Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop.

Current understanding of specific defense mechanisms in the context of neutropenic infections is limited. It has previously been reported that invasive aspergillosis, a prototypic opportunistic infection in neutropenic hosts, is associated with marked accumulation of inflammatory dendritic cells (DCs) in the lungs. Given recent data indicating that neutrophils can modulate immune responses independent of their direct microbial killing, we hypothesized that neutropenia impacts the host response to Aspergillus by determining the migration and phenotype of lung DCs. Inflammatory DCs, but not other DC subsets, were found to accumulate in the lungs of neutropenic hosts challenged with killed or live-attenuated Aspergillus as compared with nonneutropenic hosts, indicating that the accumulation was independent of neutrophil microbicidal activity. The mechanism of this accumulation in neutropenic hosts was found to be augmented influx of DCs, or their precursors, from the blood to the lungs. This effect was attributable to greatly elevated lung TNF expression in neutropenic as compared with nonneutropenic animals. This resulted in greater lung expression of the chemokine ligands CCL2 and CCL20, which, in turn, mediated enhanced recruitment of TNF-producing inflammatory DCs, resulting in a positive feedback cycle. Finally, in the context of neutropenic invasive aspergillosis, depletion of DCs resulted in impaired fungal clearance, indicating that this mechanism is protective for the host. These observations identify what we believe is a novel defense mechanism in invasive aspergillosis that is the result of alterations in DC traffic and phenotype and is specific to neutropenic hosts.

Idiopathic lymphoplasmacellular mucositis-dermatitis.

BACKGROUND: In 1952, Zoon described a series of patients with dense plasma-cell infiltrates in the glans penis. Since then, similar Zoon-like lesions (ZLL) have been described on the external female genitalia and in the airways, for which over 20 designations currently exist. METHODS: Twenty-eight cases of ZLL, twenty-two cases of lichen planus, eight cases of plasmacytoma and two cases of syphilis were evaluated from the surgical pathology archive at the University of Virginia. Twenty-four histologic data points were tabulated in each case, including 12 epidermal and 12 dermal features. RESULTS: Histopathologic findings were similar in the majority of cases of ZLL, regardless of their location. They demonstrated superficial cutaneous erosions, basal vacuolar alteration and many showed lozenge-shaped keratinocytes in the epiderms. The dermis contained a dense inflammatory infiltrate composed predominantly of plasma cells, with scattered neutrophils and lymphocytes. Dense fibrosis was seen in the upper dermis. CONCLUSIONS: A uniform nomenclature for ZLL does not exist. Based on the results of this analysis, we suggest that the generic term idiopathic lymphoplasmacellular mucositis-dermatitis be considered to encompass the lymphoplasmacellular infiltrates in the skin and mucosal surfaces considered herein. This designation is morphologically descriptive and can be applied regardless of anatomic location.

Using biomarkers as objective standards in the diagnosis of cervical biopsies.

Histopathologic diagnosis of cervical biopsies determines clinical management of patients with an abnormal cervical cancer-screening test yet is prone to poor interobserver reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce diagnostic variability of cervical biopsy evaluations but systematic, rigorous evaluations of their potential clinical utility are lacking. To address diagnostic utility of human papillomavirus (HPV) L1, p16(INK4a), and Ki-67 immunohistochemical staining for improving diagnostic accuracy, we conducted a community-based and population-based evaluation using 1455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a period of 14 months. Thin-sections of each biopsy from 1451 of 1455 (99.7%) biopsies underwent evaluation of immunohistochemical stains for the 3 biomarkers, masked to the original diagnosis, and the results were compared with an adjudicated, consensus diagnosis by 3 pathologists. p16 immunostaining, using the strongest staining as the cutpoint, was 86.7% sensitive and 82.8% specific for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2(+)) diagnoses. The performance of p16(INK4a) was more sensitive (P<0.001), less specific (P<0.001), and of similar overall accuracy for CIN2(+) compared with the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity=68.9%, specificity=97.2%). Ki-67 immunostaining was also strongly associated with a CIN2(+) diagnosis but its performance at all staining intensities was inferior to p16 immunostaining, and did not increase the accuracy of CIN2(+) diagnosis when combined with p16(INK4a) immunostaining compared with p16(INK4a) immunostaining alone. We found no utility for L1 immunostaining in distinguishing between CIN and non-CIN. In conclusion, with a rigorous evaluation, we found immunohistochemical staining for p16 to be a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2(+).

Correlations between selected tumor markers and fluorodeoxyglucose maximal standardized uptake values in esophageal cancer.

OBJECTIVE: Esophageal cancer tumor biology is best assessed clinically by 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. Both FDG-PET maximal positron emission tomography (PET) standardized uptake values (SUVmax) and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumor markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer. METHODS: FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to 42% (28/67) of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for five known esophageal cancer tumor markers (GLUT-1, p53, cyclin D1, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF)). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p value <0.05 was considered significant. RESULTS: There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (n=29, 43%), stage II (n=19, 28%), stage III disease (n=18, 27%), and stage IV disease (n=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT-1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor. CONCLUSIONS: FDG-PET SUVmax correlates with an increased expression of GLUT-1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.

Fluorodeoxyglucose positron emission tomography and tumor marker expression in non-small cell lung cancer.

OBJECTIVE: The best current noninvasive surrogate for tumor biology is fluorodeoxyglucose positron emission tomography (FDG-PET). Both FDG-PET maximal standardized uptake values and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in non-small cell lung cancer (NSCLC). However, there are limited data correlating FDG-PET with tumor markers. The purpose of this study was to determine the correlation of tumor marker expression with FDG-PET maximal standardized uptake values in NSCLC. METHODS: FDG-PET maximal standardized uptake values were calculated in patients with NSCLC (n = 149). No patient had induction chemoradiotherapy. Intraoperative NSCLC tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known NSCLC tumor markers (glucose transporter 1, p53, cyclin D1, epidermal growth factor receptor, and vascular endothelial growth factor). Each tumor marker was assessed independently by two pathologists using common grading criteria. Subgroup analysis based on histologic characteristics and regional nodal status was performed. RESULTS: FDG-PET correlated with T classification (P < .0001), N stage (P = .002), and greatest tumor dimension (P < .0001). In addition, increasing maximal standardized uptake values correlated with increased expression of glucose transporter 1 (P < .0001) and p53 (P = .04) in adenocarcinoma. Epidermal growth factor receptor expression correlated with maximal standardized uptake values without predilection for histologic subtype (P = .004). CONCLUSION: FDG-PET maximal standardized uptake values correlate with an increased expression of glucose transporter 1 and p53 in lung adenocarcinoma, but not squamous cell cancer. Future studies attempting to correlate FDG-PET with tumor biology will need to consider the effect of different tumor histologic types.

Effect of endometrioma cyst fluid exposure on peritoneal adhesion formation in a rabbit model.

OBJECTIVE: To determine whether copious lavage and suction of human endometrioma fluid placed in the peritoneal cavity of rabbits reduces adhesion formation compared to no lavage. DESIGN: Prospective, randomized, blinded study. SETTING: Academic research environment. ANIMAL(S): Twenty-four female New Zealand white rabbits. INTERVENTION(S): Rabbits randomized into three groups: [1] laparoscopy with instillation of human endometrioma material, no lavage; [2] laparoscopy with instillation of human endometrioma material, followed by clearance of all visible endometrioma fluid by saline lavage and suction; [3] laparoscopy alone. MAIN OUTCOME MEASURE(S): Six weeks after laparoscopy, adhesions scored by laparotomy using standard visual assessment scoring system and histologic microscopic evaluation. Data evaluated using Kruskal-Wallis and median nonparametric tests. RESULT(S): For groups 1, 2, and 3, respectively, mean total clinical adhesion scores were 0.67 (95% confidence interval [CI] -0.87, 2.2), 3.67 (95% CI 1.27, 6.07), and 0 (95% CI 0, 0). Group 2 had statistically significantly higher mean adhesion scores compared to group 1. Histologic adhesion scores followed the trend of clinical adhesion scores. CONCLUSION(S): In this rabbit model, human endometrioma fluid exposure in the peritoneal cavity is not associated with adhesion formation. Instillation of endometrioma fluid followed by copious saline lavage is strongly associated with adhesion formation.