Gadolinium retention in the tunica media of arterial walls-a complementary study using elemental bioimaging and immunogold staining.

Gadolinium (Gd) deposition has been found in both animal and human tissues after injections of Gd-based contrast agents (GBCAs). Without the knowledge of which tissues are most affected, it is difficult to determine whether Gd accumulation could lead to any pathological changes. The current study aims at investigating histological sections of three patients who were exposed to GBCAs during their lifetime, and identify areas of Gd accumulation. Tissue sections of three autopsy cases were investigated by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to assess the distribution of Gd, and the deposition within tissue sections was quantified. Additional application of laser ablation-inductively coupled plasma-optical emission spectroscopy (LA-ICP-OES) enabled a sensitive detection of calcium (Ca) in the vessel walls, which is usually impeded in LA-ICP-MS due to the isobaric interference with argon. Complementary LA-ICP-MS and LA-ICP-OES analysis revealed that Gd was co-localized with zinc and Ca, in the area where smooth muscle actin was present. Notably, high levels of Gd were found in the tunica media of arterial walls, which requires further research into potential Gd-related toxicity in this specific location.

Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a primary benign disease, which is characterized by papillomatous growth in the respiratory tract. Malignant transformation occurs in only 3-5% of cases, however, local growth of the benign papillomas is interpreted as clinically malignant in a markedly higher proportion of patients. Local surgical or endoscopic interventional debulking or excision is currently the commonly selected treatment method and antiviral therapy is a potential adjuvant approach. However, the long-term management of RRP patients, who commonly require multiple procedures over numerous years, is challenging and the overall therapeutic armamentarium remains unsatisfactory. The administration of systemic bevacizumab treatment in a series of five patients with long histories of RRP, who required repeated local interventions to control papilloma growth is evaluated. Treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was administered at a dose of 5 mg/kg (n=1), 10 mg/kg (n=3) or 15 mg/kg (n=1) intravenously to the five RRP patients, who were clinically classified as exhibiting progressive disease. Endoscopic evaluations were performed prior to the first infusion of bevacizumab and intermittently at variable time points during the course of therapy. Histopathological analyses were performed using pre- and post-treatment papilloma biopsies, including immunohistochemical analyses of VEGF and phosphorylated VEGF receptor (VEGFR)-2 expression. The patients received between three and 16 courses of bevacizumab (median, six courses). The first course was initiated when progression following the previous intervention was observed. An immediate response to bevacizumab treatment was demonstrated in all five RRP patients. While the cumulative number of interventions in the five patients was 18 throughout the 12 months prior to the initiation of bevacizumab treatment, only one patient required interventional treatment due to a malignant transformation during the 12 months following treatment with bevacizumab (18 vs. 1 interventions, P=0.042). Histopathological analyses revealed regressive perivascular edema and normalization of the vascular structure, however, immunohistochemical analyses of the VEGF and phosphorylated VEGFR-2 expression did not demonstrate any changes following therapy. Due to the limited number of alternative treatments, VEGF-targeted therapies may represent a promising novel strategy in the treatment of RRP, which may have the potential to modify the current treatment standards, particularly in patients with poorly accessible papilloma lesions, however, this requires further investigation in clinical trials.

Squamous cell carcinoma of the larynx arising in multifocal pharyngolaryngeal oncocytic papillary cystadenoma: a case report and review of the literature.

We report on a rare case of a laryngeal carcinoma arising in a multifocal pharyngolaryngeal oncocytic papillary cystadenoma (OPC). The disease of a 63-year-old man is well documented by computed and positron emission tomography, histology, and electron microscopy. We could show that an OPC can even develop in the pharynx. The coexistence of both tumors makes this a challenging diagnosis for pathologists. Treated by surgery and radiotherapy, both lesions dissolved. Based on the literature available, we discuss the theory that the laryngeal carcinoma might be the result of a true metaplasia facilitated by chronic irritation and recommend a regular follow-up for OPC too. As in benign oncocytic lesions, we could show that the detection of numerous mitochondria is a diagnostic indicator for malignant variants as well.

Concentrated green tea extract induces severe acute hepatitis in a 63-year-old woman--a case report with pharmaceutical analysis.

UNLABELLED: ETNOPHARMACOLOGICAL RELEVANCE: The popularity of concentrated green tea extracts as dietary supplements for a wide range of applications is increasing due to their health-promoting effects attributed to the high amounts of catechins they contain. The most important of the green tea catechins is (-)-epigallocatechin-3-O-gallate (EGCG). While their beneficiary effects have been studied extensively, a small number of adverse events have been reported in the medical literature. Here we present a typical reversible course of severe hepatitis after green tea consumption. MATERIALS AND METHODS: The case study describes in a 63-year old woman during treatment with green tea-capsules upon recommendation of a cancer support group. RESULTS: The histological finding was consistent with drug induced hepatitis, and other possible causes of hepatitis were excluded. According to the CIOMS/RUCAM score the causality was assessed as "probable". After discontinuation of medication, followed by extracorporal albumin dialysis, rapid and sustained recovery occurred. Pharmaceutically analysis (HPLC) of the green tea capsules did not give evidence for contaminants but revealed the two typical compounds of green tea, namely (-)-epigallocatechin-3-O-gallate (EGCG, 93.2%) and epicatechin (EC, 6.8%) at a very high dose level. CONCLUSION: The present case highlights the fact that such concentrated herbal extracts from green tea may not be free of adverse effects under certain circumstances. There is still a lack of a uniform European Union-wide surveillance system for adverse drug reactions of herbal products. Therefore this case underlines the importance of public awareness in the potential risks in use of herbal products.

Primary mucinous adenocarcinoma of the renal pelvis with carcinoma in situ in the ureter.

Primary epithelial tumor of the renal pelvis is rare and only 100 cases are reported in the literature [1]. Histological examination of the tumor showed glands, cysts, and papillae lined by pseudostratified columnar epithelium with hyperchromatic nuclei. Scattered signet ring-type cells were also seen floating in large pools of extracellular mucin. Sections from the ureter showed a component of adenocarcinoma in situ. No invasive tumor was identified in ureteric tissue. One case was reported with carcinoma in situ of the ureter (2). Immunohistochemically: The tumor showed positivity for CK7, CK20, CK8/18, GATA-3, MSH-2, MSH-6, MLH-1, Ber-EP4, and S-100-P with focal positivity for CDX-2, weak positivity for PMS-2 and negativity in TTF-1 and Her-2. Molecular pathological analysis revealed microsatellite stability and without mutation in K-ras-gene. Thus, a diagnosis of mucinous adenocarcinoma of the renal pelvis with in situ adenocarcinoma of the ureter was made.

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer.

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix. The occurrence of silicosis by site was investigated with regression models for exposure to quartz dust. Miners with lung silicosis had highest cumulative quartz exposure, followed by lymph node-only silicosis and no silicosis. At a cumulative quartz exposure of 40 mg/m(3) × years, the probability of lung silicosis was above 90% and the likelihood of lymph node-only silicosis and no silicosis do not differ anymore. The results support that lymph node silicosis can precede lung silicosis, at least in a proportion of subjects developing silicosis, and that lung silicosis strongly depends on the cumulative quartz dose.

Primary malignant pericardial mesothelioma - a rare cause of pericardial effusion and consecutive constrictive pericarditis: a case report.

INTRODUCTION: Primary malignant pericardial mesothelioma is a very rare pericardial tumor of unknown etiology. CASE PRESENTATION: A 61-year-old Caucasian woman was admitted to our hospital complaining of exertional dyspnea due to a large pericardial effusion. Intrapericardial fluid volume declined after repeated pericardiocentesis, but the patient progressively developed a hemodynamically relevant pericardial constriction. Pericardiectomy revealed a pericardial mesothelioma. Subsequently, four cycles of chemotherapy (dosage according to recently published trials) were administered. The patient remained asymptomatic, and there was no recurrence of the tumor after three years. CONCLUSION: Pericardial mesothelioma should be considered and managed appropriately in non-responders to pericardiocentesis, and in patients who develop constrictive pericarditis late in their clinical course.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

Computed tomography-navigated transthoracic core biopsy of pulmonary lesions: which factors affect diagnostic yield and complication rates?

RATIONALE AND OBJECTIVES: Only a few studies have systematically evaluated risk factors for pneumothorax and pulmonary hemorrhage in computed tomographically (CT)-guided transthoracic lung biopsy (TLB). We evaluated the diagnostic yield of CT-guided TLB and determined risk factors for pneumothorax and hemorrhage. METHODS: One hundred seventy-two CT-guided TLBs were performed on 159 patients (mean age 66 +/- 11 years; 72% male) using a 16-gauge core biopsy needle. Lesion and patient characteristics, lung function analysis, CT signs of emphysema, histopathologic diagnoses, and complications were recorded. Statistical analysis was performed with multivariate regression analysis. RESULTS: Histopathologic diagnosis was established in 153 cases (89%). Although lesion size was higher (47 +/- 29 vs. 43 +/- 35 mm, P = .191) and depth was lower (22 +/- 23 vs. 6 +/- 23 mm, P = .350) in procedures with histopathologic diagnosis, no parameter showed significant impact on diagnostic yield. Sensitivity and specificity for detection of malignancy were 93% and 100%, respectively, whereas positive and negative predictive values were 100% and 88%. Overall accuracy was 95%. Pneumothorax occurred in 45 procedures (26%). Hemorrhage was recorded in 17 procedures (10%). There was higher frequency of pneumothorax in smaller lesions (35 +/- 23 vs. 50 +/- 31 mm, P = .003; odds ratio = .96) and greater depth (29 +/- 29 vs. 20 +/- 19 mm, P = .05; odds ratio = 1.03). CT signs of emphysema revealed higher incidence of hemorrhage (35% vs. 23%; P = .04; odds ratio=41.03). Other parameters were nonsignificant. CONCLUSIONS: The high diagnostic yield of CT-guided TLB was not affected by lesion characteristics or emphysema. Pneumothorax rate was influenced by lesion size and depth. Hemorrhage was associated with CT signs of emphysema.

Endothelial VE-cadherin expression in human lungs.

Cell adhesion molecule vascular endothelial cadherin (VE-cadherin) is the major component of endothelial adherence junctions, maintaining endothelial cell integrity. Studies dealing with constitutive VE-cadherin expression patterns in different pulmonary vessel types (arteries, arterioles, capillaries, venules, veins) or with the influence of physiological factors such as age or sex on VE-cadherin expression have not been published yet. Knowledge of constitutive resp. varying expression patterns not only fundamentally contribute to understanding the role of VE-cadherin in the pathogenesis of pulmonary diseases but also help to develop therapies based on immunotargeting. Hence, endothelial VE-cadherin expression was studied in regular lung tissue. Fifty-eight specimens of regular lung tissue (30 females, 28 males between 1 month and 75 years old) were immunohistochemically stained with an antibody against VE-cadherin. There was strong endothelial expression of VE-cadherin in arteries, arterioles, and capillaries but almost no expression in veins and venules. Neither age nor sex had any influence on the expression pattern or staining intensity. There is a vessel type-specific expression pattern for VE-cadherin in regular human lung tissue, which is not influenced by age or sex. Further studies will have to prove whether this is influenced by pathological conditions, e.g., ARDS.

Early cytological diagnosis of diffuse malignant mesothelioma of the peritoneum: a case report.

Mesotheliomas are the most frequent primary malignant tumors of serosal cavities with a poor prognosis. A definitive and early diagnosis on effusion samples is important, because recent advances in therapy for patients with mesothelioma may result in an improved outcome if they are applied to stage I disease. We report a case of malignant peritoneal mesothelioma diagnosed repeatedly by cytology in ascites fluids 1.5 yr before the diagnosis was confirmed by biopsy histology. The cytological diagnoses were supported by immunocytochemistry, DNA-cytometry, and AgNOR-analysis. Routine cytology supported by three adjuvant methods enabled us to correctly establish the diagnosis. Our case suggests that a cytological diagnosis of malignant mesothelioma supported by adjuvant methods should not be rejected even if based on negative histological results.

Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases.

Pulmonary arterial hypertension is a severe complication of connective tissue diseases. It is currently well established that pulmonary arterial hypertension associated with connective tissue diseases such as systemic sclerosis is frequently less responsive or even refractory to pulmonary vasodilator therapies. In that setting, pulmonary venoocclusive disease is believed to contribute to treatment failures. We therefore hypothesized that pulmonary arterial hypertension associated with connective tissue diseases may be associated with obstructive lesions of pulmonary veins. Lung samples from 8 patients with pulmonary arterial hypertension associated with connective tissue disease (4 limited systemic sclerosis, 2 systemic lupus erythematosus, 1 mixed connective tissue diseases, and 1 rheumatoid arthritis) were studied by light microscopy and analyzed by immunohistochemistry (5 postmortem samples, 3 explants after lung transplantation). Findings were compared with 29 pulmonary arterial hypertension cases from patients displaying neither connective tissue diseases nor associated conditions. We found that (a) 6 (75%) of 8 patients with pulmonary arterial hypertension associated with connective tissue diseases showed significant obstructive pulmonary vascular lesions predominating in veins/preseptal venules, as compared with 5 (17.2%) of 29 non-connective tissue diseases control pulmonary arterial hypertension; (b) lesions of small muscular arteries were consistently present in pulmonary arterial hypertension associated with connective tissue diseases, showing mostly intimal fibrosis and thrombotic lesions; and (c) 6 of 8 lung samples from patients with pulmonary arterial hypertension associated with connective tissue diseases revealed perivascular inflammatory infiltration. In conclusion, our study highlights the fact that pulmonary arterial hypertension complicating the course of connective tissue diseases may be characterized by a more frequent involvement of pulmonary veins and may thus explain why these patients are less prone to respond to specific pulmonary arterial hypertension treatment as compared with idiopathic pulmonary arterial hypertension.

Experimental comparison of monofile light and heavy polypropylene meshes: less weight does not mean less biological response.

BACKGROUND: Mesh implantation is a standard procedure in hernia repair. It provides low recurrence rate but increases complication rate due to foreign-body reaction induced by alloplastic materials in surrounding tissues. It is believed that biocompatibility of meshes may be improved by reducing their weight per meter squared (m2) and altering the implant structure. AIM: The aim of this study was to evaluate the effect of weight and structure as determinants of mesh biocompatibility. METHOD: Thirty-six Wistar rats were studied. In 12 animals, conventional polypropylene (heavy) meshes (HM) were implanted; in other 12, material-reduced (light) microporous polypropylene meshes (LM); and the remaining 12 served as a sham-operated control group. Meshes were explanted after 21 and 90 days (6 animals per group). All samples were examined by light and electron microscopies. Integration of meshes in surrounding tissue, inflammatory response, fibrotic reactions, and structural changes were recorded. Quantification of the inflammatory response was achieved by CD-68 marking of macrophages and counting their number per surface unit. RESULTS: After 21 days, there was no significant difference in thickness of surrounding connective tissue between meshes in all groups studied. After 90 days, thickness of connective tissue decreased in both groups, and fibrotic reaction in the mesh bed was significantly less in the HM group. Total amount of macrophages per millimeter squared (mm2) decreased with time in HM and LM samples but was significantly lower in the HM group on day 21 (43.5%) and day 90 (46.7%). CONCLUSION: This study found worse biocompatibility of LM compared with HM. Thus, the amount of implanted mesh was not the main determinant of biocompatibility (expressed as successful incorporation and diminished foreign-body reaction) but the size of the pores.

D2-40: a reliable marker in the diagnosis of pleural mesothelioma.

OBJECTIVE: Malignant mesotheliomas of the pleura, peritoneum and pericardium can easily be confused with either metastatic adenocarcinomas or reactive pleural lesions. D2-40, a monoclonal antibody used as a marker for seminomatous germ cell tumours and lymphatic endothelial cells, was recently described in mesothelial cells and type I but not type II pneumocytes. METHOD: The immunoreactivities of D2-40 in 76 lung carcinomas of different histological types (adenocarcinomas, squamous cell, small cell, and bronchioloalveolar carcinomas) were compared with those of 36 pleural epithelioid and sarcomatoid mesotheliomas and 5 specimens of chronic pleuritis. RESULTS: While all 18 analysed epithelioid mesotheliomas displayed a strong membranous immunostaining, 18 sarcomatoid mesotheliomas showed no, or a merely faint, cytoplasmic signal, comparable with fibroblasts in chronic pleuritis. Out of all analysed lung carcinomas, 49 showed no immunoreactivity for D2-40 (64%), while the other 27 (36%) showed a focal weak to moderate and only cytoplasmic signal. CONCLUSIONS: We regard D2-40 as a valid marker in the differential diagnosis of epithelioid mesotheliomas versus pulmonary adenocarcinomas. However, this marker may not properly label sarcomatoid mesotheliomas or distinguish them from reactive pleural lesions.

Lymphoid interstitial lung disease in a patient with acute tubulointerstitial nephritis and uveitis: a new facet of a rare syndrome?

We report for the first time the appearance of lymphoid interstitial lung disease in a patient with tubulointerstitial nephritis and uveitis (TINU) syndrome. A 41-year-old woman with a 9-month history of recurrent bilateral iridocyclitis was referred to our division for examination of renal dysfunction. Renal biopsy showed extensive interstitial CD3+ lymphocytic infiltration; glomerular structures were unaffected. After oral corticosteroid therapy, renal function remained stable during the next few years. Uveitis was controlled by using topical steroids. Five years after first presentation, the patient developed symptoms suggestive of interstitial lung disease, combined with a relapse of uveitis. Lung biopsy showed lymphofollicular bronchiolitis (CD3+) associated with florid alveolitis. There was no evidence for acute infection or systemic disease to be the cause of this pathological state. Lung disease proved to be steroid responsive. A new pulmonary flare-up 3 years later responded to renewed treatment. Accounting for the histological findings, we assume both TINU syndrome and interstitial lung disease to be manifestations of a common autoimmune disorder.

Human histopathology of electroanatomic mapping after cooled-tip radiofrequency ablation to treat ventricular tachycardia in remote myocardial infarction.

INTRODUCTION: Catheter ablation of ventricular tachycardia (VT) in remote myocardial infarction (MI) often requires excessive mapping procedures. Documentation of the electrical substrate via electrogram amplitude may help to identify regions of altered myocardium resembling exit areas of reentrant VTs. METHODS AND RESULTS: A patient with multiple symptomatic monomorphic VTs (biventricular ICD, remote MI) underwent electroanatomic substrate mapping (CARTOtrade mark) for VT ablation. Regions of scar (bipolar electrogram amplitudes or=1.5 mV), and "altered" myocardium (0.5-1.5 mV) were identified. Ablation was directed to regions with "altered" myocardium based on pace map correlation. After ablation the clinical VT did not reoccur. The patient died due to worsening of heart failure 7 days afterward. During postmortal evaluation specified sites of electroanatomic mapping were correlated to histopathological findings. Annotated scar areas were documented to consist of areas with massive fibrosis (>or=80% of mural composition). Ablations were found to span through regions with intermediate fibrosis (21-79%) mapped as "altered" myocardium. Ablation produced transmural coagulation necrosis of mesh-like fibrotic tissue with interspersed remnants of myocardial cells up to a maximum depth of 7.0 mm. Subendocardial intramural bleedings were universal findings 7 days after ablation. CONCLUSIONS: Electroanatomic substrate mapping for VT ablation sufficiently identified regions of scar and normal myocardium. Regions with bipolar electrogram amplitudes between 0.5 and 1.5 mV were found to correlate to areas of "intermediate" fibrosis (21-79%) with only remnant strands of myocardial cells and were identified as target region for ablation. Cooled-tip endocardial radiofrequency ablation lead to transmural coagulation necrosis up to a depth of 7.0 mm.

Non-invasive detection of colorectal tumours by the combined application of molecular diagnosis and the faecal occult blood test.

The treatment of early-stage tumours decreases the overall mortality of colorectal tumour patients. In this retrospective study we determined the sensitivity and the specificity of the faecal occult blood test (FOBT) and the molecular diagnosis (MD). We analysed 57 stool samples from patients with colorectal carcinomas for the presence of occult blood using a standard FOBT and for alterations in the three different tumour relevant markers APC, BAT26 and L-DNA. Stool samples from 44 control donors were analysed to determine the specificity of the applied methods. Twenty-nine (51%; 95% confidence interval (CI): 38-63%) stool samples of the cancer patients gave positive FOBT results. Thirty-seven (65%; CI: 52-76%) samples showed alterations in at least one DNA marker. Sixteen (28%) samples were positive only in the FOBT, and 24 (42%) samples showed a positive result exclusively in MD. The combined application of both methods resulted in a sensitivity of 93% (CI: 83-97%) and an overall specificity of 89% (CI: 76-95%). The combined application of FOBT and MD resulted in an overall sensitivity, which could not be achieved by any of the methods alone and which is in the range of invasive diagnostic methods.