Intrapleural administration of lipoplatin in an animal model.

BACKGROUND: Lipoplatin is a new liposomal cisplatin already tested in solid tumors with encouraging results. Little is known about the activity of lipoplatin administered intrapleurally (IP). AIM: The aim of this study was to assess in an animal model the pharmacokinetics, and potentially induced histopathological lesions of lung and kidney after IP vs. IV injection of lipoplatin. METHODS: 15 male Wistar rats were assigned to an IV group at dose 10mg/kg of lipoplatin (group 1) and to IP groups at 10 (group 2) or 20mg/kg (group 3) equal to 60 and 120 mg/m(2) in humans respectively. After lipoplatin administration, serial plasma samples were analyzed by atomic absorption spectrometry for the maximum plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). Pleura, lungs and kidneys of the rats were histologically examined for possible lesions. RESULTS: The C(max) was significantly higher in groups 1 vs. 2 (p = 0.02) and vs. 3 (p = 0.01). The AUC of groups 3 vs. 1 was significantly higher (p = 0.028) but the AUC of groups 2 vs. 1 was significantly lower (p = 0.02). CL in IP rats did not differ considerably compared to the IV. Inflammatory changes were noted in the pleura of IP rats and mild kidneys lesions in IV group. CONCLUSION: Compared to the IV route, IP20 administration of lipoplatin yielded higher AUC, equal CL, but a significantly lower C(max). As C(max) is a determinant of lipoplatin toxicity, IP administration might offer a more effective therapeutic index while improving tolerability. We noted fibrotic changes in the pleura of IP rats, and mild kidneys changes in IV rats, as expected.

Altered surfactant protein-A expression in type II pneumocytes in COPD.

BACKGROUND: Pulmonary surfactant protein A (SP-A) is a lectin, with multiple functions that contribute to innate host defense and the regulation of the inflammatory process in the lung. In normal conditions, SP-A seems to protect against the effects of smoking. However, studies in smokers with or without COPD are limited. METHODS: Western blots on lung tissue specimens from 60 male subjects (32 patients with COPD, 18 smokers without COPD, and 10 control nonsmokers) for SP-A and the housekeeping protein actin were carried out. Additionally, the SP-A expression pattern was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded lung tissue sections from the same subjects. RESULTS: Western blots revealed significantly higher SP-A levels in control nonsmokers (4.8 +/- 0.05) when compared with patients with COPD (0.6 +/- 0.7) and smokers without COPD (2.4 +/- 0.9), (P < .05). However, differences that were not statistically significant were observed in SP-A levels among the patients with COPD and the smokers without COPD (P = .12). The immunohistochemical examinations showed an increase in the overall number of type II pneumocytes per high-power field in patients with COPD, but a decreased ratio of SP-A positive type II pneumocytes to total type II pneumocytes, compared with smokers without COPD (P = .001). This ratio was also correlated with FEV(1) (percent predicted [% pred]), (r = 0.490, P = .001). The overall number of alveolar macrophages per high-power field was significantly higher in patients with COPD compared with smokers without COPD (P = .001). The ratio of SP-A positive alveolar macrophages was increased in patients with COPD when compared with smokers without COPD (P = .002), while this was correlated with airway obstruction (FEV(1), % pred) (r = 0.281, P = .04). CONCLUSIONS: Our results indicate that altered SP-A expression could be another link to COPD pathogenesis and highlights the need for further studies on surfactant markers in COPD.

Decreased small airway and alveolar CD83+ dendritic cells in COPD.

BACKGROUND: Dendritic cells (DCs) have been reported to be increased in the small airways of patients with COPD, but the maturity status of these cells is unclear. We have quantified the numbers of cells expressing markers associated with DC maturation. METHODS: Lung tissue was obtained at resection for lung cancer from 41 patients with COPD (30 current smokers and 11 ex-smokers; 32 steroid-treated patients and 9 steroid-naïve patients), 19 ex-smokers without COPD and 9 never-smokers without COPD. Tissue sections were immunostained for CD1a to mark immature DCs, and for CD83, fascin, and DC-lysosome-associated membrane protein (DC-LAMP) to delineate mature DCs. RESULTS: The volume density (ie, the volume of DCs as the percentage volume of the airway wall) comprising CD83+ DCs was significantly reduced in patients with COPD (median, 0; range, 0 to 5.1%) vs smokers (median, 2.8%; range, 0 to 10.2%) and never-smokers (median, 1.9%; range, 0.8 to 5.1%) without COPD (p = 0.000 and 0.012, respectively). Using a semiquantitative score for the alveolar wall, CD83+ DCs also were decreased in patients with COPD (median, 0; range, 0 to 2%) vs smokers (median, 1%; range, 0 to 2%) and never-smokers (median, 1%; range, 0.7 to 2%) without COPD (p = 0.004 and 0.04, respectively). No differences were detected in CD83+ DCs between current smokers and ex-smokers with COPD or between steroid-treated and steroid-naive patients. No differences were detected in CD1a+ DCs. Fascin and DC-LAMP were found to have poor specificity for mature DCs. CONCLUSIONS: COPD is associated with decreased numbers of (mature) CD83+ DCs in small airways and alveoli. The relevance of such a reduction on pulmonary immune responses requires further investigation.

Different angiogenic CXC chemokine levels in bronchoalveolar lavage fluid after interferon gamma-1b therapy in idiopathic pulmonary fibrosis patients.

BACKGROUND AND AIM: Pulmonary fibrosis is a devastating disease with few treatment options. Angiogenesis that leads to aberrant vascular remodeling is regulated by an opposing balance of angiogenic and angiostatic factors. The present study aims to evaluate the role of three angiogenic (IL-8, ENA-78 and GRO-a) and three angiostatic (MIG, IP-10, ITAC) chemokines in bronchoalveolar lavage fluid (BALF), before and after treatment with Interferon gamma-1b (IFN gamma-1b). PATIENTS AND METHODS: We studied prospectively 20 patients (16 males, 4 females) of median age 68 years (range, 40-75) with histologically confirmed IPF/UIP. Patients were assigned to receive IFN gamma-1b 200 microg sc thrice a week. Angiogenic and angiostatic mediators' levels were measured by ELISA kits. RESULTS: The levels of the angiogenic chemokines significantly decreased after 12 months (mo) of IFN-gamma-1b treatment (median values in pg/ml, IL-8/CXCL8: 640 vs. 81, p<0.05, ENA-78/CXCL5: 191 vs. 51, p<0.005 and GRO-alpha: 1827 vs. 710, p<0.005). No significant differences were detected in the levels of the angiostatic chemokines after therapy (median values in pg/ml, IP-10/CXCL10: 56 vs. 56.5, p=0.6, ITAC/CXCL11: 43 vs. 47, p=0.11). However, a significant decrease in the MIG/CXCL9: 66 vs. 31, p=0.006, has been detected. CONCLUSION: These findings support the notion that IFN gamma may be one of the important mediators regulating angiogenetic balance in IPF. However, IFN gamma-1b decreases MIG levels, finding that in association with no alteration in IP-10 and I-TAC levels, could explain in part the nonbeneficial effect of this drug in IPF.

Acute lower limb ischemia as the initial symptom of acute myeloid leukemia.

Although coagulatory system disorders are well recognized in patients with acute leukemia, these usually present with either hemorrhagic complications or thrombosis of small vessels. Large vessel thrombosis is a very rare clinical presentation. We present a patient with previously undiagnosed acute myeloid leukemia (M5), who was referred to our hospital with symptoms of acute ischemia of his right lower limb. Occlusion of the right external iliac artery due to a combination of leucostasis and coagulation disorders was noted and successfully treated with urgent leukapheresis, immediate chemotherapy and surgical thromboembolectomy.

Simultaneous expression of c-erbB-1, c-erbB-2, c-erbB-3 and c-erbB-4 receptors in non-small-cell lung carcinomas: correlation with clinical outcome.

The expression of c-erbB receptors was immunohistochemically examined in paraffin embedded specimens from non-small-cell lung carcinomas. A total of 209 patients were enrolled [squamous-cell carcinomas (n=59), adenocarcinomas (n=130), large-cell carcinomas (n=15) and giant-cell carcinomas (n=5)]. The HercepTest kit scoring guidelines were used for the interpretation of positivity. C-erbB-1 was overexpressed in older patients, in squamous-cell carcinomas and in poorly-differentiated tumours, whereas c-erbB-2 overexpression with adenocarcinomas and poorly-differentiated tumours. C-erbB-4 overexpression correlated with advanced disease stage. The c-erbB-1/4 pair was the most commonly overexpressed and significantly correlated with female gender, while the c-erbB-1/2 pair with older age. Response to chemotherapy was significantly reduced in patients with tumours overexpressing c-erbB-1 receptor as well as the c-erbB-1/2 and c-erbB-3/4 receptor pairs. Patients' overall survival was significantly correlated with the co-expression of c-erbB-1 and c-erbB-4 receptors. These findings clearly suggest that specific receptors overexpression or co-overexpression is correlated with patients' disease control rate and outcome. A better understanding of the overexpression of the heterodimerized partners of c-erbB family receptors may provide a useful predictive indicator of response to molecular targeted therapies with c-erbB inhibitors.

Effects of antifibrotic agents on TGF-beta1, CTGF and IFN-gamma expression in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a deadly disease, largely unresponsive to treatment with corticosteroids and immunosuppressives. The aim of this randomized, prospective, open-label study was to characterize the molecular effects of IFN-gamma-1b and colchicine, on biomarkers expression associated with fibrosis (TGF-beta, CTGF) and immunomodulatory/antimicrobial activity (IFN-gamma), in the lungs of patients with IPF. Fourteen (14) patients with an established diagnosis of IPF received either 200 microg of IFN-gamma-1b subcutaneously three times per week, or 1mg of oral colchicine per day, for 24 months. Using RT-PCR assay, we evaluated the transcription levels of transforming growth factor beta1 (TGF-beta1), connective-tissue growth factor (CTGF), and interferon-gamma (IFN-gamma) genes in lung tissue before and after treatment with IFN-gamma-1b or colchicine. Marked mRNA expression of TGF-beta1 and CTGF, but complete lack of interferon-gamma was detected in fibrotic lung tissue at entry. After treatment, both groups exhibited increased expression of IFN-gamma gene at 6 months that was sustained at 24 months. The expression of CTGF and TGF-beta1 remained almost stable before and after treatment, in the IFN-gamma-1b group, while TGF-beta1 was statistically decreased after therapy, in the colchicine group (p=0.0002). Significant difference in DLCO (% pred), was found between the two treatment groups in favor of IFN-gamma-1b group (p=0.04). In addition, the IFN-gamma-1b group showed stability in arterial PO2 while the colchicine group significantly deteriorated (p=0.02). In conclusion, we report the effect of antifibrotic agents (IFN-gamma-1b and colchicine) in TGF-beta, CTGF, and endogenous IFN-gamma gene expression, in human fibrosis. However, extended studies are needed to verify the pathophysiological consequences of these findings.

Invasive cutaneous infection with Geotrichum candidum: sequential treatment with amphotericin B and voriconazole.

A rare case of an invasive cutaneous infection by Geotrichum candidum in an 80-year-old male patient with diabetes mellitus is reported. The primary site of infection manifested after trauma as an ulcerative lesion on the distal phalanx of the midfinger and extended throughout the right hand. Histological examination showed fungal invasion in the deep dermis without vascular involvement and G. candidum was grown in cultures from the biopsy material. Angiography revealed severe obstructive disease of the right brachial artery and its branches. Treatment, after susceptibility testing of the isolated strain, consisted of sequential administration of intravenous liposomal amphotericin B with oral voriconazole followed by liposomal amphotericin B, resulting in substantial improvement of the infection.

Total lung lavage by awake flexible fiberoptic bronchoscope in a 13-year-old girl with pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a rare, heterogeneous diffuse lung disease in childhood. We report a case of an asymptomatic 13-year old girl with PAP. She had radiolographic findings suggesting the diagnosis, which was confirmed by the "milky" bronchoalveolar lavage fluid and the histology of transbronchial biopsy. Total lung lavage was performed by flexible fiberoptic bronchoscope under local anesthesia with success. This is the first reported case of a PAP in a child that was treated by being awake during bronchoscopy. After one-year of follow-up, the patient remains free of symptoms.

Response of a patient with pleural and peritoneal mesothelioma after second-line chemotherapy with lipoplatin and gemcitabine.

We report the case of a 56-year-old patient with malignant pleural mesothelioma of epithelial type, who responded to second-line chemotherapy with lipoplatin plus gemcitabine. Diagnosis and staging of the disease was done by medical thoracoscopy with biopsies of the right pleura in December 2003, when he was treated with talc pleurodesis. Eighteen months later, he presented with pleural effusion of the left side and underwent first-line chemotherapy with cisplatin plus vinorelbine. After 8 cycles, the patient presented renal toxicity limiting further cisplatinum chemotherapy and disease progression with peritoneal invasion of the tumor and ascites. Treatment with lipoplatin-gemcitabine was decided on in November 2006, and the patient showed important improvement in the clinical status and peritoneal effusion. He survived for 36 weeks, with symptom-free survival of 34 weeks.

Oral mucosal melanoma: a malignant trap.

Oral mucosal melanomas are highly malignant tumors. The 'chameleonic' presentation of a mainly asymptomatic condition, the rarity of these lesions, the poor prognosis and the necessity of a highly specialized treatment are factors that should be seriously considered by the involved health provider. We present the case of a 75-year-old man who was referred to the Ear, Nose and Throat department. His symptoms were voice alteration and saliva drooling, progressively worsening during the last few weeks. The absence of pain was the reason for the delay of seeking medical care. The diagnosis was an oversized oral melanoma. This is an example of how the time of diagnosis and the evolution of a disease could be seriously influenced by patient's behavior. Melanomas arising from oral mucosa have poor prognosis unless they are discovered and treated early. The vigilance of the physicians is necessary to have success in this difficult task.

Active remodeling in idiopathic interstitial pneumonias: evaluation of collagen types XII and XIV.

Fibril-associated collagens with interrupted triple helices (FACITs) XII and XIV act as fibril organizers and assist in the maintenance of uniform fibril size. We investigated the spatial expression patterns of collagens XII and XIV in cryptogenic organizing pneumonia (COP)/organizing pneumonia (OP) and in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) and compared them to normal human lung. Study subjects included 10 patients with COP/OP, 10 patients with IPF/UIP, and 8 control subjects. Immunostaining for collagens XII and XIV was carried out in paraffin-embedded human lung tissue sections. Picrosirius red histochemical staining for collagen I expression and electron microcopy to evaluate fibril diameter were also performed. In normal lung, collagens XII and XIV were expressed in perivascular and subpleural connective tissue. In COP/OP, both collagens showed intense staining in perivascular connective tissue, thickened alveolar septae, and subpleural areas. In IPF/UIP, XII and XIV were expressed in perivascular connective tissue, in areas of established fibrosis, and in areas of subpleural thickening. Only collagen XII was expressed in granulation tissue plugs in COP/OP and in fibroblastic foci in IPF/UIP. Collagen type I was overexpressed in fibrotic areas. Electron micrographs revealed obvious fibril diameter alteration and fusion in the same areas. FACITs XII and XIV are expressed in normal and fibrotic lung. Unlike collagen XIV, collagen XII was expressed in granulation tissue plugs in COP/OP and in fibroblast foci in IPF/UIP. This may suggest a possible distinct role for both collagens in the modulation of the extracellular matrix during the onset of fibrotic process.

Apoptotic mechanisms in the pathogenesis of COPD.

COPD is a leading cause of morbidity and mortality, characterized by a chronic abnormal inflammatory response to noxious agents. Apoptosis is a physiologic process, critical to cellular homeostasis, in which cell death follows a programmed sequence of events. Apoptosis has been recognized to play an important role in clinical and experimental models of lung diseases. Abnormal apoptotic events in smokers' and in emphysematous lungs have been shown in epithelial and endotheliallung cells, neutrophils, lymphocytes, and myocytes. Many factors associated with COPD, including cigarette smoke, have the potential to cause apoptosis of alveolar epithelial cells, the main sites of vascular endothelial growth factor (VEGF) production. The decreased expression of VEGF, a known survival factor for endothelial cells, and its receptor, results in lung septal endothelial cell death, leading perhaps to the emphysema observed in COPD. In smokers who develop COPD there is an activation of adaptive immunity, with an infiltration of CD4+ and, especially, CD8 + cells. CD8 + cells are cytotoxic to epithelial cells through the release of granzymes and perforin, which can further induce apoptosis of alveolar cells. Moreover, any reduction in neutrophil apoptosis or dysregulation of macrophage uptake of apoptotic neutrophils could lead to chronic inflammation and tissue injury. Increased rates of T-cell apoptosis may lead to a defective immune response to infective organisms, contributing to the high frequency of infections seen in COPD. Increased apoptosis of skeletal muscle could be responsible for the skeletal muscle atrophy, the main cause of unexplained weight loss in patients with COPD. This paper is a review of the current knowledge on the apoptotic pathways involved in COPD pathogenesis and their interaction with other known contributing factors.

A novel combination of multiple primary carcinomas: urinary bladder transitional cell carcinoma, prostate adenocarcinoma and small cell lung carcinoma--report of a case and review of the literature.

BACKGROUND: The incidence of multiple primary malignant neoplasms increases with age and they are encountered more frequently nowadays than before, the phenomenon is still considered to be rare. CASE PRESENTATION: We report a case of a man in whom urinary bladder transitional cell carcinoma, metachronous prostate adenocarcinoma and small cell lung carcinoma were diagnosed within an eighteen-month period. The only known predisposing factor was that he was heavy smoker (90-100 packets per year). The literature on the phenomenon of multiple primary malignancies in a single patient is reviewed and the data is summarized. CONCLUSION: It is important for the clinicians to keep in mind the possibility of a metachronous (successive) or a synchronous (simultaneous) malignancy in a cancer patient. It is worthy mentioning this case because clustering of three primary malignancies (synchronous and metachronous) is of rare occurrence in a single patient, and, to our knowledge, this is the first report this combination of three carcinomas appearing in the same patient.

Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis.

STUDY OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic, usually fatal lung disease of unknown etiology. A common feature is the presence of microscopic areas of epithelial cell dropout. Increased apoptosis of these cells could elucidate the speculative pathogenesis of the disease. Therefore, the aim of our study was to examine the expression of p53, p21, bcl-2, bax, and caspase-3 in association with DNA strand breaks in bronchial and alveolar epithelial cells in lung specimens from IPF patients and control subjects. PATIENTS AND METHODS: We examined by immunohistochemistry the expression of p53, p21, bax, bcl-2, and caspase-3 in association with DNA strand breaks detected by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in bronchial and alveolar epithelial cells in lung specimens taken by biopsy in 12 IPF patients and 10 control subjects. An independent tissue evaluation by two pathologists graded semiquantatively the degree of staining present. RESULTS: TUNEL was positive in epithelial cells in all IPF patients and only in one control subject. The expression of p53, p21, bax, and caspase-3 was up-regulated in IPF patients compared to control subjects. Bcl-2 was expressed less in IPF patients than in control subjects. CONCLUSIONS: These results confirm that apoptotic hyperplastic epithelial cells are present in patients with IPF and that the expression of p53, p21, bax, and caspase-3 appears to be up-regulated and that of bcl-2 down-regulated in these cells. The increased expression of proapoptotic molecules in epithelial cells in IPF may be involved in the inadequate and delayed reepithelialization, which in turn contributes to fibroblast proliferation.

Meningioangiomatosis with predominantly cellular pattern.

A case of meningioangiomatosis (MA), in a 10-year-old-girl with refractory complex partial and secondary generalized seizures, starting at the age of 8 years, is presented. MRI evaluation revealed a lesion located at the left frontal lobe; the patient underwent surgical lesionectomy. Histology revealed the lesion to have the features of MA. The patient is symptom-free a year postoperation. We report the histological, immunohistochemical and imaging findings in view of previous pertinent reports.