Tumour cell uptake of the metastasis inhibitor ruthenium complex NAMI-A and its in vitro effects on KB cells

PURPOSE: The uptake of NAMI-A (imidazolium trans-imidazoledimethylsulphoxidetetrachlororuthenate) by KB cells in vitro was compared with the effects of this compound on the cell cycle phase distribution of the cells. METHODS: NAMI-A uptake was determined by flameless atomic absorption spectroscopy, and the cell cycle phase distribution was determined by flow cytometry. RESULTS: NAMI-A uptake was proportional to its concentration in the incubation medium. The use of a number of incubation conditions showed that NAMI-A uptake from MEM was independent of the presence of serum and dependent on the presence of amino acids in the incubation medium, and that NAMI-A uptake was markedly higher when the cells were incubated in PBS. The uptake increase observed in PBS did not occur when the cells were kept at 0-4 degrees C, suggesting the presence of active transportation of NAMI-A into cells. In addition, the presence of divalent cations such as Ca(2+) and Mg(2+), appeared to facilitate NAMI-A uptake. The anionic substance transport inhibitor probenecid significantly reduced the active transportation of NAMI-A into cells. The effects of NAMI-A on cell cycle distribution were strictly dependent on its uptake by tumour cells and not on its extracellular concentration. CONCLUSIONS: These findings suggest the interaction of NAMI-A with biological components resulting in possible consequences for the distribution of the compound itself. Furthermore, NAMI-A enters tumour cells both by passive diffusion and by active transportation.     

Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A

The influence of chemical stability on the antimetastatic ruthenium(III) compound imidazolium trans-imidazoletetrachlorodimethylsulphoxideruthenium(III) (NAMI-A) in aqueous solution was studied both in vitro and in vivo. The loss of dimethyl-sulphoxide (DMSO) ligand from the compound was tested by using a NAMI-A solution acidified with HCl at pH 3.0 and aged for 0, 4, 8 and 24 h prior to intraperitoneal (i.p.) injection into CBA mice bearing advanced MCa mammary carcinoma. The activity of NAMI-A on lung metastases showed no change even after the loss of DMSO ligand from up to 50% of the molecules. The reduction of NAMI-A did not modify the number of KB cells blocked in the S+G2M phases, independent of whether the reduction occurred outside the cells or after loading the cells with the compound prior to treatment with the reductants (ascorbic acid, glutathione or cysteine). In vivo, the complete reduction of NAMI-A with equivalent amounts of ascorbic acid, glutathione or cysteine prior to administration to mice bearing advanced MCa mammary carcinoma was more active than NAMI-A alone. The data show that NAMI-A, although undergoing a series of chemical modifications, maintains its antimetastatic activity in a broad range of experimental conditions.     

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A

NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours.     

Reconstruction of the middle cerebral artery after excision of a giant fusiform aneurysm

A patient with a giant fusiform aneurysm of the left inferior trunkus of the middle cerebral artery (MCA) is presented. The size of the aneurysm was 5 cm at its largest diameter. Retrograde flow was well developed. After the application of temporary clips the aneurysm was excised and microsurgical reconstructions were undertaken. Adequate flow in the reconstructed MCA trunkus was maintained. This rare case is discussed in the light of the literature.     

Pediatric EBV-positive T-cell/histiocyte-rich large B-cell lymphoma with clonal cells in the bone marrow without overt involvement

T-cell/histiocyte-rich large B-cell lymphoma (TCHRLBCL) is a variant of large B-cell lymphoma only rarely encountered in children. Here we report the case of an 8-year-old African American boy with Epstein-Barr virus (EBV)-positive TCHRLBCL who initially presented with right submandibular, anterior cervical and supraclavicular lymphadenopathy. Cytogenetic analysis of the lymph node revealed a near-triploid karyotype with complex chromosomal aberrations. Although morphologically the bone marrow was normal, the same cytogenetically abnormal clone was detected. The patient responded to chemotherapy with CHOP (doxorubicin, cyclophosphamide, vincristine and prednisone) therapy, with disappearance of the abnormal clone from the bone marrow. The patient remains in remission 26 months after the initial diagnosis.     

Antifungal activities of propolis collected by different races of honeybees against yeasts isolated from patients with superficial mycoses

Yeasts isolated from patients with superficial mycoses were tested against propolis samples collected from different regions and honeybee races. The minimum inhibitory concentration (MIC) values obtained using the agar dilution methods were compared to the diameters of growth inhibition zones by using the disk diffusion method. The results showed that Candida albicans, C. glabrata, Trichosporon spp., and Rhodotorula sp. were susceptible to low concentrations of propolis, the latter showing a higher susceptibility. Relative to the other propolis tested, the propolis sample collected by Apis mellifera caucasica possessed the highest antifungal activity against all of the superficial mycoses. In contrast, the propolis samples collected by A.m. carnica and A.m. anatolica were the least active samples. Also, the propolis sample from the Adana region is more active than samples from other regions. An increase of MIC values was accompanied by a decrease of growth inhibition zone diameters.     

Large cavernous hemangioma of the frontal bone

A 53-year-old woman presented with a rare case of cavernous hemangioma of the frontal bone manifesting as right frontal stabbing headache and local swelling. Computed tomography revealed an extensive, well-defined, radiolucent, osteolytic lesion in the right frontal bone. The inner and outer tables of the skull were eroded and the lesion had compressed the brain parenchyma. Right frontal craniotomy was performed, and the lesion with a 1 cm-wide margin of surrounding uninvolved bone was removed. The defect was reconstructed with titanium mesh. The patient did well after the operation. The cosmetic results were satisfactory and follow up at 6 months post-surgery revealed no recurrence.     

Outcome of Surgery for Lung Cancer in Young and Elderly Patients

Purpose It has been suggested that lung cancer follows a more aggressive course and has a poorer prognosis in young patients than in elderly patients. We conducted this study to determine whether the basal characteristics and survival of young patients undergoing surgical resection of lung cancer differ from those of elderly patients.Methods Eighty patients who underwent surgery for lung cancer at our hospital between 1989 and 2004 were divided into two groups according to age. Group 1 comprised 50 patients aged 45 years or younger and group 2 comprised 30 patients aged 70 years or older. The patients’ medical records were reviewed with respect to age, gender, histological diagnosis, coexisting diseases, smoking history, postoperative staging, type of operation, and postoperative morbidity, mortality, and survival results.Results The average ages were 40.2 ± 3.77 years (range, 29–45 years) in group 1 and 72.2 ± 2.53 years (range, 70–80 years) in group 2. The incidence of postoperative complications was significantly higher in group 2 (P = 0.02). However, the 5-year survival rates for patients who underwent surgery for non-small cell lung cancer did not differ between groups 1 and 2, at 33.3% versus 21.3%, respectively (P = 0.09).Conclusions The incidence of adenocarcinoma was higher in the young patients, whose prognosis was slightly better than that of the elderly patients. Coexisting diseases and postoperative complications were the major factors that adversely affected the prognosis of the elderly patients.     

Delayed gastric emptying in gastroesophageal reflux disease: the role of malrotation

The association between gastroesophageal reflux (GER) and intestinal malrotation (IM) has been well described. Delayed or impaired gastric emptying in IM is thought to be a contributing factor in the development of gastroesophageal reflux disease (GERD). The current study assessed the role of malrotation in delayed gastric emptying in children with GERD. We also evaluated the interactions between GERD, malrotation, gastric pH abnormalities, and gastric dysmotility. Sixty-seven patients between 1 and 5 years of age (mean 3.08±1.2) and with symptoms of GER, such as emesis, reactive or recurrent lung disease, and/or growth retardation, were studied in 2001–2005. Upper and lower gastrointestinal contrast studies were performed for the diagnosis of malrotation. Gastric motility was evaluated with a liquid gastric emptying protocol. GER was documented by upper gastrointestinal studies, scintigraphy, and/or 24-h pH monitoring. In our series of 44 children with GERD, there was an unexpectedly high incidence of IM: 54.5% (24/44). IM has previously been known to occur in 25% of patients with GERD. GERD was found in 24 (82.7%) of 29 patients with IM. Mean nuclear gastric emptying (MNGE) was 51.6±8.04 min in patients with isolated GERD and 96.6±20.5 min in children with IM and GERD. There was a statistically significant difference in MNGE time (p<0.05) between children with primary GERD and in those with GERD and IM. Esophageal pH monitoring showed that mean fraction time below pH 4 was 7.06±1.1% in patients with isolated GERD and 14.7±4.1% in patients with IM and GERD. GERD is common in children between 1 and 5 years old. Using gastric emptying studies and esophageal pH monitoring, we have shown that gastric dysmotility and esophageal pH abnormalities are highly prevalent, especially in children with malrotation compared with children with isolated GERD. These findings suggest that malrotation is an important factor responsible for delayed gastric emptying in GERD. Hence, we recommend that all infants and children with GERD and delayed gastric emptying undergo careful evaluation for malrotation.