue is infiltrated by neutrophils. The maximum observed levels were 26 nanomoles per gram wet weight of tissue. Attempts were then made to correlate this level to the cytotoxic potential of HP-1 by performing in vitro cytotoxicity dose-response curves on several cell lines. Most cells were killed at between 1 and 8 microM, and the response depended on the growth conditions of the cells. The levels of HP-1 that accumulate in tumors can exceed the in vitro cytolytic concentrations. The levels are also considerably in excess of those required to exert in vitro regulatory actions.

The use of biomarkers in the prediction of survival in patients with pulmonary carcinoma

Data on ten variables and 16 biomarkers were obtained on 119 patients with newly diagnosed pulmonary cancer. The prognostic value of 16 biomarkers (alpha‐1‐antitrypsin [AAT], adrenocorticotropic hormone [ACTH], alpha‐fetoprotein [AFP], carcinoembryonic antigen [CEA], human chorionic gonadotropin [HCG], immune complexes, immunoglobulins, N‐terminal peptide of proopiomelanocortin[NTERM], and tumor‐associated antibody [TAA]) was tested by adding these to the model of age, gender, stage, morphology, Feinsteins classification of symptoms, Karnofsky scale, leukocyte count, recent weight loss, and liver enzymes. Using Coxs regression method and a forward stepwise procedure, seven biomarkers (ACTH, AAT, AFP, calcitonin, HCG, TAA, and prolactin) entered the model. Elevated levels of cortisol and TAA were associated with longer survival. The selection of biomarkers by stepwise regression needs to be interpreted with caution, especially since the Z scores were found to be dependent on the particular variables included in the model. Furthermore, when dichotomized on maximum of the normal laboratory values, HCG and AFP were infrequently (2%) elevated. The lack of correlation among the biomarkers supports the hypothesis of random derepression of the genome of cancer cells. Further studies in improved modeling and the formulation of a biomarker index could enhance our understanding of the biology of cancer.

Energy loss, a novel biomechanical parameter, correlates with aortic aneurysm size and histopathologic findings

OBJECTIVEnEnergy loss is a biomechanical parameter that represents the relative amount of energy absorbed by the aorta during the cardiac cycle. We aimed to correlate energy loss with ascending aortic aneurysm size and histopathologic findings to elucidate the pathophysiology of aneurysm complications.nnnMETHODSnAneurysmal ascending aortic specimens were obtained during surgery. Control specimens were obtained from autopsy and organ donors. Biaxial tensile tests were performed on the 4 quadrants of the aortic ring. Energy loss was calculated using the integral of the stress-strain curve during loading and unloading. It was compared with the size and the traditional biomechanical parameter, stiffness (apparent modulus of elasticity). Elastin, collagen, and mucopolysaccharide content were quantified using Movat pentachrome staining of histology slides.nnnRESULTSnA total of 41 aortas were collected (34 aneurysmal, 7 control). The aneurysms exhibited increased stiffness (P < .0001) and energy loss (P < .0001) compared with the controls. Energy loss correlated significantly with aortic size (P < .0001, r(2) = .60). A hinge point was noted at a diameter of 5.5 cm, after which energy loss increased rapidly. The relationship between energy loss and size became strongly linear once the size was indexed to the body surface area (P < .0001, r(2) = .78). Energy loss correlated with the histopathologic findings, especially the collagen/elastin ratio (P = .0002, r(2) = .49). High energy loss distinguished patients with pathologic histologic findings from others with similar diameters.nnnCONCLUSIONSnAs ascending aortas dilate, they exhibit greater energy loss that rapidly increases after 5.5 cm. This mirrors the increase in complications at this size. Energy loss correlates with imbalances in elastin and collagen composition, suggesting a measurable link between the histopathologic features and mechanical function.

SOLITARY PLASMA-CELL MYELOMA OF THE SPINE IN AN ADOLESCENT: CASE REPORT OF AN UNUSUAL PRESENTATION

We report an unusual presentation of a solitary plasma-cell myeloma of the spine in an adolescent patient. Our case indicates the need to consider plasma-cell myeloma as a differential diagnosis even in younger patients.

Left Ventricular Full-Thickness Cardiomyoplasty with Pericardial Neoendocardium: Experimental Development of a Surgical Procedure

Cardiomyoplasty, a surgical procedure using stimulated skeletal muscle graft to replace or repair damaged myocardium, has been successfully performed in experimental animals and clinical patients. Whenever feasible, endocardium of the damaged myocardial segment is retained and partial-thickness cardiomyoplasty should be carried out. However, if this procedure were to be applied to enlarge a hypoplastic ventricle or to maintain normal dimensions of the ventricular cavity in some repairs in adults, full-thickness replacement of the ventricular wall with contractile skeletal muscle mass would be required. To develop such a technique, several canine experiments were carried out. In 7 dogs, simple full-thickness cardiomyoplasty was performed by using a latissimus dorsi muscle graft to repair a full-thickness left ventricular wall defect. We found it was difficult to obtain adequate hemostasis between the nonscarred myocardial tissue and the skeletal muscle graft, and excessive suturing to obtain hemostasis resulted in strangulation of the muscle grafts. The skeletal muscle-blood interface in the left ventricle was found to be highly thrombogenic. The perioperative hemorrhage and the risk of muscle graft strangulation by excessive sutures were avoided by using a pericardial patch as neoendocardium in 5 dogs that underwent similar full-thickness cardiomyoplasty procedures. Although the pericardial neoendocardium was not fully antithrombogenic in this canine model, endothelialization of the endocardium occurred within several weeks after operation. Thus, when combined with an implantable synchronized burst stimulator, this technique may in the future provide an effective full-thickness dynamic cardiomyoplasty to enlarge the ventricles and augment myocardial function in select patients.

Evolution of the Immune Response to Chronic Airway Colonization with Aspergillus fumigatus Hyphae

ABSTRACT Airway colonization by the mold Aspergillus fumigatus is common in patients with underlying lung disease and is associated with chronic airway inflammation. Studies probing the inflammatory response to colonization with A. fumigatus hyphae have been hampered by the lack of a model of chronic colonization in immunocompetent mice. By infecting mice intratracheally with conidia embedded in agar beads (Af beads), we have established an in vivo model to study the natural history of airway colonization with live A. fumigatus hyphae. Histopathological examination and galactomannan assay of lung homogenates demonstrated that hyphae exited beads and persisted in the lungs of mice up to 28 days postinfection without invasive disease. Fungal lesions within the airways were surrounded by a robust neutrophilic inflammatory reaction and peribronchial infiltration of lymphocytes. Whole-lung cytokine analysis from Af bead-infected mice revealed an increase in proinflammatory cytokines and chemokines early in infection. Evidence of a Th2 type response was observed only early in the course of colonization, including increased levels of interleukin-4 (IL-4), elevated IgE levels in serum, and a mild increase in airway responsiveness. Pulmonary T cell subset analysis during infection mirrored these results with an initial transient increase in IL-4-producing CD4+ T cells, followed by a rise in IL-17 and Foxp3+ cells by day 14. These results provide the first report of the evolution of the immune response to A. fumigatus hyphal colonization.

Solitary Plasm-Cell Myeloma of the Spine in an Adolescent: Case Report of an Unusual Presentation

We report an unusual presentation of a solitary plasma-cell myeloma of the spine in an adolescent patient. Our case indicates the need to consider plasma-cell myeloma as a differential diagnosis even in younger patients.