Carboxypeptidase-M is regulated by lipids and CSFs in macrophages and dendritic cells and expressed selectively in tissue granulomas and foam cells.

Granulomatous inflammations, characterized by the presence of activated macrophages (MAs) forming epithelioid cell (EPC) clusters, are usually easy to recognize. However, in ambiguous cases the use of a MA marker that expresses selectively in EPCs may be needed. Here, we report that carboxypeptidase-M (CPM), a MA-differentiation marker, is preferentially induced in EPCs of all granuloma types studied, but not in resting MAs. As CPM is not expressed constitutively in MAs, this allows utilization of CPM-immunohistochemistry in diagnostics of minute granuloma detection when dense non-granulomatous MAs are also present. Despite this rule, hardly any detectable CPM was found in advanced/active tubercle caseous disease, albeit in early tuberculosis granuloma, MAs still expressed CPM. Indeed, in vitro both the CPM-protein and -mRNA became downregulated when MAs were infected with live mycobacteria. In vitro, MA-CPM transcript is neither induced remarkably by interferon-γ, known to cause classical MA activation, nor by IL-4, an alternative MA activator. Instead, CPM is selectively expressed in lipid-laden MAs, including the foam cells of atherosclerotic plaques, xanthomatous lesions and lipid pneumonias. By using serum, rich in lipids, and low-density lipoprotein (LDL) or VLDL, CPM upregulation could be reproduced in vitro in monocyte-derived MAs both at transcriptional and protein levels, and the increase is repressed under lipid-depleted conditions. The microarray analyses support the notion that CPM induction correlates with a robust progressive increase in CPM gene expression during monocyte to MA maturation and dendritic cell (DC) differentiation mediated by granulocyte-MA-colony-stimulating factor+IL-4. M-CSF alone also induced CPM. These results collectively indicate that CPM upregulation in MAs is preferentially associated with increased lipid uptake, and exposure to CSF, features of EPCs, also. Therefore, CPM-immunohistochemistry is useful for granuloma and foam MA detections in tissue sections. Furthermore, the present data offer CPM for the first time to be a novel marker and cellular player in lipid uptake and/or metabolism of MAs by promoting foam cell formation.

The presence of carboxypeptidase-M in tumour cells signifies epidermal growth factor receptor expression in lung adenocarcinomas: the coexistence predicts a poor prognosis regardless of EGFR levels.

PURPOSE: Carboxypeptidase-M (CPM) is a membrane-bound peptidase that metabolizes peptides, and is present in pneumocytes. CPM hydrolyses the C-terminal arginine of epidermal growth factor (EGF) resulting in des-Arg53-EGF which binds to the EGF receptor (EGFR) with an equal or greater affinity than native EGF. Therefore, this study focused on the possible presence of CPM in human lung adenocarcinomas (ADC) and evaluated the relationship between CPM and EGFR by assessing the impact of expressions on patient clinical outcome. METHODS: This is a retrospective study of 110 patients who underwent resection of the primary tumour (92) or metastatic tissues (18) for treatment or diagnosis. Immunohistochemistry (IHC) for CPM and EGFR was made in serial sections using standard methods. RESULTS: This study demonstrates for the first time that 23.6% of ADCs express carboxypeptidase-M (26/110), mainly in membrane-bound forms. The amounts and the extent of CPM within tumours vary from low levels to obviously overexpressed forms. The immunohistochemical positivity (+) for CPM in ADCs negatively correlated with disease survival. In addition, 80% of CPM+ adenocarcinomas (21/26) showed a coexpression with EGFR suggesting a high prevalence for coexistence. The follow up data indicated a significantly shorter 5-year survival time for patients with CPM+-EGFR+ (double-positive) tumours compared to those harbouring neoplasias negative for both proteins (9.5 vs. 60.4% survivals, P < 0.001). CONCLUSION: The fact that CPM+ ADCs often co-express with EGFR suggests a functional-regulatory link between these proteins which might have therapeutical consequences. The present novel data could lead to improved IHC tests in lung adenocarcinomas for EGFR expression.

Natural course of isolated pulmonary langerhans' cell histiocytosis in a toddler. 3-year follow-up.

Isolated pulmonary Langerhans' cell histiocytosis (LCH) is distinctly rare under the age of 15 years, since the majority of patients are young adult males with heavy smoking habits. Isolated pulmonary involvement suggests that antigens inhaled from cigarette smoke are involved. Here we present a case of LCH restricted to the lungs in a toddler whose parents were heavy smokers. Since LCH was not medically treated for 3 years due to parental refusal, the disease can be regarded as having followed its natural course. During the 3-year follow-up, the disease progressed to severe pulmonary fibrosis resulting in honeycomb lungs. Based on the comparative immunohistochemical analyses of the cells obtained from bronchoalveolar lavages during the disease course, it appears that the evolution of fibrosis is rather a result from the accumulating alveolar macrophages than from the persistence of the Langerhans' cells. Passive cigarette smoking may be considered a significant risk factor in both the pathogenesis and development of pulmonary LCH in a small child.

Pulmonary arterial hypertension in mixed connective tissue disease: successful treatment with Iloprost.

This paper describes a 61-year-old woman who presented with mixed connective tissue disease, which was complicated by the development of pulmonary arterial hypertension (PAH). Her condition worsened rapidly, with development of haemopthysis, tachypnoe and cardiac arrest. Doppler echocardiography showed a high systolic pulmonary arterial pressure (98 mmHg), confirmed by the right heart catheterization. Vasculopathy of the pulmonary artery vessels was detected following open lung biopsy. No pulmonary embolism was found. Because of suspicion of flare of her underlying disease, which leads to PAH, immunosuppressive treatment was started with high doses of corticosteroid and cyclophosphamide, in combination with the prostacyclin analogue, Iloprost, and low molecular weight heparin. The therapy resulted in slow recovery over 6 weeks, with control echocardiography showing normalization of the high pulmonary pressure, and the patient being capable of returning to everyday activities.

The prevalence of prostate carcinoma and its precursor in Hungary: an autopsy study.

OBJECTIVES: The prevalence of incidental prostatic adenocarcinoma (PCa) and its precursor, high grade intraepithelial neoplasia (HGPIN) in an autopsy series from Hungarians (Central European Caucasians) was assessed and compared to similar data from the United States and European countries. METHODS: Autopsy cases (n=139; 18-95 years) with no history of urological disease were histologically examined for prostate cancer and HGPIN. After en block removal, the prostate glands were fixed in formalin, sectioned at 3-5mm intervals and embedded in paraffin. Whole-mount serial sections were stained with Hematoxylin-eosin and examined for the presence of PCa and HGPIN. The frequency of PCa and HGPIN was compared to autopsy data obtained from other geographical areas. RESULTS: We found a 38.8% prevalence of incidental PCa with increasing age-related incidence. Both PCa and HGPIN are first detected in the 3rd decade and show a steady increase with age with respect to number of foci, tumor grade and volume. In the age group 81-95, 86.6% and 60% of men had PCa and HGPIN, respectively. CONCLUSIONS: Incidental PCa and HGPIN are very prevalent in Hungarian population, comparable with the high US and the Scandinavian epidemiological data for Caucasians.

Role of human papillomavirus (HPV) testing in the follow-up of patients after treatment for cervical precancerous lesions.

OBJECTIVE: To evaluate the role of human papillomavirus (HPV) testing in post-treatment follow-up of patients after therapeutic excision of the cervix due to positive screening tests. STUDY DESIGN: A hospital-based retrospective analysis was performed with prospective collection of patient data of women screened for cervical cancer at a Gynecologic Outpatient Clinic. Patients after therapeutic excision due to positive screening results were identified and followed up with HPV testing and serial cytology. RESULTS: After 61 treatment for cervicalis intraepithelialis neoplasia (CIN), high-risk HPV infection was detected during the post-treatment follow-up at 18 cases (29.5%), 10 of them had persisting cytological atypia (positive predictive value (PPV): 56%), 5 developed CIN (PPV: 28%). When the HPV test was negative (43 patients) in the post-treatment period, neither CIN nor persisting cytological atypia developed (negative predictive value (NPV): 100%) during 1201 patient months (median 26 months). CONCLUSIONS: A negative HPV test eliminates the risk of recurrent disease after treatment for CIN.

[Interstitial lung disease in mixed connective tissue disease]. / Interstitialis légzoszervi betegség kevert kötooszöveti betegségben.

INTRODUCTION: The authors analyzed the incidence of interstitial lung disease in mixed connective tissue disease. They were seeking an answer to the following problems: the nature of the pathological course of mixed connective tissue disease complicated by and the therapy to be used in interstitial lung disease. PATIENTS AND METHODS: 179 patients were followed up during a period of 15.9 +/- 6.1 years. Interstitial lung disease was diagnosed using high resolution computed tomography. The diagnosis of interstitial lung disease was not obvious in 5 patients thus open lung biopsy was performed, which confirmed common interstitial pneumonitis. The patients were followed-up, and the data of computed tomography and respiratory function tests were detected 6 months, and then 4 years after the acute lung disease complicated by mixed connective tissue disease. RESULTS: Out of the 179 mixed connective tissue disease patients 96 (53.6%) had interstitial lung disease. The onset of interstitial lung disease was the most frequent in the 2-4 years of the disease. Four years after the first appearance of interstitial lung disease severe fibrosis was diagnosed in 24 patients (25%). A honey comb formation in the lung developed only in one patient. For the treatment of interstitial lung disease, corticosteroid treatment had to be combined with cyclophosphamide in 51 cases. In 4 patients (24%), pulmonary arterial hypertension evolved 2-4 years following interstitial lung disease. The high pulmonary arterial pressure decreased using pulsed corticosteroid treatment, cyclophosphamide, prostacyclin analogue, anticoagulants therapy and the 4 patients stay alive. The pulmonary arterial hypertension was caused by obliterative vasculopathy. CONCLUSION: Pulmonary involvement is found in more than half of the patients with mixed connective tissue disease. Early diagnosis of interstitial lung disease is possible by computed tomography. Interstitial lung disease can be treated by the combination of corticosteroids and cyclophosphamide. The authors were the first to detect the coexistence of interstitial lung disease and pulmonary arterial hypertension in mixed connective tissue disease. Subsequent respiratory alterations in these patient necessitate regular patient follow up.

Differential gene expression in human prostate cancer cells adapted to growth in bone in Beige mice.

OBJECTIVE: A metastasis model was used to identify genes potentially related to the growth of human prostate cancer in the bone. Injection of the human prostate cancer line PC3 into the femurs of Beige mice induced tumors that ruptured the femurs in 4 to 6 weeks. MATERIALS AND METHODS: The subline PC3a was cultured in vitro from one of these PC3 bone tumors. PC3a cells were reinjected into femurs, and the subline PC3b was then cultured from a resulting PC3a tumor. Likewise, PC3c was derived from a PC3b bone tumor. The PC3 tumors were osteolytic, invasive and metastatic. RESULTS: Analysis of gene expression in these PC3 sublines by differential-display RT-PCR identified two groups of transcripts whose steady state levels differed substantially from the original PC3 line. One group of transcripts increased with progressive adaptation to tumor formation in bone. The second group showed the reverse pattern. They progressively diminished in subsequent sublines, and were virtually absent in PC3b and PC3c. Two in this group were fibroblast growth factor receptor-2 and caveolin-1. They were strongly expressed in non-malignant prostate tissue. CONCLUSION: These two downregulated genes, which have been reported to play a role in the development of androgen independence and malignant progression, may reflect molecular changes in growth regulation of PC3 cells during readaptation to an intra-osseal environment.

Correlation of the genotypes for N-acetyltransferases 1 and 2 with double bladder and prostate cancers in a case-comparison study.

BACKGROUND: The arylamine N-acetyltransferases play a major role in the metabolic activation of carcinogenic amines that are present in cigarette smoke and a variety of other exogenous sources. The objective of this study was to determine the association of rapid or slow arylamine N-acetyltransferase (NAT) genotypes with smoking history and the risk for developing both bladder and prostate cancer. PATIENTS AND METHODS: The subjects analyzed were a case group of 17 double-cancer patients and 34 age-matched controls who had benign prostatic hypertrophy, but were asymptomatic for prostate or bladder cancers. Genotyping of NAT1 and NAT2 alleles was done by restriction fragment length polymorphism and/or sequencing of NAT genes amplified from genomic DNAs by the polymerase chain reaction (PCR). RESULTS: No significant correlation was found between NAT1 genotypes, double cancer, and smoking history. While NAT2-smoking interaction gave an odds ratio of only 1.70 (p = 0.117), a disproportionate number of cancer cases were genotypically rapid: 12 of 17 cancer cases vs. 13 of 34 controls (odds ratio 3.88; p = 0.040). CONCLUSION: Rapid NAT2 genotype correlated significantly with the development of double prostate-bladder cancer.