Warty carcinoma of the uterine cervix: a virus-induced disease?

IntroductionWarty carcinoma (WC) of the uterine cervix is a rare subtype of squamous-cell carcinoma (SCC), and its frequency, clinical behaviour, and aetiology are obscure. It originates from condylomas, and a viral carcinogenesis seems logical.Material and methodsRetrospective analysis was performed of all cervical carcinomas (CC), diagnosed at a single institution for a 10-year period. Analysed patients had stage I carcinoma. Patients with WC were identified, and their tumour samples were tested for high-risk HPV (hr-HPV) and EBV, using PCR and ISH. Clinical characteristics and WC rates across all stage I CC patients were assessed. All patients had minimum 3-year follow-up, and overall survival (OS) and 5-year survival rates were calculated.ResultsWC comprised 2.2% of all stage I CC (n = 630). The mean age of the patients was 48 years (range: 29–72). The primary tumour size was 2 cm in 4 (28.6%) patients, 2–4 cm in 2 (14.3%) patients, and 4 cm in 8 (57.1%) patients. Lymph node metastasis was found in 1 (7.1%) patient. EBV or hr-HPV were detected in 2 (18.2%) patients using ISH, with no coinfection reported. Hr-HPV was detected in 2 (18.2%) patients; EBV in 4 (36.4%) cases, and in 2 of them (18.2%) there was a co-infection. Thirteen patients had a follow-up of ≥ 5 years and their 5-year OS was 100%.ConclusionsWC is a rare subtype of SCC with good prognosis, regardless of viral status. In contrast to SCC, its aetiology is not related to hr-HPV. The role of EBV remains unclear and cannot currently be denied.     

Is bacterial vaginosis associated with squamous intraepithelial lesion of the uterine cervix?

The objective of this study was to analyze the association between bacterial vaginosis (BV) and squamous intraepithelial lesion (SIL). Pap smears were analyzed to verify the presence of BV and SIL. One hundred and ten women with SIL comprised the study group, while 110 women with no cytological abnormalities served as controls. BV was similarly present in women of both groups: 18% of women with SIL and 12% of women without SIL. Results were also similar when the grade of SIL was taken into consideration. BV was detected in 16% of women with low-grade SIL and in 12% of women in the control group, while a higher rate of BV (33%) was found among women with high-grade SIL in comparison to the controls (12%). This difference, however, was not statistically significant. BV tended to be more common among women with high-grade SIL than in women with no cytological abnormalities.     

The role of the mast cell in asthma: induction of airway hyperresponsiveness by interaction with smooth muscle?

In a recent study, the difference between asthma and eosinophilic bronchitis (a condition characterized by cough but not airway hyperresponsiveness or airflow obstruction) was infiltration of airway smooth muscle (ASM) by mast cells. Mast cells produce a variety of lipid mediators, chemokines, cytokines, and enzymes that may interact with ASM cells to cause hyperreactivity to constrictive stimuli and proliferation, and activated ASM can produce stem cell factor and other chemokines, cytokines, and growth factors that may act in recruitment, differentiation, and retention of mast cells. Mast cell infiltration of the airways in asthma is T-cell-dependent, and TH2 cytokines from T cells and other sources act in mast cell expansion from circulating and tissue precursors. The recent data on interactions of mast cells and ASM suggest that this could be an important contributor to airway hyperresponsiveness in asthma. Why this occurs in asthma and how it is sustained remain to be established.     

What evidence implicates airway smooth muscle in the cause of BHR?

Bronchial hyperresponsiveness (BHR), the occurrence of excessive bronchoconstriction in response to relatively small constrictor stimuli, is a cardinal feature of asthma. Here, we consider the role that airway smooth muscle might play in the generation of BHR. The weight of evidence suggests that smooth muscle isolated from asthmatic tissues exhibits normal sensitivity to constrictor agonists when studied during isometric contraction, but the increased muscle mass within asthmatic airways might generate more total force than the lesser amount of muscle found in normal bronchi. Another salient difference between asthmatic and normal individuals lies in the effect of deep inhalation (DI) on bronchoconstriction. DI often substantially reverses induced bronchoconstriction in normals, while it often has much less effect on spontaneous or induced bronchoconstriction in asthmatics. It has been proposed that abnormal dynamic aspects of airway smooth muscle contraction—velocity of contraction or plasticity-elasticity balance—might underlie the abnormal DI response in asthma. We suggest a speculative model in which abnormally long actin filaments might account for abnormally increased elasticity of contracted airway smooth muscle.     

Airway hyperresponsiveness, remodeling, and smooth muscle mass: right answer, wrong reason?

We quantified the effects of airway wall remodeling upon airway smooth muscle (ASM) shortening. Isolated ASM from sheep was attached to a servo-controller that applied a physiologic load. This load could be altered to reflect specified changes of airway wall geometry, elasticity, parenchymal tethering, transpulmonary pressure (P(L)), and fluctuations in P(L) associated with breathing. Starting at a reference length (L(ref)), ASM was stimulated with acetlycholine and held at constant P(L) of 4 cm H(2)O for 2 h. When all compartments were thickened to simulate the asthmatic airway but P(L) was held fixed, ASM shortened much more than that in the normal airway (to 0.52 L(ref) versus 0.66 L(ref)). When breathing with deep inspirations (DIs) was initiated, within the first three DIs the ASM in the normal airway lengthened to 0.84 L(ref), whereas that in the asthmatic airway remained stuck at 0.53 L(ref). Thickening of the smooth muscle layer alone produced the greatest muscle shortening (to 0.47 L(ref)) when compared with thickening of only submucosal (to 0.67 L(ref)) or only adventitial (to 0.62 L(ref)) compartments. With increased ASM mass, the ASM failed to lengthen in response to DIs, whereas in the airway with thickened submucosal and adventitial layers ASM lengthened dramatically (to 0.83 L(ref)). These findings confirm the long-held conclusion that increased muscle mass is the functionally dominant derangement, but mechanisms accounting for this conclusion differ dramatically from those previously presumed. Furthermore, increased ASM mass explained both hyperresponsiveness and the failure of a DI to relax the asthmatic airway.     

Do biophysical properties of the airway smooth muscle in culture predict airway hyperresponsiveness?

Airway hyperresponsiveness is a cardinal feature of asthma but remains largely unexplained. In asthma, the key end-effector of acute airway narrowing is the airway smooth muscle (ASM) cell. Here we report novel biophysical properties of the ASM cell isolated from the relatively hyporesponsive Lewis rat versus the relatively hyperresponsive Fisher rat. We focused upon the ability of the cytoskeleton (CSK) of the ASM cell to stiffen, to generate contractile forces, and to remodel. We used optical magnetic twisting cytometry to measure cell stiffness and traction microscopy to measure contractile forces. To measure remodeling dynamics, we quantified spontaneous nanoscale motions of a microbead tightly anchored to the CSK. In response to a panel of contractile and relaxing agonists, Fisher ASM cells showed greater stiffening, bigger contractile forces, and faster CSK remodeling; they also exhibited higher effective temperature of the CSK matrix. These physical differences measured at the level of the single cell in vitro were consistent with strain-related differences in airway responsiveness in vivo. As such, comprehensive biophysical characterizations of CSK dynamics at the level of the cell in culture may provide novel perspectives on the ASM and its contributions to the excessive airway narrowing in asthma.     

Well-differentiated papillary villoglandular adenocarcinoma of the uterine cervix with a focal high-grade component: is there a need for reassessment?

Well-differentiated villoglandular adenocarcinoma of the uterine cervix is characterized by an exophytic growth pattern with variably sized papillae that are lined by stratified columnar cells with no more than moderate cytologic atypia. Based on the favorable outcomes in most of the previously reported cases, it has been suggested that some patients with this subtype may be managed conservatively. The case described herein is an otherwise prototypical well-differentiated villoglandular adenocarcinoma but which was associated with a 4.9-mm focus of poorly differentiated carcinoma at its invasive edge. A review of the literature revealed a variety of findings that suggests a need to reassess the potential morphologic and biologic spectrum of this group of tumors. Five of the approximately 89 reported cases were associated with a higher-grade component of the same or a different histologic subtype. At least one patient with apparently stage 1A1 disease was found to have a positive lymph node. Another patient with stage 1B1 disease but no stromal invasion died of her disease following multiple recurrences. Finally, the frequency of lymphovascular invasion and/or lymph node involvement in recent series far exceeds what was found in the two original series. Our case suggests that well-differentiated villoglandular adenocarcinoma is not a diagnosis that should be unequivocally rendered on a small biopsy since other components may be present and the patients may be undertreated. We urge caution when conservative management (cone biopsy alone when margins are negative and there is no lymphovascular invasion) is offered to patients with this tumor since knowledge about its true biologic spectrum appears to still be in evolution.     

Remodeling of the airway smooth muscle cell: are we built of glass?

Classical understanding of airway lumen narrowing in asthma has held that the isometric force generated by airway smooth muscle (ASM) must be at every instant in a static mechanical equilibrium with the external load against which the muscle has shortened. It has been established recently, however, that this balance of static forces does not apply in the setting of tidal loading as occurs during breathing and must give way to the broader concepts of (1). the perturbed contractile state that exists far from static equilibrium conditions and (2). mechanical plasticity of the ASM cell. Here we describe the hypothesis that the well-established static contractile state, the newly-elaborated perturbed contractile state, as well as the remarkable mechanical plasticity of the ASM cell, are all subsumed under a rubric that is at once surprising, unifying and mechanistic. The specific hypothesis suggested is that the ASM cell behaves as a glassy material [Phys. Rev. Lett. 87 (2001) 148102]. A glass is a material that has the disordered molecular state of a liquid and, at the same time, the rigidity of a solid. If the hypothesis is true, then the ability of the ASM cytoskeleton (CSK) to deform, to flow and to remodel would be determined by an effective temperature-called the noise temperature-representing the level of jostling (i.e. molecular noise or agitation) present in the intracellular microenvironment. The abilities of the CSK to deform, to flow and to reorganize represent basic biological processes that underlie a variety of higher cell functions. If supported by the data, therefore, this integrative hypothesis might have implications in medicine and biology that go beyond the immediate issues of smooth muscle shortening and its role in asthma.     

Evolutionary history or function? Which preponderates in the expression of the muscle mass of the thoracic limb in wild carnivorans?

Thoracic limbs are extremely versatile and exhibit informative characteristics about habits of the Carnivora order in the wild. Despite this relevance, comparative studies with quantitative variables on thoracic limb muscles are still scarce in carnivorans. The aims of this study were to measure the mass of the intrinsic muscles of the thoracic limb of neotropical species of the Carnivora order and to establish comparative conjectures. For this purpose, 39 thoracic limbs of 10 neotropical carnivorans species were dissected. The mass of each muscle was measured on a digital scale, muscles were grouped by function, and the mass average percentage that each functional group of muscles occupied in the thoracic limb was calculated. The data of the present study was added to that available in the literature for 22 other carnivoran species. Three groups of species were considered: Canidae, Musteloidea, and Feliformia. Comparatively, the eight canid species included in this analyses concentrate muscle mass proximally in the thoracic limb to prioritize essential cursoriality. The nine musteloids had more muscle mass in the distal muscles due to the demand for versatility and manual strength, and the 14 Feliformia species exhibited an intermediate trend. The analysis of clusters revealed a great overlap of the percentage distribution of muscle mass with the phylogeny previously established for carnivorans. It could be verified that the distribution of muscle masses meets the demand of the locomotor habits of the species up to a certain level, from which phylogeny begins to limit morphological adaptations.     

Decrease in interferon-γ production by peripheral blood mononuclear cells in patients with uterine cervical cancer

The interferon- (IFN-) productivity of peripheral blood mononuclear cells (PBMCs) was examined in 30 patients with uterine cervical cancer. The patients under 50 years of age had decreased IFN- production compared with the age-matched controls. The IFN- productivity in the patients over 50 years of age was decreased as well as in the age-matched controls. The proportion of monocytes in PBMCs did not correlate with the IFN- productivity. The prostaglandin E₂ (PGE₂) productivity of PBMCs increased with the progress of cancer. PGE₂ inhibited the IFN- production by PBMCs, and the sensitivity of PBMCs to PGE₂ was increased in the patients and controls over 60 years of age. The addition of indomethacin resulted in an increase in IFN- production by PBMCs. These results suggest that the increased production of PGE₂ and/or increased sensitivity to PGE₂ are responsible for the decreased IFN- production in patients with cervical cancer.     

Airway smooth muscle: immunomodulatory cells that modulate airway remodeling?

Although the pathogenesis of asthma remains unclear, substantial progress has been made over the past decades in the characterization of airway inflammation as a pathogenetic mechanism in asthma. New evidence suggests that airway smooth muscle (ASM), the most important cell modulating bronchomotor tone, plays an important immunomodulatory role in the orchestration and perpetuation of airway inflammation. Evidence now suggests that the signaling pathways that modulate leukocyte function may be disparate from those found in resident effector cells such as ASM, fibroblasts and epithelial cells. Further investigation and understanding of the critical signaling pathways that modulate ASM cell release, secretion of chemokines/cytokines and expression of cell adhesion molecules (CAMs) may offer new therapeutic approaches in the treatment of asthma.     

Neurotrophins: a link between airway inflammation and airway smooth muscle contractility in asthma?

BACKGROUND: Bronchial asthma (BA) is characterized by a unique type of airway inflammation, epithelial cell damage and increased airway smooth muscle (ASM) contractility. The regulatory network between the immunological events and the neuronal control of ASM contractility remains to be defined. METHODS: Utilizing a well-characterized mouse model of airway inflammation and BA, we analyzed the production and function of neurotrophins in allergic asthma. To confirm these data in humans, segmental allergen provocation was performed in mild asthmatics. RESULTS: Allergen-induced airway inflammation was associated with increased local production of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in mice as well as in humans. In bronchoalveolar lavage fluid (BALF), NGF levels were increased 4- to 5-fold in men and mice 1 day after allergen provocation. The increase in BDNF was about 2-fold in both models. Treatment of mice with anti-NGF prevented development of airway hyperresponsiveness (AHR). In the human study group, NGF levels in BALF after allergen provocation were correlated significantly with baseline FEV1 levels. CONCLUSION: These data strongly suggest that neurotrophins serve as a link between airway inflammation and neuronal control of ASM constriction in BA.